HCV

Until recently, chronic hepatitis C virus (HCV) treatment had poor efficacy and was provided only by specialists such as hepatologists and gastroenterologists. However, the introduction of safe, effective direct-acting antivirals (DAAs) has revolutionized HCV treatment.

One pivotal transformation has been the expansion of treatment to nonspecialist physicians. Nevertheless, various factors must be considered when initiating treatment for HCV.

Dr Elizabeth Verna, director of hepatology research at Columbia University in New York City, examines the essential treatment considerations for chronic HCV in treatment-naive patients.

First, she outlines recommended first-line therapies and the simplified HCV treatment algorithm recently issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. She then discusses patient-specific factors, such as cirrhosis, co-infections, age, and pregnancy, that can create treatment challenges and change the algorithm.

In closing, she talks about changes in HCV screening recommendations and how diagnosis and treatment of this infectious disease largely rest in the hands of general practitioners who are the first line of defense in controlling HCV spread.

--

Associate Professor of Medicine, Director of Hepatology Research, Associate Physician, Department of Medicine, Columbia University, New York, NY

Elizabeth Verna, MD, has disclosed the following relevant financial relationships:

Received research grant from: Salix

Until recently, chronic hepatitis C virus (HCV) treatment had poor efficacy and was provided only by specialists such as hepatologists and gastroenterologists. However, the introduction of safe, effective direct-acting antivirals (DAAs) has revolutionized HCV treatment.

One pivotal transformation has been the expansion of treatment to nonspecialist physicians. Nevertheless, various factors must be considered when initiating treatment for HCV.

Dr Elizabeth Verna, director of hepatology research at Columbia University in New York City, examines the essential treatment considerations for chronic HCV in treatment-naive patients.

First, she outlines recommended first-line therapies and the simplified HCV treatment algorithm recently issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. She then discusses patient-specific factors, such as cirrhosis, co-infections, age, and pregnancy, that can create treatment challenges and change the algorithm.

In closing, she talks about changes in HCV screening recommendations and how diagnosis and treatment of this infectious disease largely rest in the hands of general practitioners who are the first line of defense in controlling HCV spread.

--

Associate Professor of Medicine, Director of Hepatology Research, Associate Physician, Department of Medicine, Columbia University, New York, NY

Elizabeth Verna, MD, has disclosed the following relevant financial relationships:

Received research grant from: Salix

Until recently, chronic hepatitis C virus (HCV) treatment had poor efficacy and was provided only by specialists such as hepatologists and gastroenterologists. However, the introduction of safe, effective direct-acting antivirals (DAAs) has revolutionized HCV treatment.

One pivotal transformation has been the expansion of treatment to nonspecialist physicians. Nevertheless, various factors must be considered when initiating treatment for HCV.

Dr Elizabeth Verna, director of hepatology research at Columbia University in New York City, examines the essential treatment considerations for chronic HCV in treatment-naive patients.

First, she outlines recommended first-line therapies and the simplified HCV treatment algorithm recently issued by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. She then discusses patient-specific factors, such as cirrhosis, co-infections, age, and pregnancy, that can create treatment challenges and change the algorithm.

In closing, she talks about changes in HCV screening recommendations and how diagnosis and treatment of this infectious disease largely rest in the hands of general practitioners who are the first line of defense in controlling HCV spread.

--

Associate Professor of Medicine, Director of Hepatology Research, Associate Physician, Department of Medicine, Columbia University, New York, NY

Elizabeth Verna, MD, has disclosed the following relevant financial relationships:

Received research grant from: Salix

Dr. Ponni V. Perumalswami is an Associate Professor of Internal Medicine in the Division of Gastroenterology and Hepatology at the University of Michigan; Ann Arbor VA Healthcare System. Dr. Perumalswami's areas of clinical interest include cirrhosis, acute/chronic liver diseases and liver transplantation. Her research program focuses on community outreach for hepatitis B and C screening and linking patients to care. 

Q: For patients with liver disease who live in underserved and vulnerable communities, what barriers to that care are more prominent or at the primary systemic-level?

Dr. Perumalswami: I think a major barrier has been our approach to thinking about these barriers, so I'm glad you are asking this question in terms of what the systemic-level barriers are rather than, for example, patient-level barriers. I'll use viral hepatitis as an example in terms of liver-disease care. I think for a very long time we've placed an unfair, onus on patients, leaving them to find their own care and to navigate existing system-level barriers such as language proficiency, health literacy, lack of insurance, and long distances to access specialists by themselves. This “do-it-yourself” approach has created a systemic-level barrier to finding specialists, and it remains a major problem. We would do a better job of improving access to care by re-thinking all barriers to care as system-and provider-level barriers rather than patient-level barriers because it is often the case that solutions that address systems barriers can address these issues.

Many specialists, like myself, are often geographically clustered at tertiary care and urban academic centers but the reality is that patients who are at risk for living with liver disease live all over, including rural areas, where fewer specialists practice. But advancements in treatments of certain liver diseases, such as hepatitis C virus (HCV), have made it possible for frontline community providers to treat patients. Expanding these patients' treatment options, in large part, is dependent on payer policy changes to allow treatment by non-specialists, reducing the cost of treatment and giving frontline workers the support they need so that they are more confident to offer treatment while differentiating the occasional patient who may need referral to a specialist.

Cost is also a systemic-level barrier for our underserved patients with liver disease and comes in many forms. Barriers related to cost include lack or type of insurance, traveling distances which also entails a cost for time (i.e. loss of wages, caregiver support), and cost of treatments. There are certain restrictions on HCV treatments that designate who can administer them and at what point in disease progression the therapy be introduced. These restrictions have been arbitrarily set by payers for treatments like direct-acting antivirals (DAA) and unfortunately dictate "when they can be obtained" and "who can prescribe them." Instead, we should spend time and effort to determine how we can have more providers practicing in different spaces, who might be equipped and motivated to provide treatment, and do it safely and easily.

Another barrier I will mention is the lack of integrated care for patients with certain liver diseases within healthcare systems. Notable examples include integrated care for those with alcohol-associated liver disease and viral hepatitis, who often have co-occurring mental health issues and substance use, addiction, or opioid use disorders. We need to think through how we can get integrated treatment and care to these patients, instead of making them come to us as individual specialists. By integrating medical care into behavioral health practices or other treatment settings, and perhaps by considering nontraditional treatment modalities, we can overcome barriers to care that are all too often siloed.

The last thing that I will mention with regards to patient-level barriers is that liver diseases and their care by providers has been very stigmatized, particularly for patients with underlying mental health and/or addiction disorders. These patients do not always feel comfortable coming to see clinicians in their practices so we must recognize that our offices may be stigmatized places for some patients with liver disease. Because of this, it is vital to think about how we can integrate care into trusted spaces for patient populations who might be at risk or are living with liver disease.

Q: What aspects of these barriers have you focused on to improve screening and links to care in communities at risk?

Dr. Perumalswami: A lot of my work is focused on patients in populations who are at risk for viral hepatitis and on screening them, educating them, and linking them to care in their communities. The challenge in successfully treating patients with a liver disease is that most liver diseases remain silent until they've progressed to a very advanced stage. Certain populations are at a higher risk for contracting these diseases compared to others. For example, with hepatitis B virus, we know that foreign-born populations have a higher infection rate, and how and when they seek care might be very different in terms of being symptom-driven versus preventive care as a result of cultural factors around health seeking behaviors. Our team has attempted to take a more proactive approach; first, to understand who might be at risk, and second, to try to bring screening to trusted places where patients can easily access care. We have found this proactive approach to be very successful in terms of identifying people who are not yet diagnosed with liver disease and then linking them into care.

The first step is knowing which populations you want to target with respect to individual types of liver disease, then working with community partners to bring screening out into the community. Obviously, the challenging part is getting people linked into care. As stated previously, many liver diseases in their earlier stages stay silent and manifest without symptoms, thus why it is vital to offer at-risk patients testing or screening. 

The next step is to raise patient awareness and provide education as to why it is important to seek care; to get a thorough evaluation in terms of the extent of the liver disease and how to best manage and treat it, long term. For example, we have found that care coordination works very well with patients living with HCV. For patients with hepatitis B, we have found that culturally informed patient navigation services are very helpful, so we work with peers in the community who speak the same language and who come from the same communities as the patients identified as at-risk. This combined strategy of testing and then linking to care has been very successful.

I will say an important part of the care-coordination piece is addressing the competing priorities that patients have in their lives. For example, if they need housing, we refer them to housing services; if they have food insecurities, we try to address the need. Once you address their basic determinants of health, you have established a basis for trust while helping patients contend with important competing priorities. This way, your team has enabled potential patients to prioritize and engage in health care.

Q: How have you integrated HCV treatment into harm reduction and opioid use disorder settings?

Dr. Perumalswami: I am fortunate to be involved with a program here in Michigan whose goal is to increase HCV treatment through an open access, HCV consultation program through the Michigan Opioid Collaborative. The premise is to find motivated, interested providers who want to learn how to offer HCV treatment to patients in their communities; the majority of these providers are in rural parts of Michigan. In this setting, we are working with frontline medical personnel in the community, many of whom are either addiction providers or are offering opioid use disorder treatment, and who are also seeing HCV patients. We have set up an open-case consulting program where providers can submit cases for review with guidance from hepatologists. Attendance is optional and we meet for an hour, every other week and we talk through cases in more detail as a group. The result is that the providers have reported that they feel less isolated doing this as a team, having a place to discuss cases and work through practical challenges that can arise with this patient base. While HCV treatment advances have made great strides, many providers want reassurance or guidance in terms how to implement these programs so as a group, we walk through a few cases, demonstrate how to check for drug-drug interactions and how to perform fibrosis assessments. After these providers go through this training, they become more comfortable giving treatment on their own.

The second project, which I have also been fortunate to be involved in, is led by my colleague Dr. Jeffrey Weiss at Mount Sinai Hospital and is located at a syringe exchange program in a Brooklyn, New York. Here, patients attend receive in-person and/or telemedicine-based HCV treatment, which is a new model of care for us. While it has produced a different set of challenges in terms of engaging and bringing treatment to patients in a new space, it has been a great way to meet our objectives of helping patients to be treated where they are comfortable accessing care and services.

Q: Has the pandemic created any new challenges in treating at risk or special populations?

Dr. Perumalswami: The pandemic presented many new challenges. The primary impact that COVID-19 has had on our patients has been with the disruption in care; particularly for those patients who already found it challenging to seek and receive care. For patients who benefitted from following a routine, other pandemic-related challenges were the restrictions placed on our practices, and the reduced hours patients had to contend with access services and treatments at places such as syringe exchange programs or methadone programs.

Many of our patients have expressed feeling isolated as they are not able to get the same type of support that they were previously receiving. The decreases in viral hepatitis outreach, in screening in the community, and in practices resulted in a decrease in diagnosis and treatment.

We have also heard numerous discussions with regards to better reimbursements for phone call and telehealth sessions, but we must recognize that those things are not accessible to all patients. Many of our most vulnerable populations, do not have working phones, stable housing, or smart devices to access telehealth, so while there have been technological advances that can provide access to care and better reimbursement procedures, there are still many limitations that our patients are facing.

(AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project).

Dr. Ponni V. Perumalswami is an Associate Professor of Internal Medicine in the Division of Gastroenterology and Hepatology at the University of Michigan; Ann Arbor VA Healthcare System. Dr. Perumalswami's areas of clinical interest include cirrhosis, acute/chronic liver diseases and liver transplantation. Her research program focuses on community outreach for hepatitis B and C screening and linking patients to care. 

Q: For patients with liver disease who live in underserved and vulnerable communities, what barriers to that care are more prominent or at the primary systemic-level?

Dr. Perumalswami: I think a major barrier has been our approach to thinking about these barriers, so I'm glad you are asking this question in terms of what the systemic-level barriers are rather than, for example, patient-level barriers. I'll use viral hepatitis as an example in terms of liver-disease care. I think for a very long time we've placed an unfair, onus on patients, leaving them to find their own care and to navigate existing system-level barriers such as language proficiency, health literacy, lack of insurance, and long distances to access specialists by themselves. This “do-it-yourself” approach has created a systemic-level barrier to finding specialists, and it remains a major problem. We would do a better job of improving access to care by re-thinking all barriers to care as system-and provider-level barriers rather than patient-level barriers because it is often the case that solutions that address systems barriers can address these issues.

Many specialists, like myself, are often geographically clustered at tertiary care and urban academic centers but the reality is that patients who are at risk for living with liver disease live all over, including rural areas, where fewer specialists practice. But advancements in treatments of certain liver diseases, such as hepatitis C virus (HCV), have made it possible for frontline community providers to treat patients. Expanding these patients' treatment options, in large part, is dependent on payer policy changes to allow treatment by non-specialists, reducing the cost of treatment and giving frontline workers the support they need so that they are more confident to offer treatment while differentiating the occasional patient who may need referral to a specialist.

Cost is also a systemic-level barrier for our underserved patients with liver disease and comes in many forms. Barriers related to cost include lack or type of insurance, traveling distances which also entails a cost for time (i.e. loss of wages, caregiver support), and cost of treatments. There are certain restrictions on HCV treatments that designate who can administer them and at what point in disease progression the therapy be introduced. These restrictions have been arbitrarily set by payers for treatments like direct-acting antivirals (DAA) and unfortunately dictate "when they can be obtained" and "who can prescribe them." Instead, we should spend time and effort to determine how we can have more providers practicing in different spaces, who might be equipped and motivated to provide treatment, and do it safely and easily.

Another barrier I will mention is the lack of integrated care for patients with certain liver diseases within healthcare systems. Notable examples include integrated care for those with alcohol-associated liver disease and viral hepatitis, who often have co-occurring mental health issues and substance use, addiction, or opioid use disorders. We need to think through how we can get integrated treatment and care to these patients, instead of making them come to us as individual specialists. By integrating medical care into behavioral health practices or other treatment settings, and perhaps by considering nontraditional treatment modalities, we can overcome barriers to care that are all too often siloed.

The last thing that I will mention with regards to patient-level barriers is that liver diseases and their care by providers has been very stigmatized, particularly for patients with underlying mental health and/or addiction disorders. These patients do not always feel comfortable coming to see clinicians in their practices so we must recognize that our offices may be stigmatized places for some patients with liver disease. Because of this, it is vital to think about how we can integrate care into trusted spaces for patient populations who might be at risk or are living with liver disease.

Q: What aspects of these barriers have you focused on to improve screening and links to care in communities at risk?

Dr. Perumalswami: A lot of my work is focused on patients in populations who are at risk for viral hepatitis and on screening them, educating them, and linking them to care in their communities. The challenge in successfully treating patients with a liver disease is that most liver diseases remain silent until they've progressed to a very advanced stage. Certain populations are at a higher risk for contracting these diseases compared to others. For example, with hepatitis B virus, we know that foreign-born populations have a higher infection rate, and how and when they seek care might be very different in terms of being symptom-driven versus preventive care as a result of cultural factors around health seeking behaviors. Our team has attempted to take a more proactive approach; first, to understand who might be at risk, and second, to try to bring screening to trusted places where patients can easily access care. We have found this proactive approach to be very successful in terms of identifying people who are not yet diagnosed with liver disease and then linking them into care.

The first step is knowing which populations you want to target with respect to individual types of liver disease, then working with community partners to bring screening out into the community. Obviously, the challenging part is getting people linked into care. As stated previously, many liver diseases in their earlier stages stay silent and manifest without symptoms, thus why it is vital to offer at-risk patients testing or screening. 

The next step is to raise patient awareness and provide education as to why it is important to seek care; to get a thorough evaluation in terms of the extent of the liver disease and how to best manage and treat it, long term. For example, we have found that care coordination works very well with patients living with HCV. For patients with hepatitis B, we have found that culturally informed patient navigation services are very helpful, so we work with peers in the community who speak the same language and who come from the same communities as the patients identified as at-risk. This combined strategy of testing and then linking to care has been very successful.

I will say an important part of the care-coordination piece is addressing the competing priorities that patients have in their lives. For example, if they need housing, we refer them to housing services; if they have food insecurities, we try to address the need. Once you address their basic determinants of health, you have established a basis for trust while helping patients contend with important competing priorities. This way, your team has enabled potential patients to prioritize and engage in health care.

Q: How have you integrated HCV treatment into harm reduction and opioid use disorder settings?

Dr. Perumalswami: I am fortunate to be involved with a program here in Michigan whose goal is to increase HCV treatment through an open access, HCV consultation program through the Michigan Opioid Collaborative. The premise is to find motivated, interested providers who want to learn how to offer HCV treatment to patients in their communities; the majority of these providers are in rural parts of Michigan. In this setting, we are working with frontline medical personnel in the community, many of whom are either addiction providers or are offering opioid use disorder treatment, and who are also seeing HCV patients. We have set up an open-case consulting program where providers can submit cases for review with guidance from hepatologists. Attendance is optional and we meet for an hour, every other week and we talk through cases in more detail as a group. The result is that the providers have reported that they feel less isolated doing this as a team, having a place to discuss cases and work through practical challenges that can arise with this patient base. While HCV treatment advances have made great strides, many providers want reassurance or guidance in terms how to implement these programs so as a group, we walk through a few cases, demonstrate how to check for drug-drug interactions and how to perform fibrosis assessments. After these providers go through this training, they become more comfortable giving treatment on their own.

The second project, which I have also been fortunate to be involved in, is led by my colleague Dr. Jeffrey Weiss at Mount Sinai Hospital and is located at a syringe exchange program in a Brooklyn, New York. Here, patients attend receive in-person and/or telemedicine-based HCV treatment, which is a new model of care for us. While it has produced a different set of challenges in terms of engaging and bringing treatment to patients in a new space, it has been a great way to meet our objectives of helping patients to be treated where they are comfortable accessing care and services.

Q: Has the pandemic created any new challenges in treating at risk or special populations?

Dr. Perumalswami: The pandemic presented many new challenges. The primary impact that COVID-19 has had on our patients has been with the disruption in care; particularly for those patients who already found it challenging to seek and receive care. For patients who benefitted from following a routine, other pandemic-related challenges were the restrictions placed on our practices, and the reduced hours patients had to contend with access services and treatments at places such as syringe exchange programs or methadone programs.

Many of our patients have expressed feeling isolated as they are not able to get the same type of support that they were previously receiving. The decreases in viral hepatitis outreach, in screening in the community, and in practices resulted in a decrease in diagnosis and treatment.

We have also heard numerous discussions with regards to better reimbursements for phone call and telehealth sessions, but we must recognize that those things are not accessible to all patients. Many of our most vulnerable populations, do not have working phones, stable housing, or smart devices to access telehealth, so while there have been technological advances that can provide access to care and better reimbursement procedures, there are still many limitations that our patients are facing.

(AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project).

Dr. Ponni V. Perumalswami is an Associate Professor of Internal Medicine in the Division of Gastroenterology and Hepatology at the University of Michigan; Ann Arbor VA Healthcare System. Dr. Perumalswami's areas of clinical interest include cirrhosis, acute/chronic liver diseases and liver transplantation. Her research program focuses on community outreach for hepatitis B and C screening and linking patients to care. 

Q: For patients with liver disease who live in underserved and vulnerable communities, what barriers to that care are more prominent or at the primary systemic-level?

Dr. Perumalswami: I think a major barrier has been our approach to thinking about these barriers, so I'm glad you are asking this question in terms of what the systemic-level barriers are rather than, for example, patient-level barriers. I'll use viral hepatitis as an example in terms of liver-disease care. I think for a very long time we've placed an unfair, onus on patients, leaving them to find their own care and to navigate existing system-level barriers such as language proficiency, health literacy, lack of insurance, and long distances to access specialists by themselves. This “do-it-yourself” approach has created a systemic-level barrier to finding specialists, and it remains a major problem. We would do a better job of improving access to care by re-thinking all barriers to care as system-and provider-level barriers rather than patient-level barriers because it is often the case that solutions that address systems barriers can address these issues.

Many specialists, like myself, are often geographically clustered at tertiary care and urban academic centers but the reality is that patients who are at risk for living with liver disease live all over, including rural areas, where fewer specialists practice. But advancements in treatments of certain liver diseases, such as hepatitis C virus (HCV), have made it possible for frontline community providers to treat patients. Expanding these patients' treatment options, in large part, is dependent on payer policy changes to allow treatment by non-specialists, reducing the cost of treatment and giving frontline workers the support they need so that they are more confident to offer treatment while differentiating the occasional patient who may need referral to a specialist.

Cost is also a systemic-level barrier for our underserved patients with liver disease and comes in many forms. Barriers related to cost include lack or type of insurance, traveling distances which also entails a cost for time (i.e. loss of wages, caregiver support), and cost of treatments. There are certain restrictions on HCV treatments that designate who can administer them and at what point in disease progression the therapy be introduced. These restrictions have been arbitrarily set by payers for treatments like direct-acting antivirals (DAA) and unfortunately dictate "when they can be obtained" and "who can prescribe them." Instead, we should spend time and effort to determine how we can have more providers practicing in different spaces, who might be equipped and motivated to provide treatment, and do it safely and easily.

Another barrier I will mention is the lack of integrated care for patients with certain liver diseases within healthcare systems. Notable examples include integrated care for those with alcohol-associated liver disease and viral hepatitis, who often have co-occurring mental health issues and substance use, addiction, or opioid use disorders. We need to think through how we can get integrated treatment and care to these patients, instead of making them come to us as individual specialists. By integrating medical care into behavioral health practices or other treatment settings, and perhaps by considering nontraditional treatment modalities, we can overcome barriers to care that are all too often siloed.

The last thing that I will mention with regards to patient-level barriers is that liver diseases and their care by providers has been very stigmatized, particularly for patients with underlying mental health and/or addiction disorders. These patients do not always feel comfortable coming to see clinicians in their practices so we must recognize that our offices may be stigmatized places for some patients with liver disease. Because of this, it is vital to think about how we can integrate care into trusted spaces for patient populations who might be at risk or are living with liver disease.

Q: What aspects of these barriers have you focused on to improve screening and links to care in communities at risk?

Dr. Perumalswami: A lot of my work is focused on patients in populations who are at risk for viral hepatitis and on screening them, educating them, and linking them to care in their communities. The challenge in successfully treating patients with a liver disease is that most liver diseases remain silent until they've progressed to a very advanced stage. Certain populations are at a higher risk for contracting these diseases compared to others. For example, with hepatitis B virus, we know that foreign-born populations have a higher infection rate, and how and when they seek care might be very different in terms of being symptom-driven versus preventive care as a result of cultural factors around health seeking behaviors. Our team has attempted to take a more proactive approach; first, to understand who might be at risk, and second, to try to bring screening to trusted places where patients can easily access care. We have found this proactive approach to be very successful in terms of identifying people who are not yet diagnosed with liver disease and then linking them into care.

The first step is knowing which populations you want to target with respect to individual types of liver disease, then working with community partners to bring screening out into the community. Obviously, the challenging part is getting people linked into care. As stated previously, many liver diseases in their earlier stages stay silent and manifest without symptoms, thus why it is vital to offer at-risk patients testing or screening. 

The next step is to raise patient awareness and provide education as to why it is important to seek care; to get a thorough evaluation in terms of the extent of the liver disease and how to best manage and treat it, long term. For example, we have found that care coordination works very well with patients living with HCV. For patients with hepatitis B, we have found that culturally informed patient navigation services are very helpful, so we work with peers in the community who speak the same language and who come from the same communities as the patients identified as at-risk. This combined strategy of testing and then linking to care has been very successful.

I will say an important part of the care-coordination piece is addressing the competing priorities that patients have in their lives. For example, if they need housing, we refer them to housing services; if they have food insecurities, we try to address the need. Once you address their basic determinants of health, you have established a basis for trust while helping patients contend with important competing priorities. This way, your team has enabled potential patients to prioritize and engage in health care.

Q: How have you integrated HCV treatment into harm reduction and opioid use disorder settings?

Dr. Perumalswami: I am fortunate to be involved with a program here in Michigan whose goal is to increase HCV treatment through an open access, HCV consultation program through the Michigan Opioid Collaborative. The premise is to find motivated, interested providers who want to learn how to offer HCV treatment to patients in their communities; the majority of these providers are in rural parts of Michigan. In this setting, we are working with frontline medical personnel in the community, many of whom are either addiction providers or are offering opioid use disorder treatment, and who are also seeing HCV patients. We have set up an open-case consulting program where providers can submit cases for review with guidance from hepatologists. Attendance is optional and we meet for an hour, every other week and we talk through cases in more detail as a group. The result is that the providers have reported that they feel less isolated doing this as a team, having a place to discuss cases and work through practical challenges that can arise with this patient base. While HCV treatment advances have made great strides, many providers want reassurance or guidance in terms how to implement these programs so as a group, we walk through a few cases, demonstrate how to check for drug-drug interactions and how to perform fibrosis assessments. After these providers go through this training, they become more comfortable giving treatment on their own.

The second project, which I have also been fortunate to be involved in, is led by my colleague Dr. Jeffrey Weiss at Mount Sinai Hospital and is located at a syringe exchange program in a Brooklyn, New York. Here, patients attend receive in-person and/or telemedicine-based HCV treatment, which is a new model of care for us. While it has produced a different set of challenges in terms of engaging and bringing treatment to patients in a new space, it has been a great way to meet our objectives of helping patients to be treated where they are comfortable accessing care and services.

Q: Has the pandemic created any new challenges in treating at risk or special populations?

Dr. Perumalswami: The pandemic presented many new challenges. The primary impact that COVID-19 has had on our patients has been with the disruption in care; particularly for those patients who already found it challenging to seek and receive care. For patients who benefitted from following a routine, other pandemic-related challenges were the restrictions placed on our practices, and the reduced hours patients had to contend with access services and treatments at places such as syringe exchange programs or methadone programs.

Many of our patients have expressed feeling isolated as they are not able to get the same type of support that they were previously receiving. The decreases in viral hepatitis outreach, in screening in the community, and in practices resulted in a decrease in diagnosis and treatment.

We have also heard numerous discussions with regards to better reimbursements for phone call and telehealth sessions, but we must recognize that those things are not accessible to all patients. Many of our most vulnerable populations, do not have working phones, stable housing, or smart devices to access telehealth, so while there have been technological advances that can provide access to care and better reimbursement procedures, there are still many limitations that our patients are facing.

(AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project).

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

Joseph K. Lim, MD, is the Director of Clinical Hepatology and Professor of Medicine in the Department of Medicine, Section of Digestive Diseases, Yale Liver Center, at the Yale University School of Medicine in New Haven, Connecticut. Dr. Lim's primary clinical and research interests are focused on viral hepatitis and non-alcoholic steatohepatitis.

What are some of the reasons for first line direct-acting antiviral (DAA) regimen failures in hepatitis C virus (HCV)?

Dr. Lim: In clinical practice, approximately 5% to 10% of patients will fail to achieve sustained virologic response (SVR). The most common reason is incompletion of treatment as a result of non-adherence, intolerance, adverse effects, or other medical/logistical factors that interfere with treatment. Another reason is reinfection, in which an individual who achieves viral eradication is re-exposed to HCV and develops a new infection. Each scenario warrants a careful evaluation to help identify which factors contributed to treatment failure.

Regarding incomplete treatment, it is important to identify other issues that require attention before considering retreatment. If there are other potential medications with potential drug-drug interaction (DDI) which influence the absorption of the DAA medications, that is important to identify (e.g. proton pump inhibitors).
 

Finally, if there are other non-medical reasons—psychosocial reasons, substance use reasons, or psychiatric reasons—that may prevent a patient from completing a full treatment course, it is important to identify and manage these before reconsidering DAA therapy.

What is the current standard of care for patients who failed a first line DAA regimen?

Dr. Lim: Fewer than 5% to 10% of patients treated with a first-line regimen fail to achieve a sustained virologic response (SVR). A significant proportion may develop resistance-associated substitutions (RASs) which may affect susceptibility to other DAA regimens, but fortunately, multiple studies have confirmed that retreatment of these patients with a contemporary DAA treatment regimen is associated with similarly high rates of SVR exceeding 90%.
 

The current guidelines by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) suggest retreating these patients with a triple combination regimen of sofosbuvir, velpatasvir, plus voxilaprevir (also known as SOF/VEL/VOX) or glecaprevir plus pibrentasvir (GP).

Both are viable options for those who fail first line regimens, but with important nuances: 1) for patients who are genotype 1, either of these options is considered a valid regimen strategy; 2) for patients with genotype 2 through 6, the SOF/VEL/VOX combination is recommended; 3) for patients who have signature mutations for either the protease or the nonstructural protein 5A (NS5A), an individualized approach is needed to determine which strategy will be most efficacious; 4) for patients who have cirrhosis, and particularly those with decompensated cirrhosis, protease inhibitor-based combinations are contraindicated because of the risk of liver toxicity and/or hepatic decompensation, which is associated with an FDA black box warning.

Treatment of the very small number of patients who fail the second-line regimen with either GP or SOF/VEL/VOXis an area of significant controversy, and for which the evidence-based guidance in 2021 is quite limited. However, the AASLD and the IDSA recommend 2 potential regimens, including SOF/VEL/VOX plus weight-based ribavirin for 24 weeks, or sofosbuvir plus GP plus weight-based ribavirin for 16 weeks.

Why can it be difficult to differentiate true virological failure from relapse caused by non-adherence or from reinfection?

Dr. Lim: When I speak with patients who have failed DAAs, the majority state that they took every single pill. And although that leaves us in a conundrum where we cannot chalk it up to possible non-adherence, we do wish to determine whether the timing of when they took the medications was consistent.

We ask about whether there are other medications that may interact with these medications. Before we start treatment, we work with a pharmacist and online drug interaction websites to make sure that we do our best to avoid other medications that may interact with DAAs and impact the chance of achieving sustained virologic response (SVR). Despite those efforts, on occasion, patients report that they forgot they were taking a drug or supplement that could interfere with DAA absorption.

Lastly, in patients who offered no history of taking other medications and a report of 100% adherence, we make a presumption that this is probably true virological failure with development of virologic resistance. In 2021, AASLD/IDSA guidelines do not routinely recommend resistance testing for all patients who fail a first-line regimen because it frequently does not influence our decision on retreatment and may not always impact susceptibility to SOF/VEL/VOX or GP. However, in patients who have a history of multiple lines of treatment failure, some of whom have failed 4 or more previous treatment regimens, I do perform resistance testing on an individualized basis to inform our retreatment strategy.

With regards to the question about reinfection, there is no routine way this is assessed in clinical practice. From a public health perspective, we can perform phylogenetic testing, which can help distinguish the very specific viral strains to connect individuals in terms of the root of the infection. But in clinical practice, we do not use phylogenetic testing because if a patient’s initial genotype was genotype 1 and then they get reinfected, and their genotype was genotype 3, you do not need any special testing. At that point you know it is a different virus than what you initially had, and so that is the easiest way to make a distinction. If they have a different genotype of HCV the second time around, we generally will conclude that it represents reinfection rather than virologic relapse, although conversely, the discovery of the same genotype does not exclude reinfection.

Ninety-five percent of individuals treated with DAA agents are cured of HCV infection. Of the 5% who failed first line DAA regimens, what are their options and chances for being cured?

Dr. Lim: Again, retreatment with either SOF/VEL/VOX or GP is associated with a very high rate of SVR. Specifically, for SOF/VEL/VOX, there are two phase 3 clinical trials. One is POLARIS-1 for genotypes 1 through 6 and the other is POLARIS-4 for those with genotype 1 through 4. In both of those clinical trials, they reported a 96% to 97% chance of achieving SVR.^{1, 2}  For GP, the MAGELLAN-1 protocol looked at patients, specifically genotype 1, and found that GP was associated with a 96% chance of SVR.³ As such, there is robust prospective RCT evidence validating the safety and efficacy of both SOF/VEL/VOX and GP for patients who fail first line DAA regimens.

How do people with HIV and persons who use drugs factor into DAA failures, and how does it affect them? How can their unique needs be met, and what special considerations can be made for them going forward?

Dr. Lim: Historically, HIV was viewed within our community as a “special population.” And the reason why was that with some older regimens, including those requiring pegylated interferon, the chance of achieving SVR was about 20% lower than those who had HCV monoinfection. But with our contemporary DAA regimens, that differential has washed away. The expected sustained virologic response rates of those with HCV alone or with coinfection of HIV is identical, around 95%. However, from a reinfection perspective, the available data suggests no difference in rates of virologic relapse or virologic failure or treatment failure or the risk of reinfection in HIV coinfected individuals. However, patients with HIV are taking antiretroviral therapy (ART) regimens that are associated with potential DDIs, which require special attention. On occasion, modification of the ART is needed to permit safe administration of HCV DAAs. In contrast, persons who inject drugs (PWID) remain a special population because of unique challenges and considerations required in the decision of who to treat, when to treat, and how to treat.

In terms of who to treat, there has been a paradigm shift. In the past, we would want to delay treatment until patients were drug-free for 6 months or greater. Many of our current insurance policies still mandate that patients be confirmed to be drug-free for a required amount of time before they will authorize the drug's release from the pharmacy. But at this time, that paradigm has shifted to where we, as a liver community, view HCV treatment as prevention. The concept is that within injection drug communities, if we can treat and eradicate HCV in super users of injection drugs, not only does it benefit that individual patient, but it may also benefit their community of injection drug users and prevent spread to others.

It is a high priority in 2021 that clinicians within the GI, liver, and infectious disease communities are willing to treat patients who are actively injecting drugs or in the process of going through relapse prevention, and/or rehabilitation. We must accept that persons who inject drugs may experience relapse to substance use which may be associated with HCV reinfection rates as high as 10% to 15% of cases. While these numbers are significant in my view, from a public health perspective and a clinical perspective, this should not dissuade clinicians from considering an individualized approach to offering DAA therapy to all patients, including those who are PWID.

Joseph K. Lim, MD, is the Director of Clinical Hepatology and Professor of Medicine in the Department of Medicine, Section of Digestive Diseases, Yale Liver Center, at the Yale University School of Medicine in New Haven, Connecticut. Dr. Lim's primary clinical and research interests are focused on viral hepatitis and non-alcoholic steatohepatitis.

What are some of the reasons for first line direct-acting antiviral (DAA) regimen failures in hepatitis C virus (HCV)?

Dr. Lim: In clinical practice, approximately 5% to 10% of patients will fail to achieve sustained virologic response (SVR). The most common reason is incompletion of treatment as a result of non-adherence, intolerance, adverse effects, or other medical/logistical factors that interfere with treatment. Another reason is reinfection, in which an individual who achieves viral eradication is re-exposed to HCV and develops a new infection. Each scenario warrants a careful evaluation to help identify which factors contributed to treatment failure.

Regarding incomplete treatment, it is important to identify other issues that require attention before considering retreatment. If there are other potential medications with potential drug-drug interaction (DDI) which influence the absorption of the DAA medications, that is important to identify (e.g. proton pump inhibitors).
 

Finally, if there are other non-medical reasons—psychosocial reasons, substance use reasons, or psychiatric reasons—that may prevent a patient from completing a full treatment course, it is important to identify and manage these before reconsidering DAA therapy.

What is the current standard of care for patients who failed a first line DAA regimen?

Dr. Lim: Fewer than 5% to 10% of patients treated with a first-line regimen fail to achieve a sustained virologic response (SVR). A significant proportion may develop resistance-associated substitutions (RASs) which may affect susceptibility to other DAA regimens, but fortunately, multiple studies have confirmed that retreatment of these patients with a contemporary DAA treatment regimen is associated with similarly high rates of SVR exceeding 90%.
 

The current guidelines by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) suggest retreating these patients with a triple combination regimen of sofosbuvir, velpatasvir, plus voxilaprevir (also known as SOF/VEL/VOX) or glecaprevir plus pibrentasvir (GP).

Both are viable options for those who fail first line regimens, but with important nuances: 1) for patients who are genotype 1, either of these options is considered a valid regimen strategy; 2) for patients with genotype 2 through 6, the SOF/VEL/VOX combination is recommended; 3) for patients who have signature mutations for either the protease or the nonstructural protein 5A (NS5A), an individualized approach is needed to determine which strategy will be most efficacious; 4) for patients who have cirrhosis, and particularly those with decompensated cirrhosis, protease inhibitor-based combinations are contraindicated because of the risk of liver toxicity and/or hepatic decompensation, which is associated with an FDA black box warning.

Treatment of the very small number of patients who fail the second-line regimen with either GP or SOF/VEL/VOXis an area of significant controversy, and for which the evidence-based guidance in 2021 is quite limited. However, the AASLD and the IDSA recommend 2 potential regimens, including SOF/VEL/VOX plus weight-based ribavirin for 24 weeks, or sofosbuvir plus GP plus weight-based ribavirin for 16 weeks.

Why can it be difficult to differentiate true virological failure from relapse caused by non-adherence or from reinfection?

Dr. Lim: When I speak with patients who have failed DAAs, the majority state that they took every single pill. And although that leaves us in a conundrum where we cannot chalk it up to possible non-adherence, we do wish to determine whether the timing of when they took the medications was consistent.

We ask about whether there are other medications that may interact with these medications. Before we start treatment, we work with a pharmacist and online drug interaction websites to make sure that we do our best to avoid other medications that may interact with DAAs and impact the chance of achieving sustained virologic response (SVR). Despite those efforts, on occasion, patients report that they forgot they were taking a drug or supplement that could interfere with DAA absorption.

Lastly, in patients who offered no history of taking other medications and a report of 100% adherence, we make a presumption that this is probably true virological failure with development of virologic resistance. In 2021, AASLD/IDSA guidelines do not routinely recommend resistance testing for all patients who fail a first-line regimen because it frequently does not influence our decision on retreatment and may not always impact susceptibility to SOF/VEL/VOX or GP. However, in patients who have a history of multiple lines of treatment failure, some of whom have failed 4 or more previous treatment regimens, I do perform resistance testing on an individualized basis to inform our retreatment strategy.

With regards to the question about reinfection, there is no routine way this is assessed in clinical practice. From a public health perspective, we can perform phylogenetic testing, which can help distinguish the very specific viral strains to connect individuals in terms of the root of the infection. But in clinical practice, we do not use phylogenetic testing because if a patient’s initial genotype was genotype 1 and then they get reinfected, and their genotype was genotype 3, you do not need any special testing. At that point you know it is a different virus than what you initially had, and so that is the easiest way to make a distinction. If they have a different genotype of HCV the second time around, we generally will conclude that it represents reinfection rather than virologic relapse, although conversely, the discovery of the same genotype does not exclude reinfection.

Ninety-five percent of individuals treated with DAA agents are cured of HCV infection. Of the 5% who failed first line DAA regimens, what are their options and chances for being cured?

Dr. Lim: Again, retreatment with either SOF/VEL/VOX or GP is associated with a very high rate of SVR. Specifically, for SOF/VEL/VOX, there are two phase 3 clinical trials. One is POLARIS-1 for genotypes 1 through 6 and the other is POLARIS-4 for those with genotype 1 through 4. In both of those clinical trials, they reported a 96% to 97% chance of achieving SVR.^{1, 2}  For GP, the MAGELLAN-1 protocol looked at patients, specifically genotype 1, and found that GP was associated with a 96% chance of SVR.³ As such, there is robust prospective RCT evidence validating the safety and efficacy of both SOF/VEL/VOX and GP for patients who fail first line DAA regimens.

How do people with HIV and persons who use drugs factor into DAA failures, and how does it affect them? How can their unique needs be met, and what special considerations can be made for them going forward?

Dr. Lim: Historically, HIV was viewed within our community as a “special population.” And the reason why was that with some older regimens, including those requiring pegylated interferon, the chance of achieving SVR was about 20% lower than those who had HCV monoinfection. But with our contemporary DAA regimens, that differential has washed away. The expected sustained virologic response rates of those with HCV alone or with coinfection of HIV is identical, around 95%. However, from a reinfection perspective, the available data suggests no difference in rates of virologic relapse or virologic failure or treatment failure or the risk of reinfection in HIV coinfected individuals. However, patients with HIV are taking antiretroviral therapy (ART) regimens that are associated with potential DDIs, which require special attention. On occasion, modification of the ART is needed to permit safe administration of HCV DAAs. In contrast, persons who inject drugs (PWID) remain a special population because of unique challenges and considerations required in the decision of who to treat, when to treat, and how to treat.

In terms of who to treat, there has been a paradigm shift. In the past, we would want to delay treatment until patients were drug-free for 6 months or greater. Many of our current insurance policies still mandate that patients be confirmed to be drug-free for a required amount of time before they will authorize the drug's release from the pharmacy. But at this time, that paradigm has shifted to where we, as a liver community, view HCV treatment as prevention. The concept is that within injection drug communities, if we can treat and eradicate HCV in super users of injection drugs, not only does it benefit that individual patient, but it may also benefit their community of injection drug users and prevent spread to others.

It is a high priority in 2021 that clinicians within the GI, liver, and infectious disease communities are willing to treat patients who are actively injecting drugs or in the process of going through relapse prevention, and/or rehabilitation. We must accept that persons who inject drugs may experience relapse to substance use which may be associated with HCV reinfection rates as high as 10% to 15% of cases. While these numbers are significant in my view, from a public health perspective and a clinical perspective, this should not dissuade clinicians from considering an individualized approach to offering DAA therapy to all patients, including those who are PWID.

Joseph K. Lim, MD, is the Director of Clinical Hepatology and Professor of Medicine in the Department of Medicine, Section of Digestive Diseases, Yale Liver Center, at the Yale University School of Medicine in New Haven, Connecticut. Dr. Lim's primary clinical and research interests are focused on viral hepatitis and non-alcoholic steatohepatitis.

What are some of the reasons for first line direct-acting antiviral (DAA) regimen failures in hepatitis C virus (HCV)?

Dr. Lim: In clinical practice, approximately 5% to 10% of patients will fail to achieve sustained virologic response (SVR). The most common reason is incompletion of treatment as a result of non-adherence, intolerance, adverse effects, or other medical/logistical factors that interfere with treatment. Another reason is reinfection, in which an individual who achieves viral eradication is re-exposed to HCV and develops a new infection. Each scenario warrants a careful evaluation to help identify which factors contributed to treatment failure.

Regarding incomplete treatment, it is important to identify other issues that require attention before considering retreatment. If there are other potential medications with potential drug-drug interaction (DDI) which influence the absorption of the DAA medications, that is important to identify (e.g. proton pump inhibitors).
 

Finally, if there are other non-medical reasons—psychosocial reasons, substance use reasons, or psychiatric reasons—that may prevent a patient from completing a full treatment course, it is important to identify and manage these before reconsidering DAA therapy.

What is the current standard of care for patients who failed a first line DAA regimen?

Dr. Lim: Fewer than 5% to 10% of patients treated with a first-line regimen fail to achieve a sustained virologic response (SVR). A significant proportion may develop resistance-associated substitutions (RASs) which may affect susceptibility to other DAA regimens, but fortunately, multiple studies have confirmed that retreatment of these patients with a contemporary DAA treatment regimen is associated with similarly high rates of SVR exceeding 90%.
 

The current guidelines by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) suggest retreating these patients with a triple combination regimen of sofosbuvir, velpatasvir, plus voxilaprevir (also known as SOF/VEL/VOX) or glecaprevir plus pibrentasvir (GP).

Both are viable options for those who fail first line regimens, but with important nuances: 1) for patients who are genotype 1, either of these options is considered a valid regimen strategy; 2) for patients with genotype 2 through 6, the SOF/VEL/VOX combination is recommended; 3) for patients who have signature mutations for either the protease or the nonstructural protein 5A (NS5A), an individualized approach is needed to determine which strategy will be most efficacious; 4) for patients who have cirrhosis, and particularly those with decompensated cirrhosis, protease inhibitor-based combinations are contraindicated because of the risk of liver toxicity and/or hepatic decompensation, which is associated with an FDA black box warning.

Treatment of the very small number of patients who fail the second-line regimen with either GP or SOF/VEL/VOXis an area of significant controversy, and for which the evidence-based guidance in 2021 is quite limited. However, the AASLD and the IDSA recommend 2 potential regimens, including SOF/VEL/VOX plus weight-based ribavirin for 24 weeks, or sofosbuvir plus GP plus weight-based ribavirin for 16 weeks.

Why can it be difficult to differentiate true virological failure from relapse caused by non-adherence or from reinfection?

Dr. Lim: When I speak with patients who have failed DAAs, the majority state that they took every single pill. And although that leaves us in a conundrum where we cannot chalk it up to possible non-adherence, we do wish to determine whether the timing of when they took the medications was consistent.

We ask about whether there are other medications that may interact with these medications. Before we start treatment, we work with a pharmacist and online drug interaction websites to make sure that we do our best to avoid other medications that may interact with DAAs and impact the chance of achieving sustained virologic response (SVR). Despite those efforts, on occasion, patients report that they forgot they were taking a drug or supplement that could interfere with DAA absorption.

Lastly, in patients who offered no history of taking other medications and a report of 100% adherence, we make a presumption that this is probably true virological failure with development of virologic resistance. In 2021, AASLD/IDSA guidelines do not routinely recommend resistance testing for all patients who fail a first-line regimen because it frequently does not influence our decision on retreatment and may not always impact susceptibility to SOF/VEL/VOX or GP. However, in patients who have a history of multiple lines of treatment failure, some of whom have failed 4 or more previous treatment regimens, I do perform resistance testing on an individualized basis to inform our retreatment strategy.

With regards to the question about reinfection, there is no routine way this is assessed in clinical practice. From a public health perspective, we can perform phylogenetic testing, which can help distinguish the very specific viral strains to connect individuals in terms of the root of the infection. But in clinical practice, we do not use phylogenetic testing because if a patient’s initial genotype was genotype 1 and then they get reinfected, and their genotype was genotype 3, you do not need any special testing. At that point you know it is a different virus than what you initially had, and so that is the easiest way to make a distinction. If they have a different genotype of HCV the second time around, we generally will conclude that it represents reinfection rather than virologic relapse, although conversely, the discovery of the same genotype does not exclude reinfection.

Ninety-five percent of individuals treated with DAA agents are cured of HCV infection. Of the 5% who failed first line DAA regimens, what are their options and chances for being cured?

Dr. Lim: Again, retreatment with either SOF/VEL/VOX or GP is associated with a very high rate of SVR. Specifically, for SOF/VEL/VOX, there are two phase 3 clinical trials. One is POLARIS-1 for genotypes 1 through 6 and the other is POLARIS-4 for those with genotype 1 through 4. In both of those clinical trials, they reported a 96% to 97% chance of achieving SVR.^{1, 2}  For GP, the MAGELLAN-1 protocol looked at patients, specifically genotype 1, and found that GP was associated with a 96% chance of SVR.³ As such, there is robust prospective RCT evidence validating the safety and efficacy of both SOF/VEL/VOX and GP for patients who fail first line DAA regimens.

How do people with HIV and persons who use drugs factor into DAA failures, and how does it affect them? How can their unique needs be met, and what special considerations can be made for them going forward?

Dr. Lim: Historically, HIV was viewed within our community as a “special population.” And the reason why was that with some older regimens, including those requiring pegylated interferon, the chance of achieving SVR was about 20% lower than those who had HCV monoinfection. But with our contemporary DAA regimens, that differential has washed away. The expected sustained virologic response rates of those with HCV alone or with coinfection of HIV is identical, around 95%. However, from a reinfection perspective, the available data suggests no difference in rates of virologic relapse or virologic failure or treatment failure or the risk of reinfection in HIV coinfected individuals. However, patients with HIV are taking antiretroviral therapy (ART) regimens that are associated with potential DDIs, which require special attention. On occasion, modification of the ART is needed to permit safe administration of HCV DAAs. In contrast, persons who inject drugs (PWID) remain a special population because of unique challenges and considerations required in the decision of who to treat, when to treat, and how to treat.

In terms of who to treat, there has been a paradigm shift. In the past, we would want to delay treatment until patients were drug-free for 6 months or greater. Many of our current insurance policies still mandate that patients be confirmed to be drug-free for a required amount of time before they will authorize the drug's release from the pharmacy. But at this time, that paradigm has shifted to where we, as a liver community, view HCV treatment as prevention. The concept is that within injection drug communities, if we can treat and eradicate HCV in super users of injection drugs, not only does it benefit that individual patient, but it may also benefit their community of injection drug users and prevent spread to others.

It is a high priority in 2021 that clinicians within the GI, liver, and infectious disease communities are willing to treat patients who are actively injecting drugs or in the process of going through relapse prevention, and/or rehabilitation. We must accept that persons who inject drugs may experience relapse to substance use which may be associated with HCV reinfection rates as high as 10% to 15% of cases. While these numbers are significant in my view, from a public health perspective and a clinical perspective, this should not dissuade clinicians from considering an individualized approach to offering DAA therapy to all patients, including those who are PWID.

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

What are the largest factors creating barriers to hepatitis C virus (HCV) elimination?
 

Dr. Lim: In 2020 there remain important barriers to access to treatment because of the high cost of drugs used to eradicate HCV. There are still opportunities for us to interact with major payors to ensure adequate access, both with private commercial payers, as well as with Medicaid. We know very well that there are existing barriers that impact a significant proportion of patients, but if you look at data from the private sector, it turns out that we are doing pretty well; At least 80% of payers are covering direct-acting antiviral (DAA) medications with minimal restriction.

However, with Medicaid it is quite the reverse story; In about two-thirds of states, there are at least one or more restrictions based on the stage of their fibrosis, sobriety requirements for alcohol and drug use, and specialty providers to prescribe the medication, among others. Based on data from the National Viral Hepatitis Roundtable, it is clear that there are still many states where if you have mild disease, or recently used drugs or alcohol, or are in a rural area where you do not have access to a gastroenterologist or infectious disease specialist, you cannot get treatment. That is still a major concern for access to care.

When we think about elimination, eradication, and extinction of human diseases, HCV represents one of the few for which we actually have the tools to cure the condition permanently with a simple regimen of 1 to 3 pills per day for 2 or 3 months, with a cure rate exceeding 95%. This is truly remarkable and provides us with a historic opportunity to eradicate HCV in the United States and worldwide.

When we can diagnose HCV and offer treatment, we have a very good success rate—but therein lies the challenge. The key rate limiting steps to achieving elimination are found in ongoing deficits in the HCV care cascade, including screening, diagnosis, linkage to care, and treatment. We believe that right now only about 50% of affected persons have been diagnosed, and therefore much work remains to be done in the screening/diagnosis step of the care cascade if we are to achieve meaningful progress towards HCV elimination.

In that spirit, there have been important advances in terms of policy and legislation to support broader population-based screening. The CDC and US Preventive Services Task Force initially recommended that all baby boomers (those born between 1945 and 1965) should be screened for HCV, in addition to those with established risk factors. These include individuals who have used drugs, either through a nose or through the vein, had a blood transfusion before 1992, tattoos or body piercings, accidental needlestick exposures, or high risk sexual contacts, However, data show that risk factor-based screening simply does not work. It is difficult for clinicians to routinely ask sensitive questions about historical risk factors.

Despite the remarkable success in development of curative therapies for HCV, the rate of new incident HCV infections has not been going down—It has actually been doubling to tripling over the last 5 years. We now have what we call a bi-modal distribution of HCV, which includes baby boomers and a second younger group, between age 18 and 34. The primary route of transmission in this younger cohort is injection drug use, which is largely tied to the opiate epidemic.

It is in this context that within the last year, 4 different organizations—the CDC, the United States Preventive Services Task Force (USPSTF), the American Association for the Study of Liver Diseases (AASLD), and the Infectious Diseases Society of America (IDSA)—have expanded their guidance documents to now recommend one-time HCV screening in all adults age 18 or older plus all pregnant women regardless of age. This guidance replaces the old guidelines focused on baby boomers and individuals with risk factors. This represents a fundamental and consequential shift in US strategy to improve population-based screening.

There is also a sense that a treatment as prevention strategy can be particularly impactful in reducing spread among high-risk populations, especially in persons who inject drugs (PWID). The concept is that if you can effectively remove HCV in high-risk populations by treating active users, this may prevent spread of HCV to others who would otherwise be exposed. Although HCV treatment in patients with active drug use has historically been viewed with skepticism, and in fact remains an exclusion factor by some payors, DAA therapy in PWID is strongly recommended by the AASLD/IDSA guidelines and is increasingly embraced in both specialty and non-specialty (eg, methadone clinics, community health centers, prison clinics) settings.

Could you please elaborate more on the updated CDC guidelines and the impact that those are having in practice?

Dr. Lim: Although the revised screening guidelines by CDC and other organizations represent a critical step to promote awareness by clinicians regarding the compelling evidence to support universal HCV screening of all American adults, the reality is that just because there is a recommendation for it, does not mean that it will always be followed. Clinicians in primary care and specialty practices alike are already burdened by guideline fatigue, and an ever-growing list of mandates of standard clinical practice such as colon cancer screening, mammography, cholesterol checks, etc., and now all of this in the context of COVID-19. This further complicates the task of implementing HCV screening recommendations in real-world clinical practice.

New data published this year show that the screening rates among baby boomers have increased from approximately 10% to 20% since the original recommendations in 2014. Although this represents an important step in the right direction, it is clear there is significant room for improvement. It remains to be seen what impact this transition from birth cohort screening to universal screening of all Americans age 18 and older will have on our ability to identify previously unidentified infected persons.

In 2016 the World Health Organization (WHO) Global Health Sector Strategy called for the elimination of HCV as a major health threat by 2030. At the current rate of transmission, and considering all the barriers you mentioned that still exist, do you think that this is still a realistic timeframe? Is there any other action that physicians specifically maintain to help reach the goal?

Dr. Lim: WHO's vision was to eliminate hepatitis C by 2030 as defined as the following: 1) diagnose 90% of infected persons, 2) offer treatment to 80% of infected persons, and 3) reduce HCV-associated mortality by 65%.

Unfortunately, the United States is highly unlikely to meet this goal by 2030. Based on recently published models, only 3 of 50 states may have a chance at meeting the elimination target by that deadline. But as a country, we already know that is just simply not going to happen—unless there are dramatic changes in governmental and multi-stakeholder commitment.

Globally, there are an estimated 12 countries that are projected to achieve elimination by 2030. Some of the most prominent examples include Egypt, The Republic of Georgia, Australia, Italy, and Japan. The United States is not in this grouping, and in fact our current models suggest that we may not even achieve this goal by 2050.

There is much work that needs to be done to address some of the systemic and institutional infrastructure issues that will support effective implementation of screening, diagnosis, and linkage of care. Drug access—although that remains an important issue—is actually not the driving factor in terms of our inability to meet our targets. Within the United States, the Department of Health and Human Services has taken the lead on developing a US-based strategy. Although there has been strong language to articulate what is required and the intentionality to work on HCV elimination, this has not yet been associated with adequate funding at the federal level. Without this funding, we are destined to make only modest progress towards elimination targets within the short and intermediate timeframe.  Despite these challenges, organizations such as the AASLD, CDC, National Viral Hepatitis Roundtable, World Hepatitis Alliance, and the Coalition for Global Hepatitis Elimination remain vocal advocates to secure necessary resources and will continue to lead US efforts to implement effective strategies on the road to viral hepatitis elimination. These organizations cannot fulfill this mission alone—each of us as clinicians play a vital role in carrying out CDC and USPSTF recommendations in our individual clinical settings to ensure broad-based screening and diagnosis, timely linkage to care, and antiviral treatment.

What are the largest factors creating barriers to hepatitis C virus (HCV) elimination?
 

Dr. Lim: In 2020 there remain important barriers to access to treatment because of the high cost of drugs used to eradicate HCV. There are still opportunities for us to interact with major payors to ensure adequate access, both with private commercial payers, as well as with Medicaid. We know very well that there are existing barriers that impact a significant proportion of patients, but if you look at data from the private sector, it turns out that we are doing pretty well; At least 80% of payers are covering direct-acting antiviral (DAA) medications with minimal restriction.

However, with Medicaid it is quite the reverse story; In about two-thirds of states, there are at least one or more restrictions based on the stage of their fibrosis, sobriety requirements for alcohol and drug use, and specialty providers to prescribe the medication, among others. Based on data from the National Viral Hepatitis Roundtable, it is clear that there are still many states where if you have mild disease, or recently used drugs or alcohol, or are in a rural area where you do not have access to a gastroenterologist or infectious disease specialist, you cannot get treatment. That is still a major concern for access to care.

When we think about elimination, eradication, and extinction of human diseases, HCV represents one of the few for which we actually have the tools to cure the condition permanently with a simple regimen of 1 to 3 pills per day for 2 or 3 months, with a cure rate exceeding 95%. This is truly remarkable and provides us with a historic opportunity to eradicate HCV in the United States and worldwide.

When we can diagnose HCV and offer treatment, we have a very good success rate—but therein lies the challenge. The key rate limiting steps to achieving elimination are found in ongoing deficits in the HCV care cascade, including screening, diagnosis, linkage to care, and treatment. We believe that right now only about 50% of affected persons have been diagnosed, and therefore much work remains to be done in the screening/diagnosis step of the care cascade if we are to achieve meaningful progress towards HCV elimination.

In that spirit, there have been important advances in terms of policy and legislation to support broader population-based screening. The CDC and US Preventive Services Task Force initially recommended that all baby boomers (those born between 1945 and 1965) should be screened for HCV, in addition to those with established risk factors. These include individuals who have used drugs, either through a nose or through the vein, had a blood transfusion before 1992, tattoos or body piercings, accidental needlestick exposures, or high risk sexual contacts, However, data show that risk factor-based screening simply does not work. It is difficult for clinicians to routinely ask sensitive questions about historical risk factors.

Despite the remarkable success in development of curative therapies for HCV, the rate of new incident HCV infections has not been going down—It has actually been doubling to tripling over the last 5 years. We now have what we call a bi-modal distribution of HCV, which includes baby boomers and a second younger group, between age 18 and 34. The primary route of transmission in this younger cohort is injection drug use, which is largely tied to the opiate epidemic.

It is in this context that within the last year, 4 different organizations—the CDC, the United States Preventive Services Task Force (USPSTF), the American Association for the Study of Liver Diseases (AASLD), and the Infectious Diseases Society of America (IDSA)—have expanded their guidance documents to now recommend one-time HCV screening in all adults age 18 or older plus all pregnant women regardless of age. This guidance replaces the old guidelines focused on baby boomers and individuals with risk factors. This represents a fundamental and consequential shift in US strategy to improve population-based screening.

There is also a sense that a treatment as prevention strategy can be particularly impactful in reducing spread among high-risk populations, especially in persons who inject drugs (PWID). The concept is that if you can effectively remove HCV in high-risk populations by treating active users, this may prevent spread of HCV to others who would otherwise be exposed. Although HCV treatment in patients with active drug use has historically been viewed with skepticism, and in fact remains an exclusion factor by some payors, DAA therapy in PWID is strongly recommended by the AASLD/IDSA guidelines and is increasingly embraced in both specialty and non-specialty (eg, methadone clinics, community health centers, prison clinics) settings.

Could you please elaborate more on the updated CDC guidelines and the impact that those are having in practice?

Dr. Lim: Although the revised screening guidelines by CDC and other organizations represent a critical step to promote awareness by clinicians regarding the compelling evidence to support universal HCV screening of all American adults, the reality is that just because there is a recommendation for it, does not mean that it will always be followed. Clinicians in primary care and specialty practices alike are already burdened by guideline fatigue, and an ever-growing list of mandates of standard clinical practice such as colon cancer screening, mammography, cholesterol checks, etc., and now all of this in the context of COVID-19. This further complicates the task of implementing HCV screening recommendations in real-world clinical practice.

New data published this year show that the screening rates among baby boomers have increased from approximately 10% to 20% since the original recommendations in 2014. Although this represents an important step in the right direction, it is clear there is significant room for improvement. It remains to be seen what impact this transition from birth cohort screening to universal screening of all Americans age 18 and older will have on our ability to identify previously unidentified infected persons.

In 2016 the World Health Organization (WHO) Global Health Sector Strategy called for the elimination of HCV as a major health threat by 2030. At the current rate of transmission, and considering all the barriers you mentioned that still exist, do you think that this is still a realistic timeframe? Is there any other action that physicians specifically maintain to help reach the goal?

Dr. Lim: WHO's vision was to eliminate hepatitis C by 2030 as defined as the following: 1) diagnose 90% of infected persons, 2) offer treatment to 80% of infected persons, and 3) reduce HCV-associated mortality by 65%.

Unfortunately, the United States is highly unlikely to meet this goal by 2030. Based on recently published models, only 3 of 50 states may have a chance at meeting the elimination target by that deadline. But as a country, we already know that is just simply not going to happen—unless there are dramatic changes in governmental and multi-stakeholder commitment.

Globally, there are an estimated 12 countries that are projected to achieve elimination by 2030. Some of the most prominent examples include Egypt, The Republic of Georgia, Australia, Italy, and Japan. The United States is not in this grouping, and in fact our current models suggest that we may not even achieve this goal by 2050.

There is much work that needs to be done to address some of the systemic and institutional infrastructure issues that will support effective implementation of screening, diagnosis, and linkage of care. Drug access—although that remains an important issue—is actually not the driving factor in terms of our inability to meet our targets. Within the United States, the Department of Health and Human Services has taken the lead on developing a US-based strategy. Although there has been strong language to articulate what is required and the intentionality to work on HCV elimination, this has not yet been associated with adequate funding at the federal level. Without this funding, we are destined to make only modest progress towards elimination targets within the short and intermediate timeframe.  Despite these challenges, organizations such as the AASLD, CDC, National Viral Hepatitis Roundtable, World Hepatitis Alliance, and the Coalition for Global Hepatitis Elimination remain vocal advocates to secure necessary resources and will continue to lead US efforts to implement effective strategies on the road to viral hepatitis elimination. These organizations cannot fulfill this mission alone—each of us as clinicians play a vital role in carrying out CDC and USPSTF recommendations in our individual clinical settings to ensure broad-based screening and diagnosis, timely linkage to care, and antiviral treatment.

What are the largest factors creating barriers to hepatitis C virus (HCV) elimination?
 

Dr. Lim: In 2020 there remain important barriers to access to treatment because of the high cost of drugs used to eradicate HCV. There are still opportunities for us to interact with major payors to ensure adequate access, both with private commercial payers, as well as with Medicaid. We know very well that there are existing barriers that impact a significant proportion of patients, but if you look at data from the private sector, it turns out that we are doing pretty well; At least 80% of payers are covering direct-acting antiviral (DAA) medications with minimal restriction.

However, with Medicaid it is quite the reverse story; In about two-thirds of states, there are at least one or more restrictions based on the stage of their fibrosis, sobriety requirements for alcohol and drug use, and specialty providers to prescribe the medication, among others. Based on data from the National Viral Hepatitis Roundtable, it is clear that there are still many states where if you have mild disease, or recently used drugs or alcohol, or are in a rural area where you do not have access to a gastroenterologist or infectious disease specialist, you cannot get treatment. That is still a major concern for access to care.

When we think about elimination, eradication, and extinction of human diseases, HCV represents one of the few for which we actually have the tools to cure the condition permanently with a simple regimen of 1 to 3 pills per day for 2 or 3 months, with a cure rate exceeding 95%. This is truly remarkable and provides us with a historic opportunity to eradicate HCV in the United States and worldwide.

When we can diagnose HCV and offer treatment, we have a very good success rate—but therein lies the challenge. The key rate limiting steps to achieving elimination are found in ongoing deficits in the HCV care cascade, including screening, diagnosis, linkage to care, and treatment. We believe that right now only about 50% of affected persons have been diagnosed, and therefore much work remains to be done in the screening/diagnosis step of the care cascade if we are to achieve meaningful progress towards HCV elimination.

In that spirit, there have been important advances in terms of policy and legislation to support broader population-based screening. The CDC and US Preventive Services Task Force initially recommended that all baby boomers (those born between 1945 and 1965) should be screened for HCV, in addition to those with established risk factors. These include individuals who have used drugs, either through a nose or through the vein, had a blood transfusion before 1992, tattoos or body piercings, accidental needlestick exposures, or high risk sexual contacts, However, data show that risk factor-based screening simply does not work. It is difficult for clinicians to routinely ask sensitive questions about historical risk factors.

Despite the remarkable success in development of curative therapies for HCV, the rate of new incident HCV infections has not been going down—It has actually been doubling to tripling over the last 5 years. We now have what we call a bi-modal distribution of HCV, which includes baby boomers and a second younger group, between age 18 and 34. The primary route of transmission in this younger cohort is injection drug use, which is largely tied to the opiate epidemic.

It is in this context that within the last year, 4 different organizations—the CDC, the United States Preventive Services Task Force (USPSTF), the American Association for the Study of Liver Diseases (AASLD), and the Infectious Diseases Society of America (IDSA)—have expanded their guidance documents to now recommend one-time HCV screening in all adults age 18 or older plus all pregnant women regardless of age. This guidance replaces the old guidelines focused on baby boomers and individuals with risk factors. This represents a fundamental and consequential shift in US strategy to improve population-based screening.

There is also a sense that a treatment as prevention strategy can be particularly impactful in reducing spread among high-risk populations, especially in persons who inject drugs (PWID). The concept is that if you can effectively remove HCV in high-risk populations by treating active users, this may prevent spread of HCV to others who would otherwise be exposed. Although HCV treatment in patients with active drug use has historically been viewed with skepticism, and in fact remains an exclusion factor by some payors, DAA therapy in PWID is strongly recommended by the AASLD/IDSA guidelines and is increasingly embraced in both specialty and non-specialty (eg, methadone clinics, community health centers, prison clinics) settings.

Could you please elaborate more on the updated CDC guidelines and the impact that those are having in practice?

Dr. Lim: Although the revised screening guidelines by CDC and other organizations represent a critical step to promote awareness by clinicians regarding the compelling evidence to support universal HCV screening of all American adults, the reality is that just because there is a recommendation for it, does not mean that it will always be followed. Clinicians in primary care and specialty practices alike are already burdened by guideline fatigue, and an ever-growing list of mandates of standard clinical practice such as colon cancer screening, mammography, cholesterol checks, etc., and now all of this in the context of COVID-19. This further complicates the task of implementing HCV screening recommendations in real-world clinical practice.

New data published this year show that the screening rates among baby boomers have increased from approximately 10% to 20% since the original recommendations in 2014. Although this represents an important step in the right direction, it is clear there is significant room for improvement. It remains to be seen what impact this transition from birth cohort screening to universal screening of all Americans age 18 and older will have on our ability to identify previously unidentified infected persons.

In 2016 the World Health Organization (WHO) Global Health Sector Strategy called for the elimination of HCV as a major health threat by 2030. At the current rate of transmission, and considering all the barriers you mentioned that still exist, do you think that this is still a realistic timeframe? Is there any other action that physicians specifically maintain to help reach the goal?

Dr. Lim: WHO's vision was to eliminate hepatitis C by 2030 as defined as the following: 1) diagnose 90% of infected persons, 2) offer treatment to 80% of infected persons, and 3) reduce HCV-associated mortality by 65%.

Unfortunately, the United States is highly unlikely to meet this goal by 2030. Based on recently published models, only 3 of 50 states may have a chance at meeting the elimination target by that deadline. But as a country, we already know that is just simply not going to happen—unless there are dramatic changes in governmental and multi-stakeholder commitment.

Globally, there are an estimated 12 countries that are projected to achieve elimination by 2030. Some of the most prominent examples include Egypt, The Republic of Georgia, Australia, Italy, and Japan. The United States is not in this grouping, and in fact our current models suggest that we may not even achieve this goal by 2050.

There is much work that needs to be done to address some of the systemic and institutional infrastructure issues that will support effective implementation of screening, diagnosis, and linkage of care. Drug access—although that remains an important issue—is actually not the driving factor in terms of our inability to meet our targets. Within the United States, the Department of Health and Human Services has taken the lead on developing a US-based strategy. Although there has been strong language to articulate what is required and the intentionality to work on HCV elimination, this has not yet been associated with adequate funding at the federal level. Without this funding, we are destined to make only modest progress towards elimination targets within the short and intermediate timeframe.  Despite these challenges, organizations such as the AASLD, CDC, National Viral Hepatitis Roundtable, World Hepatitis Alliance, and the Coalition for Global Hepatitis Elimination remain vocal advocates to secure necessary resources and will continue to lead US efforts to implement effective strategies on the road to viral hepatitis elimination. These organizations cannot fulfill this mission alone—each of us as clinicians play a vital role in carrying out CDC and USPSTF recommendations in our individual clinical settings to ensure broad-based screening and diagnosis, timely linkage to care, and antiviral treatment.

The high price of direct-acting antiviral (DAA) oral medications has made patient access challenging despite the availability of multiple effective treatment options for hepatitis C virus (HCV). Has there been any recent progress in making these treatments more affordable to patients? 

Dr. Jakab:  Certainly. We used to have great difficulty getting these medications to our patients, regardless of whether they were covered by private insurance or through the United States Department of Veterans Affairs (VA). The last few years have been amazing, not only in terms of availability of more regimens that are equally effective in curing HCV, but also in terms of patient access. I think this is capitalism at its best. Having competition—more regimens on the market—has helped drive the prices down.

These regimens are expensive, but very few patients actually pay the sticker price because the insurance plans end up negotiating a much better fee for a preferred regimen. The reality is considerably better now than it used to be even a few years ago, with more effective regimens available, and at an affordable price.

There is not much transparency in terms of pricing, so it is usually difficult to figure it out how much one insurance plan pays versus another. From the patient's perspective the progress is visible and translated in many patients being cured from HCV.

Have any of your patients faced other treatment access challenges unrelated to financial cost?

Dr. Jakab:  Historically, when the first DAAs became available, there were certain requirements put forward by insurance companies before these medications were approved given their high price at that time. Unfortunately, some of them are still in effect.

Providers still must document their clinical evaluation and laboratory testing before these medications get approved, which is important for clinical care, but some insurance plans will only cover HCV treatment for patients with advanced (stage 3 or 4) fibrosis.

Another requirement that pains me a lot—though again, great progress has been made—has to do with sobriety for patients who use drugs or alcohol. Some plans require 3 to 6 months of sobriety, or for the patient to be connected to a substance use disorder clinic or a relapse program.

There have also been some restrictions regarding which providers could prescribe these medications. Initially this was limited to hepatology, gastroenterology, or infectious disease specialists. Given the fact that the current DAA regimens are so easy to use due to their short duration of treatment and minimal side effects, more providers are comfortable with prescribing these medications. It certainly helps that CDC recommendations support the expansion of the provider pool to include primary care providers and substance use disorder providers. Physician assistants and APRNs have been increasingly involved in prescribing these medications as well. Pharmacists help us get the approval from the insurance companies, but PharmDs also treat many HCV patients.

Certain states are ahead of others in terms of eliminating Medicaid requirements that decrease patient access to HCV medications. I am lucky to be in Connecticut, which is one of the states where Medicaid restrictions have pretty much been lifted in terms of fibrosis staging or sobriety or prescriber requirements. This progress had a lot to do with patient and provider advocacy. Back in 2015 the New Haven Legal Assistance lobbied the state’s policymakers and Medicaid leadership to change these requirements. For patients covered by commercial insurance plans there are some requirements still in place, but overall, it is much better.

I have also witnessed the revolution of HCV treatment at the VA. A few years back we were restricting the use of these medications for patients with advanced fibrosis. Now the VA has all the available medications on the formulary, and there are no restrictions in terms of fibrosis staging, or sobriety requirements.

How has your team at the West Haven VA helped patients access HCV care through collaboration with other providers?

Dr. Jakab: It has been amazing to see how innovative people can be. It is true that if there is a will, there is a way. We finally had those medications so effective in curing HCV but were faced with challenges getting them to our patients. There was a huge effort throughout the VA, which is the national leader in the treatment of HCV, with more than 100,000 veterans cured. VA Connecticut was part of the movement: we expanded our liver clinic team to include a nurse practitioner, a PharmD, RN care coordinators, and a health psychologist. This way we could help our patients overcome many psychosocial or medical barriers and get them successfully treated.

The last step was going where the patients were. We realized that some patients who would benefit from treatment would not necessarily engage with us in liver clinic, even if they kept up with seeing their primary care physician. So instead of trying to get the patients into the liver clinic, we developed a program called HELP C, which stands for “HEpatitis C Leaders in Primary Care. The purpose of the program was to educate primary care providers interested in treating HCV. We continue to provide support for them through teleconferences or being available for any questions. This way we could indirectly treat patients with HCV without having them come to the liver clinic.

We also collaborated with our colleagues from substance use disorder clinics, to make sure they are updated in terms of ease of HCV treatment and need to screen for HCV in these high-risk patients.

Is there any other action that physicians can take to help improve HCV treatment accessibility for their patients?

Dr. Jakab: Education of patients, providers and policy makers is most important, and a lot of that responsibility is on those of us who are already helping patients to get to their HCV cure. It has to do with breaking barriers. Many providers still have misconceptions, for example, when it comes to patients who are actively using drugs. They feel that we should not spend resources on these patients because of their lack of engagement in terms of treatment of their substance use disorder and risk of relapse. However, we do have data proving that even patients who are actively injecting drugs achieve a high level of compliance with medications and a high level of cure in the range of 95% or so. Having the sobriety requirement on some insurance plans is a significant barrier to treatment, and it does not help select the patients who will successfully achieve HCV cure. All patients should be treated. In fact, by focusing on this high-risk category of patients, society benefits overall because by decreasing the HCV burden, we get closer to HCV eradication.

It is also important that the providers who are interested in treating HCV get familiar with the paperwork required to get these medications approved, also partnering with subspecialty pharmacies particularly when dealing with commercial insurances. In addition, there are assistance programs for patients who do not have insurance, or they are underinsured, or they get denied by their insurance plan. At the end of the day, helping a patient to get treated is worth the extra time spent with bureaucracy.

I would also encourage providers to continue looking for innovative approaches, and to try to develop multidisciplinary programs. Care coordination—partnering with pharmacy, psychology, and social work subspecialties—is what worked best for us at the West Haven VA. We were able to treat patients that were written off many times before; patients who suffered homelessness, struggled with medication adherence for their high blood pressure, or diabetes. They were patients about whom everybody said, “You guys are crazy. They will never get the treatment completed, never mind getting cured of HCV.” But they did—so it is all about advocating for your patients and partnering with the right people.

The high price of direct-acting antiviral (DAA) oral medications has made patient access challenging despite the availability of multiple effective treatment options for hepatitis C virus (HCV). Has there been any recent progress in making these treatments more affordable to patients? 

Dr. Jakab:  Certainly. We used to have great difficulty getting these medications to our patients, regardless of whether they were covered by private insurance or through the United States Department of Veterans Affairs (VA). The last few years have been amazing, not only in terms of availability of more regimens that are equally effective in curing HCV, but also in terms of patient access. I think this is capitalism at its best. Having competition—more regimens on the market—has helped drive the prices down.

These regimens are expensive, but very few patients actually pay the sticker price because the insurance plans end up negotiating a much better fee for a preferred regimen. The reality is considerably better now than it used to be even a few years ago, with more effective regimens available, and at an affordable price.

There is not much transparency in terms of pricing, so it is usually difficult to figure it out how much one insurance plan pays versus another. From the patient's perspective the progress is visible and translated in many patients being cured from HCV.

Have any of your patients faced other treatment access challenges unrelated to financial cost?

Dr. Jakab:  Historically, when the first DAAs became available, there were certain requirements put forward by insurance companies before these medications were approved given their high price at that time. Unfortunately, some of them are still in effect.

Providers still must document their clinical evaluation and laboratory testing before these medications get approved, which is important for clinical care, but some insurance plans will only cover HCV treatment for patients with advanced (stage 3 or 4) fibrosis.

Another requirement that pains me a lot—though again, great progress has been made—has to do with sobriety for patients who use drugs or alcohol. Some plans require 3 to 6 months of sobriety, or for the patient to be connected to a substance use disorder clinic or a relapse program.

There have also been some restrictions regarding which providers could prescribe these medications. Initially this was limited to hepatology, gastroenterology, or infectious disease specialists. Given the fact that the current DAA regimens are so easy to use due to their short duration of treatment and minimal side effects, more providers are comfortable with prescribing these medications. It certainly helps that CDC recommendations support the expansion of the provider pool to include primary care providers and substance use disorder providers. Physician assistants and APRNs have been increasingly involved in prescribing these medications as well. Pharmacists help us get the approval from the insurance companies, but PharmDs also treat many HCV patients.

Certain states are ahead of others in terms of eliminating Medicaid requirements that decrease patient access to HCV medications. I am lucky to be in Connecticut, which is one of the states where Medicaid restrictions have pretty much been lifted in terms of fibrosis staging or sobriety or prescriber requirements. This progress had a lot to do with patient and provider advocacy. Back in 2015 the New Haven Legal Assistance lobbied the state’s policymakers and Medicaid leadership to change these requirements. For patients covered by commercial insurance plans there are some requirements still in place, but overall, it is much better.

I have also witnessed the revolution of HCV treatment at the VA. A few years back we were restricting the use of these medications for patients with advanced fibrosis. Now the VA has all the available medications on the formulary, and there are no restrictions in terms of fibrosis staging, or sobriety requirements.

How has your team at the West Haven VA helped patients access HCV care through collaboration with other providers?

Dr. Jakab: It has been amazing to see how innovative people can be. It is true that if there is a will, there is a way. We finally had those medications so effective in curing HCV but were faced with challenges getting them to our patients. There was a huge effort throughout the VA, which is the national leader in the treatment of HCV, with more than 100,000 veterans cured. VA Connecticut was part of the movement: we expanded our liver clinic team to include a nurse practitioner, a PharmD, RN care coordinators, and a health psychologist. This way we could help our patients overcome many psychosocial or medical barriers and get them successfully treated.

The last step was going where the patients were. We realized that some patients who would benefit from treatment would not necessarily engage with us in liver clinic, even if they kept up with seeing their primary care physician. So instead of trying to get the patients into the liver clinic, we developed a program called HELP C, which stands for “HEpatitis C Leaders in Primary Care. The purpose of the program was to educate primary care providers interested in treating HCV. We continue to provide support for them through teleconferences or being available for any questions. This way we could indirectly treat patients with HCV without having them come to the liver clinic.

We also collaborated with our colleagues from substance use disorder clinics, to make sure they are updated in terms of ease of HCV treatment and need to screen for HCV in these high-risk patients.

Is there any other action that physicians can take to help improve HCV treatment accessibility for their patients?

Dr. Jakab: Education of patients, providers and policy makers is most important, and a lot of that responsibility is on those of us who are already helping patients to get to their HCV cure. It has to do with breaking barriers. Many providers still have misconceptions, for example, when it comes to patients who are actively using drugs. They feel that we should not spend resources on these patients because of their lack of engagement in terms of treatment of their substance use disorder and risk of relapse. However, we do have data proving that even patients who are actively injecting drugs achieve a high level of compliance with medications and a high level of cure in the range of 95% or so. Having the sobriety requirement on some insurance plans is a significant barrier to treatment, and it does not help select the patients who will successfully achieve HCV cure. All patients should be treated. In fact, by focusing on this high-risk category of patients, society benefits overall because by decreasing the HCV burden, we get closer to HCV eradication.

It is also important that the providers who are interested in treating HCV get familiar with the paperwork required to get these medications approved, also partnering with subspecialty pharmacies particularly when dealing with commercial insurances. In addition, there are assistance programs for patients who do not have insurance, or they are underinsured, or they get denied by their insurance plan. At the end of the day, helping a patient to get treated is worth the extra time spent with bureaucracy.

I would also encourage providers to continue looking for innovative approaches, and to try to develop multidisciplinary programs. Care coordination—partnering with pharmacy, psychology, and social work subspecialties—is what worked best for us at the West Haven VA. We were able to treat patients that were written off many times before; patients who suffered homelessness, struggled with medication adherence for their high blood pressure, or diabetes. They were patients about whom everybody said, “You guys are crazy. They will never get the treatment completed, never mind getting cured of HCV.” But they did—so it is all about advocating for your patients and partnering with the right people.

The high price of direct-acting antiviral (DAA) oral medications has made patient access challenging despite the availability of multiple effective treatment options for hepatitis C virus (HCV). Has there been any recent progress in making these treatments more affordable to patients? 

Dr. Jakab:  Certainly. We used to have great difficulty getting these medications to our patients, regardless of whether they were covered by private insurance or through the United States Department of Veterans Affairs (VA). The last few years have been amazing, not only in terms of availability of more regimens that are equally effective in curing HCV, but also in terms of patient access. I think this is capitalism at its best. Having competition—more regimens on the market—has helped drive the prices down.

These regimens are expensive, but very few patients actually pay the sticker price because the insurance plans end up negotiating a much better fee for a preferred regimen. The reality is considerably better now than it used to be even a few years ago, with more effective regimens available, and at an affordable price.

There is not much transparency in terms of pricing, so it is usually difficult to figure it out how much one insurance plan pays versus another. From the patient's perspective the progress is visible and translated in many patients being cured from HCV.

Have any of your patients faced other treatment access challenges unrelated to financial cost?

Dr. Jakab:  Historically, when the first DAAs became available, there were certain requirements put forward by insurance companies before these medications were approved given their high price at that time. Unfortunately, some of them are still in effect.

Providers still must document their clinical evaluation and laboratory testing before these medications get approved, which is important for clinical care, but some insurance plans will only cover HCV treatment for patients with advanced (stage 3 or 4) fibrosis.

Another requirement that pains me a lot—though again, great progress has been made—has to do with sobriety for patients who use drugs or alcohol. Some plans require 3 to 6 months of sobriety, or for the patient to be connected to a substance use disorder clinic or a relapse program.

There have also been some restrictions regarding which providers could prescribe these medications. Initially this was limited to hepatology, gastroenterology, or infectious disease specialists. Given the fact that the current DAA regimens are so easy to use due to their short duration of treatment and minimal side effects, more providers are comfortable with prescribing these medications. It certainly helps that CDC recommendations support the expansion of the provider pool to include primary care providers and substance use disorder providers. Physician assistants and APRNs have been increasingly involved in prescribing these medications as well. Pharmacists help us get the approval from the insurance companies, but PharmDs also treat many HCV patients.

Certain states are ahead of others in terms of eliminating Medicaid requirements that decrease patient access to HCV medications. I am lucky to be in Connecticut, which is one of the states where Medicaid restrictions have pretty much been lifted in terms of fibrosis staging or sobriety or prescriber requirements. This progress had a lot to do with patient and provider advocacy. Back in 2015 the New Haven Legal Assistance lobbied the state’s policymakers and Medicaid leadership to change these requirements. For patients covered by commercial insurance plans there are some requirements still in place, but overall, it is much better.

I have also witnessed the revolution of HCV treatment at the VA. A few years back we were restricting the use of these medications for patients with advanced fibrosis. Now the VA has all the available medications on the formulary, and there are no restrictions in terms of fibrosis staging, or sobriety requirements.

How has your team at the West Haven VA helped patients access HCV care through collaboration with other providers?

Dr. Jakab: It has been amazing to see how innovative people can be. It is true that if there is a will, there is a way. We finally had those medications so effective in curing HCV but were faced with challenges getting them to our patients. There was a huge effort throughout the VA, which is the national leader in the treatment of HCV, with more than 100,000 veterans cured. VA Connecticut was part of the movement: we expanded our liver clinic team to include a nurse practitioner, a PharmD, RN care coordinators, and a health psychologist. This way we could help our patients overcome many psychosocial or medical barriers and get them successfully treated.

The last step was going where the patients were. We realized that some patients who would benefit from treatment would not necessarily engage with us in liver clinic, even if they kept up with seeing their primary care physician. So instead of trying to get the patients into the liver clinic, we developed a program called HELP C, which stands for “HEpatitis C Leaders in Primary Care. The purpose of the program was to educate primary care providers interested in treating HCV. We continue to provide support for them through teleconferences or being available for any questions. This way we could indirectly treat patients with HCV without having them come to the liver clinic.

We also collaborated with our colleagues from substance use disorder clinics, to make sure they are updated in terms of ease of HCV treatment and need to screen for HCV in these high-risk patients.

Is there any other action that physicians can take to help improve HCV treatment accessibility for their patients?

Dr. Jakab: Education of patients, providers and policy makers is most important, and a lot of that responsibility is on those of us who are already helping patients to get to their HCV cure. It has to do with breaking barriers. Many providers still have misconceptions, for example, when it comes to patients who are actively using drugs. They feel that we should not spend resources on these patients because of their lack of engagement in terms of treatment of their substance use disorder and risk of relapse. However, we do have data proving that even patients who are actively injecting drugs achieve a high level of compliance with medications and a high level of cure in the range of 95% or so. Having the sobriety requirement on some insurance plans is a significant barrier to treatment, and it does not help select the patients who will successfully achieve HCV cure. All patients should be treated. In fact, by focusing on this high-risk category of patients, society benefits overall because by decreasing the HCV burden, we get closer to HCV eradication.

It is also important that the providers who are interested in treating HCV get familiar with the paperwork required to get these medications approved, also partnering with subspecialty pharmacies particularly when dealing with commercial insurances. In addition, there are assistance programs for patients who do not have insurance, or they are underinsured, or they get denied by their insurance plan. At the end of the day, helping a patient to get treated is worth the extra time spent with bureaucracy.

I would also encourage providers to continue looking for innovative approaches, and to try to develop multidisciplinary programs. Care coordination—partnering with pharmacy, psychology, and social work subspecialties—is what worked best for us at the West Haven VA. We were able to treat patients that were written off many times before; patients who suffered homelessness, struggled with medication adherence for their high blood pressure, or diabetes. They were patients about whom everybody said, “You guys are crazy. They will never get the treatment completed, never mind getting cured of HCV.” But they did—so it is all about advocating for your patients and partnering with the right people.

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

[email protected]

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

[email protected]

The U.S. Preventive Services Task Force has issued a draft recommendation statement for screening for hepatitis C virus (HCV) infection in adolescents and adults, and now suggests that all adults aged 18-79 years receive screening.

Wikimedia Commons/BruceBlaus

This proposal represents an update and expansion of its current recommendation for screening for HCV infection. The draft recommendation incorporates new evidence and would replace the recommendation made in 2013, which calls for screening in persons at high risk for infection and one-time screening in adults born between 1945 and 1965 (Grade B).

“Today, more people are infected with hepatitis C than there were a decade ago, but there are now better treatments available. The evidence now shows more people can benefit from screening; therefore, we are recommending to screen all adults ages 18-79 for hepatitis C,” task force chair Douglas K. Owens, MD, MS, said in a bulletin issued by the USPSTF.

To update the previous recommendation, the USPSTF conducted a systematic review that included a total of 97 studies. No direct evidence was found regarding the benefits of HCV screening versus no screening or repeat versus one-time screening, and no new studies analyzed the psychological and social consequences of HCV screening.

Evidence concerning direct-acting antiviral (DAA) treatment was more compelling given that 49 trials found DAA therapy to be associated with pooled sustained virologic response (SVR) rates between 95.5% and 98.9% across genotypes. The rate of serious adverse events caused by DAA treatment was 1.9%, and the discontinuation of treatment because of adverse events was 0.4%. In seven trials involving adolescents, SVR rates after antiviral treatment were similar to those in adults.

Achieving an SVR after DAA treatment was associated with a decreased risk in those treated of all-cause mortality (hazard ratio, 0.40; 95% confidence interval, 0.28-0.56), liver mortality (HR, 0.11; 95% CI, 0.04-0.27), cirrhosis (HR, 0.36; 95% CI, 0.33-0.40), and hepatocellular carcinoma (HR, 0.29; 95% CI, 0.23-0.38), compared with those who did not respond.

Because of the evidence collected, the USPSTF issued a B recommendation for HCV screening in adults and recommended screening for all people aged 18-79 years in the draft recommendation statement. “Clinicians may want to consider screening in adolescents younger than age 18 years and in adults older than age 79 years who are at high risk [for HCV],” the proposal says.

The draft recommendation statement and evidence review is available at www.uspreventiveservicestaskforce.org. The public comment period will last until Sept. 23, 2019.

[email protected]

BOSTON – A lot of people do well with HIV thanks to potent antiretrovirals, but there’s still at least one group that needs extra attention: HIV patients with chronic kidney disease (CKD), according to Lene Ryom, MD, PhD, an HIV researcher at the University of Copenhagen.

She was the lead investigator on a review of 2,467 HIV patients with CKD – which is becoming more common in HIV as patients live longer – and 33,427 HIV patients without CKD.

decade3d/Thinkstock

The subjects were all participants in the D:A:D project [Data Collection on Adverse Events of Anti-HIV Drugs], an ongoing international cohort study based at the University of Copenhagen, and funded by pharmaceutical companies, among others.

Dr. Ryom had no disclosures.

[email protected]

SOURCE: Ryom L et al. CROI, Abstract 75.

BOSTON – A lot of people do well with HIV thanks to potent antiretrovirals, but there’s still at least one group that needs extra attention: HIV patients with chronic kidney disease (CKD), according to Lene Ryom, MD, PhD, an HIV researcher at the University of Copenhagen.

She was the lead investigator on a review of 2,467 HIV patients with CKD – which is becoming more common in HIV as patients live longer – and 33,427 HIV patients without CKD.

decade3d/Thinkstock

The subjects were all participants in the D:A:D project [Data Collection on Adverse Events of Anti-HIV Drugs], an ongoing international cohort study based at the University of Copenhagen, and funded by pharmaceutical companies, among others.

Dr. Ryom had no disclosures.

[email protected]

SOURCE: Ryom L et al. CROI, Abstract 75.

BOSTON – A lot of people do well with HIV thanks to potent antiretrovirals, but there’s still at least one group that needs extra attention: HIV patients with chronic kidney disease (CKD), according to Lene Ryom, MD, PhD, an HIV researcher at the University of Copenhagen.

She was the lead investigator on a review of 2,467 HIV patients with CKD – which is becoming more common in HIV as patients live longer – and 33,427 HIV patients without CKD.

decade3d/Thinkstock

The subjects were all participants in the D:A:D project [Data Collection on Adverse Events of Anti-HIV Drugs], an ongoing international cohort study based at the University of Copenhagen, and funded by pharmaceutical companies, among others.

Dr. Ryom had no disclosures.

[email protected]

SOURCE: Ryom L et al. CROI, Abstract 75.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.

Bioengineered liver models have enabled recapitulation of liver architecture with precise control over cellular microenvironments, resulting in stabilized liver functions for several weeks in vitro. Studies have focused on using these models to investigate cell responses to drugs and other stimuli (for example, viruses and cell differentiation cues) to predict clinical outcomes. Gregory H. Underhill, PhD, from the department of bioengineering at the University of Illinois at Urbana-Champaign and Salman R. Khetani, PhD, from the department of bioengineering at the University of Illinois in Chicago presented a comprehensive review of the these advances in bioengineered liver models in Cellular and Molecular Gastroenterology and Hepatology (doi: 10.1016/j.jcmgh.2017.11.012).

Drug-induced liver injury (DILI) is a leading cause of drug attrition in the United States, with some marketed drugs causing cell necrosis, hepatitis, cholestasis, fibrosis, or a mixture of injury types. Although the Food and Drug Administration requires preclinical drug testing in animal models, differences in species-specific drug metabolism pathways and human genetics may result in inadequate identification of potential for human DILI. Some bioengineered liver models for in vitro studies are based on tissue engineering using high-throughput microarrays, protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting.

High-throughput cell microarrays enable systematic analysis of a large number of drugs or compounds at a relatively low cost. Several culture platforms have been developed using multiple sources of liver cells, including cancerous and immortalized cell lines. These platforms show enhanced capabilities to evaluate combinatorial effects of multiple signals with independent control of biochemical and biomechanical cues. For instance, a microchip platform for transducing 3-D liver cell cultures with genes for drug metabolism enzymes featuring 532 reaction vessels (micropillars and corresponding microwells) was able to provide information about certain enzyme combinations that led to drug toxicity in cells. The high-throughput cell microarrays are, however, primarily dependent on imaging-based readouts and have a limited ability to investigate cell responses to gradients of microenvironmental signals.

Liver development, physiology, and pathophysiology are dependent on homotypic and heterotypic interactions between parenchymal and nonparenchymal cells (NPCs). Cocultures with both liver- and nonliver-derived NPC types, in vitro, can induce liver functions transiently and have proven useful for investigating host responses to sepsis, mutagenesis, xenobiotic metabolism and toxicity, response to oxidative stress, lipid metabolism, and induction of the acute-phase response. Micropatterned cocultures (MPCCs) are designed to allow the use of different NPC types without significantly altering hepatocyte homotypic interactions. Cell-cell interactions can be precisely controlled to allow for stable functions for up to 4-6 weeks, whereas more randomly distributed cocultures have limited stability. Unlike randomly distributed cocultures, MPCCs can be infected with HBV, HCV, and malaria. Potential limitations of MPCCs include the requirement for specialized equipment and devices for patterning collagen for hepatocyte attachment.

Randomly distributed spheroids or organoids enable 3-D establishment of homotypic cell-cell interactions surrounded by an extracellular matrix. The spheroids can be further cocultured with NPCs that facilitate heterotypic cell-cell interactions and allow the evaluation of outcomes resulting from drugs and other stimuli. Hepatic spheroids maintain major liver functions for several weeks and have proven to be compatible with multiple applications within the drug development pipeline.

These spheroids showed greater sensitivity in identifying known hepatotoxic drugs than did short-term primary human hepatocyte (PHH) monolayers. PHHs secreted liver proteins, such as albumin, transferrin, and fibrinogen, and showed cytochrome-P450 activities for 77-90 days when cultured on a nylon scaffold containing a mixture of liver NPCs and PHHs.

Nanopillar plates can be used to create induced pluripotent stem cell–derived human hepatocyte-like cell (iHep) spheroids; although these spheroids showed some potential for initial drug toxicity screening, they had lower overall sensitivity than conventional PHH monolayers, which suggests that further maturation of iHeps is likely required.

Potential limitations of randomly distributed spheroids include necrosis of cells in the center of larger spheroids and the requirement for expensive confocal microscopy for high-content imaging of entire spheroid cultures. To overcome the limitation of disorganized cell type interactions over time within the randomly distributed spheroids/organoids, bioprinted human liver organoids are designed to allow precise control of cell placement.

Yet another bioengineered liver model is based on perfusion systems or bioreactors that enable dynamic fluid flow for nutrient and waste exchange. These so called liver-on-a-chip devices contain hepatocyte aggregates adhered to collagen-coated microchannel walls; these are then perfused at optimal flow rates both to meet the oxygen demands of the hepatocytes and deliver low shear stress to the cells that’s similar to what would be the case in vivo. Layered architectures can be created with single-chamber or multichamber, microfluidic device designs that can sustain cell functionality for 2-4 weeks.

Some of the limitations of perfusion systems include the potential binding of drugs to tubing and materials used, large dead volume requiring higher quantities of novel compounds for the treatment of cell cultures, low throughput, and washing away of built-up beneficial molecules with perfusion.

The ongoing development of more sophisticated engineering tools for manipulating cells in culture will lead to continued advances in bioengineered livers that will show improving sensitivity for the prediction of clinically relevant drug and disease outcomes.

This work was funded by National Institutes of Health grants. The author Dr. Khetani disclosed a conflict of interest with Ascendance Biotechnology, which has licensed the micropatterned coculture and related systems from Massachusetts Institute of Technology, Cambridge, and Colorado State University, Fort Collins, for commercial distribution. Dr. Underhill disclosed no conflicts.

SOURCE: Underhill GH and Khetani SR. Cell Molec Gastro Hepatol. 2017. doi: org/10.1016/j.jcmgh.2017.11.012.