User login
How to choose between highly effective HBV therapies
MAUI, HAWAII – With three highly effective, guideline-recommended nucleoside/tide therapies for chronic hepatitis B virus (HBV) infection now available, the selection of the optimal antiviral agent for a given patient can seem daunting.
Norah Terrault, MD, offered guidance on this score at the Gastroenterology Updates, IBD, Liver Disease meeting.
As the current guidelines of the American Association for the Study of Liver Disease and European Association for the Study of the Liver make clear, these agents are to be used in targeting patients with active disease, defined by elevated alanine aminotransferase and HBV DNA levels and/or advanced fibrosis. These antivirals aim at long-term HBV control rather than disease cure.
Although numerous investigational drugs are in development with a focus on cure, the day of curative therapy has not yet arrived, noted Dr. Terrault, a professor of medicine and the director of the viral hepatitis center at the University of California, San Francisco.
Randomized trials presented at the 2017 annual meeting of European Association for the Study of the Liver demonstrated that the newest agent, tenofovir alafenamide (TAF), was as effective as tenofovir disoproxil fumarate (TDF) at suppressing HBV DNA through 96 weeks in both hepatitis B e-antigen (HBeAg)–negative and HBeAg-positive patients.
Moreover, TAF had a small but statistically significant advantage in terms of seroconversion rate at week 96 in the HBeAg-positive group, by a margin of 18%-12%. The alanine aminotransferase normalization rate was also significantly higher in the TAF group, by a margin of 81%-71% in HBeAg-negative patients and 75%-68% in HBeAg-positive patients.
“This [TAF] is a very good drug, a nice one to have at our disposal,” according to Dr. Terrault. “The primary reason we wanted it has to do with its safety profile.”
Its potential benefit in this regard was illustrated in a pair of multinational phase 3 clinical trials totaling nearly 1,300 patients with chronic HBV presented at the 2017 meeting of American Association for the Study of Liver Disease. After completing 96 weeks of double-blind treatment with TAF or TDF, everyone was switched to open-label TAF.
“There was a nice rebound in creatinine clearance and bone density when the switch was made from TDF to TAF,” she observed. “This is encouraging data for us, in that if you have a patient on TDF and you are concerned about renal or bone safety, you can do the switch to TAF and very quickly see some recovery in those abnormalities.”
Dr. Terrault offered the following guidance in selecting HBV therapy: For most patients with no comorbidities, monotherapy with either TAF, TDF, or entecavir is an excellent approach.
However, in a patient who has preexisting bone or renal disease – or who is at increased risk for such disease based upon age greater than 60 years, a history of fragility fractures, chronic systemic corticosteroid therapy, or renal abnormalities – entecavir or TAF is a better option than TDF.
TAF becomes the preferred choice over entecavir if the patient has previously been exposed to a nucleoside or if the patient is coinfected with HIV because the drug is approved for treatment of HIV and HBV, while entecavir is not.
Also, no dose adjustment of TAF is needed so long as the creatinine clearance is at least 15 mL/min, whereas the dose-adjustment threshold is 50 mL/min for both entecavir and TDF.
Conversely, entecavir, an older and less expensive drug than TAF, deserves priority in a patient with no prior exposure to a nucleoside, no HIV coinfection, or in an individual with a creatinine clearance below 15 mL/min after dose adjustment. TAF hasn’t been studied in patients with a creatinine clearance that low.
Also, TAF has not been studied in pregnant women or in patients with decompensated cirrhosis, the hepatologist noted.
Dr. Terrault serves as a consultant to AbbVie, Biotest, CoCrystal Pharmaceuticals, and Gilead Sciences.
MAUI, HAWAII – With three highly effective, guideline-recommended nucleoside/tide therapies for chronic hepatitis B virus (HBV) infection now available, the selection of the optimal antiviral agent for a given patient can seem daunting.
Norah Terrault, MD, offered guidance on this score at the Gastroenterology Updates, IBD, Liver Disease meeting.
As the current guidelines of the American Association for the Study of Liver Disease and European Association for the Study of the Liver make clear, these agents are to be used in targeting patients with active disease, defined by elevated alanine aminotransferase and HBV DNA levels and/or advanced fibrosis. These antivirals aim at long-term HBV control rather than disease cure.
Although numerous investigational drugs are in development with a focus on cure, the day of curative therapy has not yet arrived, noted Dr. Terrault, a professor of medicine and the director of the viral hepatitis center at the University of California, San Francisco.
Randomized trials presented at the 2017 annual meeting of European Association for the Study of the Liver demonstrated that the newest agent, tenofovir alafenamide (TAF), was as effective as tenofovir disoproxil fumarate (TDF) at suppressing HBV DNA through 96 weeks in both hepatitis B e-antigen (HBeAg)–negative and HBeAg-positive patients.
Moreover, TAF had a small but statistically significant advantage in terms of seroconversion rate at week 96 in the HBeAg-positive group, by a margin of 18%-12%. The alanine aminotransferase normalization rate was also significantly higher in the TAF group, by a margin of 81%-71% in HBeAg-negative patients and 75%-68% in HBeAg-positive patients.
“This [TAF] is a very good drug, a nice one to have at our disposal,” according to Dr. Terrault. “The primary reason we wanted it has to do with its safety profile.”
Its potential benefit in this regard was illustrated in a pair of multinational phase 3 clinical trials totaling nearly 1,300 patients with chronic HBV presented at the 2017 meeting of American Association for the Study of Liver Disease. After completing 96 weeks of double-blind treatment with TAF or TDF, everyone was switched to open-label TAF.
“There was a nice rebound in creatinine clearance and bone density when the switch was made from TDF to TAF,” she observed. “This is encouraging data for us, in that if you have a patient on TDF and you are concerned about renal or bone safety, you can do the switch to TAF and very quickly see some recovery in those abnormalities.”
Dr. Terrault offered the following guidance in selecting HBV therapy: For most patients with no comorbidities, monotherapy with either TAF, TDF, or entecavir is an excellent approach.
However, in a patient who has preexisting bone or renal disease – or who is at increased risk for such disease based upon age greater than 60 years, a history of fragility fractures, chronic systemic corticosteroid therapy, or renal abnormalities – entecavir or TAF is a better option than TDF.
TAF becomes the preferred choice over entecavir if the patient has previously been exposed to a nucleoside or if the patient is coinfected with HIV because the drug is approved for treatment of HIV and HBV, while entecavir is not.
Also, no dose adjustment of TAF is needed so long as the creatinine clearance is at least 15 mL/min, whereas the dose-adjustment threshold is 50 mL/min for both entecavir and TDF.
Conversely, entecavir, an older and less expensive drug than TAF, deserves priority in a patient with no prior exposure to a nucleoside, no HIV coinfection, or in an individual with a creatinine clearance below 15 mL/min after dose adjustment. TAF hasn’t been studied in patients with a creatinine clearance that low.
Also, TAF has not been studied in pregnant women or in patients with decompensated cirrhosis, the hepatologist noted.
Dr. Terrault serves as a consultant to AbbVie, Biotest, CoCrystal Pharmaceuticals, and Gilead Sciences.
MAUI, HAWAII – With three highly effective, guideline-recommended nucleoside/tide therapies for chronic hepatitis B virus (HBV) infection now available, the selection of the optimal antiviral agent for a given patient can seem daunting.
Norah Terrault, MD, offered guidance on this score at the Gastroenterology Updates, IBD, Liver Disease meeting.
As the current guidelines of the American Association for the Study of Liver Disease and European Association for the Study of the Liver make clear, these agents are to be used in targeting patients with active disease, defined by elevated alanine aminotransferase and HBV DNA levels and/or advanced fibrosis. These antivirals aim at long-term HBV control rather than disease cure.
Although numerous investigational drugs are in development with a focus on cure, the day of curative therapy has not yet arrived, noted Dr. Terrault, a professor of medicine and the director of the viral hepatitis center at the University of California, San Francisco.
Randomized trials presented at the 2017 annual meeting of European Association for the Study of the Liver demonstrated that the newest agent, tenofovir alafenamide (TAF), was as effective as tenofovir disoproxil fumarate (TDF) at suppressing HBV DNA through 96 weeks in both hepatitis B e-antigen (HBeAg)–negative and HBeAg-positive patients.
Moreover, TAF had a small but statistically significant advantage in terms of seroconversion rate at week 96 in the HBeAg-positive group, by a margin of 18%-12%. The alanine aminotransferase normalization rate was also significantly higher in the TAF group, by a margin of 81%-71% in HBeAg-negative patients and 75%-68% in HBeAg-positive patients.
“This [TAF] is a very good drug, a nice one to have at our disposal,” according to Dr. Terrault. “The primary reason we wanted it has to do with its safety profile.”
Its potential benefit in this regard was illustrated in a pair of multinational phase 3 clinical trials totaling nearly 1,300 patients with chronic HBV presented at the 2017 meeting of American Association for the Study of Liver Disease. After completing 96 weeks of double-blind treatment with TAF or TDF, everyone was switched to open-label TAF.
“There was a nice rebound in creatinine clearance and bone density when the switch was made from TDF to TAF,” she observed. “This is encouraging data for us, in that if you have a patient on TDF and you are concerned about renal or bone safety, you can do the switch to TAF and very quickly see some recovery in those abnormalities.”
Dr. Terrault offered the following guidance in selecting HBV therapy: For most patients with no comorbidities, monotherapy with either TAF, TDF, or entecavir is an excellent approach.
However, in a patient who has preexisting bone or renal disease – or who is at increased risk for such disease based upon age greater than 60 years, a history of fragility fractures, chronic systemic corticosteroid therapy, or renal abnormalities – entecavir or TAF is a better option than TDF.
TAF becomes the preferred choice over entecavir if the patient has previously been exposed to a nucleoside or if the patient is coinfected with HIV because the drug is approved for treatment of HIV and HBV, while entecavir is not.
Also, no dose adjustment of TAF is needed so long as the creatinine clearance is at least 15 mL/min, whereas the dose-adjustment threshold is 50 mL/min for both entecavir and TDF.
Conversely, entecavir, an older and less expensive drug than TAF, deserves priority in a patient with no prior exposure to a nucleoside, no HIV coinfection, or in an individual with a creatinine clearance below 15 mL/min after dose adjustment. TAF hasn’t been studied in patients with a creatinine clearance that low.
Also, TAF has not been studied in pregnant women or in patients with decompensated cirrhosis, the hepatologist noted.
Dr. Terrault serves as a consultant to AbbVie, Biotest, CoCrystal Pharmaceuticals, and Gilead Sciences.
EXPERT ANALYSIS FROM GUILD 2018
Where the latest HCV drug combos fit in
MAUI, HAWAII – The addition of the two latest treatment regimens to receive approval for hepatitis C essentially closes the circle on treatment of this disease, Steven L. Flamm, MD, declared at the Gastroenterology Updates, IBD, Liver Disease meeting.
“We now have good options available for all the hepatitis C scenarios you will ever see in your practice,” said Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
Moreover, this wide range of highly effective, well-tolerated therapies is having a major clinical impact.
“We’re already seeing a decline in the number of patients who are listed for liver transplantation with hepatitis C as the indication with UNOS [the United Organ Sharing database],” the gastroenterologist noted, citing a study presented at the 2017 annual meeting of the American Association for the Study of Liver Disease that showed that the proportion of patients who join the transplant wait-list with hepatitis C as their qualifying diagnosis has fallen by 35% since approval of the direct-acting antiviral (DAA) regimens in late 2013.
What’s special about the two newest DAA treatment regimens – sofosbuvir/velpatasvir/voxilaprevir (Vosevi) and glecaprevir/pibrentasvir (Mavyret) – is that they are pangenotypic, they are effective in prior treatment failures, they don’t need to be accompanied by ribavirin, and there is no need for baseline pretreatment resistance-associated substitution testing, Dr. Flamm noted.
“So if you have a patient sitting in front of you with any genotype of hepatitis C infection who has failed on NS5a-inhibitor therapy, you can tell them in general their chance of getting an SVR [sustained viral response] with sofosbuvir/velpatasvir/voxilaprevir is about 97%. And you can give it without worrying about what resistances they might have to begin with,” he said.
His copanelist Norah Terrault, MD, agreed that these two regimens are important additions.
“Glecaprevir/pibrentasvir is the first pangenic 8-week regimen for noncirrhotics. This is a major advance. And now having sofosbuvir/velpatasvir/voxilaprevir for treatment-experienced patients, that’s another strong advance,” commented Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
Dr. Flamm said the biggest remaining challenge in the treatment of hepatitis C is to gain improved access to therapy.
“The public-aid patients make up 30%-35% of patients with hepatitis C in my part of the country, and they still can’t get therapy unless they have cirrhosis. We can’t even treat people who have stage 2 fibrosis if they’re public-aid patients in Illinois. So we can’t achieve the goal of eliminating hepatitis C,” Dr. Flamm said.
He reported having no financial conflicts regarding his presentation.
Encourage your patients to visit AGA’s new online GI Patient Center to learn more about digestive diseases, including HCV, at gastro.org/patient.
MAUI, HAWAII – The addition of the two latest treatment regimens to receive approval for hepatitis C essentially closes the circle on treatment of this disease, Steven L. Flamm, MD, declared at the Gastroenterology Updates, IBD, Liver Disease meeting.
“We now have good options available for all the hepatitis C scenarios you will ever see in your practice,” said Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
Moreover, this wide range of highly effective, well-tolerated therapies is having a major clinical impact.
“We’re already seeing a decline in the number of patients who are listed for liver transplantation with hepatitis C as the indication with UNOS [the United Organ Sharing database],” the gastroenterologist noted, citing a study presented at the 2017 annual meeting of the American Association for the Study of Liver Disease that showed that the proportion of patients who join the transplant wait-list with hepatitis C as their qualifying diagnosis has fallen by 35% since approval of the direct-acting antiviral (DAA) regimens in late 2013.
What’s special about the two newest DAA treatment regimens – sofosbuvir/velpatasvir/voxilaprevir (Vosevi) and glecaprevir/pibrentasvir (Mavyret) – is that they are pangenotypic, they are effective in prior treatment failures, they don’t need to be accompanied by ribavirin, and there is no need for baseline pretreatment resistance-associated substitution testing, Dr. Flamm noted.
“So if you have a patient sitting in front of you with any genotype of hepatitis C infection who has failed on NS5a-inhibitor therapy, you can tell them in general their chance of getting an SVR [sustained viral response] with sofosbuvir/velpatasvir/voxilaprevir is about 97%. And you can give it without worrying about what resistances they might have to begin with,” he said.
His copanelist Norah Terrault, MD, agreed that these two regimens are important additions.
“Glecaprevir/pibrentasvir is the first pangenic 8-week regimen for noncirrhotics. This is a major advance. And now having sofosbuvir/velpatasvir/voxilaprevir for treatment-experienced patients, that’s another strong advance,” commented Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
Dr. Flamm said the biggest remaining challenge in the treatment of hepatitis C is to gain improved access to therapy.
“The public-aid patients make up 30%-35% of patients with hepatitis C in my part of the country, and they still can’t get therapy unless they have cirrhosis. We can’t even treat people who have stage 2 fibrosis if they’re public-aid patients in Illinois. So we can’t achieve the goal of eliminating hepatitis C,” Dr. Flamm said.
He reported having no financial conflicts regarding his presentation.
Encourage your patients to visit AGA’s new online GI Patient Center to learn more about digestive diseases, including HCV, at gastro.org/patient.
MAUI, HAWAII – The addition of the two latest treatment regimens to receive approval for hepatitis C essentially closes the circle on treatment of this disease, Steven L. Flamm, MD, declared at the Gastroenterology Updates, IBD, Liver Disease meeting.
“We now have good options available for all the hepatitis C scenarios you will ever see in your practice,” said Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
Moreover, this wide range of highly effective, well-tolerated therapies is having a major clinical impact.
“We’re already seeing a decline in the number of patients who are listed for liver transplantation with hepatitis C as the indication with UNOS [the United Organ Sharing database],” the gastroenterologist noted, citing a study presented at the 2017 annual meeting of the American Association for the Study of Liver Disease that showed that the proportion of patients who join the transplant wait-list with hepatitis C as their qualifying diagnosis has fallen by 35% since approval of the direct-acting antiviral (DAA) regimens in late 2013.
What’s special about the two newest DAA treatment regimens – sofosbuvir/velpatasvir/voxilaprevir (Vosevi) and glecaprevir/pibrentasvir (Mavyret) – is that they are pangenotypic, they are effective in prior treatment failures, they don’t need to be accompanied by ribavirin, and there is no need for baseline pretreatment resistance-associated substitution testing, Dr. Flamm noted.
“So if you have a patient sitting in front of you with any genotype of hepatitis C infection who has failed on NS5a-inhibitor therapy, you can tell them in general their chance of getting an SVR [sustained viral response] with sofosbuvir/velpatasvir/voxilaprevir is about 97%. And you can give it without worrying about what resistances they might have to begin with,” he said.
His copanelist Norah Terrault, MD, agreed that these two regimens are important additions.
“Glecaprevir/pibrentasvir is the first pangenic 8-week regimen for noncirrhotics. This is a major advance. And now having sofosbuvir/velpatasvir/voxilaprevir for treatment-experienced patients, that’s another strong advance,” commented Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
Dr. Flamm said the biggest remaining challenge in the treatment of hepatitis C is to gain improved access to therapy.
“The public-aid patients make up 30%-35% of patients with hepatitis C in my part of the country, and they still can’t get therapy unless they have cirrhosis. We can’t even treat people who have stage 2 fibrosis if they’re public-aid patients in Illinois. So we can’t achieve the goal of eliminating hepatitis C,” Dr. Flamm said.
He reported having no financial conflicts regarding his presentation.
Encourage your patients to visit AGA’s new online GI Patient Center to learn more about digestive diseases, including HCV, at gastro.org/patient.
EXPERT ANALYSIS FROM GUILD 2018
Where the latest HCV drug combos fit in
MAUI, HAWAII – The addition of the two latest treatment regimens to receive approval for hepatitis C essentially closes the circle on treatment of this disease, Steven L. Flamm, MD, declared at the Gastroenterology Updates, IBD, Liver Disease meeting.
“We now have good options available for all the hepatitis C scenarios you will ever see in your practice,” said Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
“We’re already seeing a decline in the number of patients who are listed for liver transplantation with hepatitis C as the indication with UNOS [the United Organ Sharing database],” the gastroenterologist noted, citing a study presented at the 2017 annual meeting of the American Association for the Study of Liver Disease that showed that the proportion of patients who join the transplant wait-list with hepatitis C as their qualifying diagnosis has fallen by 35% since approval of the direct-acting antiviral (DAA) regimens in late 2013.
What’s special about the two newest DAA treatment regimens – sofosbuvir/velpatasvir/voxilaprevir (Vosevi) and glecaprevir/pibrentasvir (Mavyret) – is that they are pangenotypic, they are effective in prior treatment failures, they don’t need to be accompanied by ribavirin, and there is no need for baseline pretreatment resistance-associated substitution testing, Dr. Flamm noted.
“So if you have a patient sitting in front of you with any genotype of hepatitis C infection who has failed on NS5a-inhibitor therapy, you can tell them in general their chance of getting an SVR [sustained viral response] with sofosbuvir/velpatasvir/voxilaprevir is about 97%. And you can give it without worrying about what resistances they might have to begin with,” he said.
His copanelist Norah Terrault, MD, agreed that these two regimens are important additions.
“Glecaprevir/pibrentasvir is the first pangenic 8-week regimen for noncirrhotics. This is a major advance. And now having sofosbuvir/velpatasvir/voxilaprevir for treatment-experienced patients, that’s another strong advance,” commented Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
Dr. Flamm said the biggest remaining challenge in the treatment of hepatitis C is to gain improved access to therapy.
“The public-aid patients make up 30%-35% of patients with hepatitis C in my part of the country, and they still can’t get therapy unless they have cirrhosis. We can’t even treat people who have stage 2 fibrosis if they’re public-aid patients in Illinois. So we can’t achieve the goal of eliminating hepatitis C,” Dr. Flamm said.
He reported having no financial conflicts regarding his presentation.
MAUI, HAWAII – The addition of the two latest treatment regimens to receive approval for hepatitis C essentially closes the circle on treatment of this disease, Steven L. Flamm, MD, declared at the Gastroenterology Updates, IBD, Liver Disease meeting.
“We now have good options available for all the hepatitis C scenarios you will ever see in your practice,” said Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
“We’re already seeing a decline in the number of patients who are listed for liver transplantation with hepatitis C as the indication with UNOS [the United Organ Sharing database],” the gastroenterologist noted, citing a study presented at the 2017 annual meeting of the American Association for the Study of Liver Disease that showed that the proportion of patients who join the transplant wait-list with hepatitis C as their qualifying diagnosis has fallen by 35% since approval of the direct-acting antiviral (DAA) regimens in late 2013.
What’s special about the two newest DAA treatment regimens – sofosbuvir/velpatasvir/voxilaprevir (Vosevi) and glecaprevir/pibrentasvir (Mavyret) – is that they are pangenotypic, they are effective in prior treatment failures, they don’t need to be accompanied by ribavirin, and there is no need for baseline pretreatment resistance-associated substitution testing, Dr. Flamm noted.
“So if you have a patient sitting in front of you with any genotype of hepatitis C infection who has failed on NS5a-inhibitor therapy, you can tell them in general their chance of getting an SVR [sustained viral response] with sofosbuvir/velpatasvir/voxilaprevir is about 97%. And you can give it without worrying about what resistances they might have to begin with,” he said.
His copanelist Norah Terrault, MD, agreed that these two regimens are important additions.
“Glecaprevir/pibrentasvir is the first pangenic 8-week regimen for noncirrhotics. This is a major advance. And now having sofosbuvir/velpatasvir/voxilaprevir for treatment-experienced patients, that’s another strong advance,” commented Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
Dr. Flamm said the biggest remaining challenge in the treatment of hepatitis C is to gain improved access to therapy.
“The public-aid patients make up 30%-35% of patients with hepatitis C in my part of the country, and they still can’t get therapy unless they have cirrhosis. We can’t even treat people who have stage 2 fibrosis if they’re public-aid patients in Illinois. So we can’t achieve the goal of eliminating hepatitis C,” Dr. Flamm said.
He reported having no financial conflicts regarding his presentation.
MAUI, HAWAII – The addition of the two latest treatment regimens to receive approval for hepatitis C essentially closes the circle on treatment of this disease, Steven L. Flamm, MD, declared at the Gastroenterology Updates, IBD, Liver Disease meeting.
“We now have good options available for all the hepatitis C scenarios you will ever see in your practice,” said Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
“We’re already seeing a decline in the number of patients who are listed for liver transplantation with hepatitis C as the indication with UNOS [the United Organ Sharing database],” the gastroenterologist noted, citing a study presented at the 2017 annual meeting of the American Association for the Study of Liver Disease that showed that the proportion of patients who join the transplant wait-list with hepatitis C as their qualifying diagnosis has fallen by 35% since approval of the direct-acting antiviral (DAA) regimens in late 2013.
What’s special about the two newest DAA treatment regimens – sofosbuvir/velpatasvir/voxilaprevir (Vosevi) and glecaprevir/pibrentasvir (Mavyret) – is that they are pangenotypic, they are effective in prior treatment failures, they don’t need to be accompanied by ribavirin, and there is no need for baseline pretreatment resistance-associated substitution testing, Dr. Flamm noted.
“So if you have a patient sitting in front of you with any genotype of hepatitis C infection who has failed on NS5a-inhibitor therapy, you can tell them in general their chance of getting an SVR [sustained viral response] with sofosbuvir/velpatasvir/voxilaprevir is about 97%. And you can give it without worrying about what resistances they might have to begin with,” he said.
His copanelist Norah Terrault, MD, agreed that these two regimens are important additions.
“Glecaprevir/pibrentasvir is the first pangenic 8-week regimen for noncirrhotics. This is a major advance. And now having sofosbuvir/velpatasvir/voxilaprevir for treatment-experienced patients, that’s another strong advance,” commented Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
Dr. Flamm said the biggest remaining challenge in the treatment of hepatitis C is to gain improved access to therapy.
“The public-aid patients make up 30%-35% of patients with hepatitis C in my part of the country, and they still can’t get therapy unless they have cirrhosis. We can’t even treat people who have stage 2 fibrosis if they’re public-aid patients in Illinois. So we can’t achieve the goal of eliminating hepatitis C,” Dr. Flamm said.
He reported having no financial conflicts regarding his presentation.
Treatment of HCV in special populations
MAUI, HAWAII – Treatment of acute rather than chronic hepatitis C infection is well worth considering in selected circumstances, Norah Terrault, MD, asserted at the Gastroenterology Updates, IBD, Liver Disease meeting.
This is not at present guideline-recommended therapy. Current American Association for the Study of Liver Disease/Infectious Diseases Society of America guidance states that while there is emerging data to support treatment of acute hepatitis C, the evidence isn’t yet sufficiently robust to support a particular regimen or duration. The guidelines currently recommend waiting 6 months to see if the acute infection resolves spontaneously, as happens in a minority of cases, or becomes chronic, at which point it becomes guideline-directed treatment time. But Dr. Terrault believes persuasive evidence to back treatment of acute hepatitis C infection (HCV) is forthcoming, and she noted that the guidelines leave the door ajar by stating, “There are instances wherein a clinician may decide that the benefits of early treatment outweigh waiting for possible spontaneous clearance.”
Treatment of acute HCV
Dr. Terrault deems treatment of acute HCV warranted in circumstances in which there is significant danger of transmission from the acutely infected individual to others. For example, health care providers with a needlestick HCV infection, injecting drug users, and men with acute HCV/HIV coinfection. She also treats acute HCV in patients with underlying chronic liver disease.
“Clearly, I wouldn’t want those individuals to have any worsening of their liver function, so I would treat them acutely,” explained Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
She cited as particularly impressive the results of the SWIFT-C trial presented by Suzanna Naggie, MD, of Duke University, Durham, N.C., at the 2017 AASLD annual meeting. In this modest-size, National Institutes of Health–sponsored, multicenter study of HIV-infected men with acute HCV coinfection, the sustained viral response (SVR) rate with 8 weeks of ledipasvir/sofosbuvir (Harvoni) was 100%, regardless of their baseline HCV RNA level.
“I think this is remarkable. They cleared virus quite late and yet they went on to achieve HCV eradication. It highlights how little we really know about the treatment of individuals in this phase and that relying on HCV RNA levels may not tell the whole story. I think this is important data to suggest maybe when we treat acute hepatitis C we can use a shorter duration of treatment for that population. There are also other small studies testing 8 weeks of treatment in non–HIV-infected individuals with acute hepatitis C in which they also showed very high SVR rates,” the hepatologist said.
Copanelist Steven L. Flamm, MD, said that when he encounters a patient with acute HCV he, too, is prepared to offer treatment – he finds the available supporting evidence sufficiently compelling – but he often encounters a problem.
“Sometimes I’m blocked by insurance companies because this isn’t officially approved,” noted Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
“You’re right,” Dr. Terrault commented, “we have to make a pretty compelling argument to the insurer as to why we’re treating. But ‘treat to prevent transmission to others’ usually is successful in our hands.”
HCV in patients with end-stage renal disease
The product labeling for sofosbuvir (Sovaldi) says the drug’s safety and efficacy haven’t been established in patients with severe renal impairment or end-stage renal disease. However, a small multicenter study presented at the 2017 AASLD meeting demonstrated that 12 weeks of ledipasvir/sofosbuvir achieved a 100% SVR rate in patients with genotype 1 HCV and severe renal impairment, including some on dialysis, with no clinically meaningful change in estimated glomerular filtration rate or any signal of cardiac arrhythmia.
“The serum drug levels went up significantly, but reassuringly they saw no meaningful safety signals,” according to Dr. Terrault. “This, I think, is initial reassuring information that we were all very much waiting for.”
Still, as the AASLD/IDSA guidelines point out, ledipasvir/sofosbuvir is not a recommended option for HCV treatment in end-stage renal disease.
“In general, I think glecapravir/pibrentasvir [Mavyret] has become the go-to drug for patients who have renal dysfunction because it’s a pangenic regimen, it doesn’t require use of sofosbuvir, and there’s no dose adjustment. But I would say you could encounter situations where you might want to use sofosbuvir, and for me that situation is typically those direct-acting, antiviral-experienced patients who have failed other therapies and you really need to use sofosbuvir/velpatasvir/voxilaprevir [Vosevi] as your last or rescue therapy,” the hepatologist continued.
HCV in liver transplant recipients
“In the years before the direct-acting antivirals, treating transplant patients was always very challenging,” Dr. Terrault recalled. “They had very low response rates to therapy. That’s all gone away. Now we can say that liver transplant recipients who require treatment have response rates that are the same as in individuals who have not had a transplant. These patients are now being treated earlier and earlier after their transplant because you can do it safely.”
She pointed to a study presented at the 2017 AASLD meeting by Kosh Agarwal, MD, of Kings College London. It involved 79 adults with recurrent genotypes 1-4 HCV infection post–liver transplant who were treated with sofosbuvir/velpatasvir (Epclusa) for 12 weeks with a total SVR rate of 96%.
“The nice thing about sofosbuvir/velpatasvir is there are no drug-drug interactions with immunosuppressive drugs. Now it’s very easy to take care of these patients. The SVR rates are excellent,” Dr. Terrault observed.
The other combination that’s been studied specifically in liver transplant recipients, and in kidney transplant recipients as well, is glecapravir/pibrentasvir. In the MAGELLAN-2 study of 100 such patients with genotypes 1-6 HCV, the SVR rate was 99% with no drug-related adverse events leading to discontinuation.
Persons who inject drugs
The Centers for Disease Control and Prevention and the World Health Organization want HCV eradicated by 2030. If that’s going to happen, physicians will have to become more comfortable treating the disease in injectable drug users, a population with a high prevalence of HCV. Several studies have now shown that very high SVR rates can be achieved with direct-acting antiviral regimens as short as 8 weeks in these individuals, even if they are concurrently injecting drugs.
“There is increasing evidence that we should be doing more treatment in persons who inject drugs. Many of these individuals have very early disease and their response rates are excellent,” according to Dr. Terrault.
Moreover, their reinfection rates “are not outrageous,” she said: 1% or less in individuals who stopped injecting drugs decades prior to anti-HCV treatment, 5%-10% over the course of 3-5 years in those who continue injecting drugs after achieving SVR, and about 2% in those on methadone substitution therapy.
“These are very acceptable levels of reinfection if our goal is to move toward elimination of hepatitis C in this population,” she said.
She reported having no financial conflicts regarding her presentation.
MAUI, HAWAII – Treatment of acute rather than chronic hepatitis C infection is well worth considering in selected circumstances, Norah Terrault, MD, asserted at the Gastroenterology Updates, IBD, Liver Disease meeting.
This is not at present guideline-recommended therapy. Current American Association for the Study of Liver Disease/Infectious Diseases Society of America guidance states that while there is emerging data to support treatment of acute hepatitis C, the evidence isn’t yet sufficiently robust to support a particular regimen or duration. The guidelines currently recommend waiting 6 months to see if the acute infection resolves spontaneously, as happens in a minority of cases, or becomes chronic, at which point it becomes guideline-directed treatment time. But Dr. Terrault believes persuasive evidence to back treatment of acute hepatitis C infection (HCV) is forthcoming, and she noted that the guidelines leave the door ajar by stating, “There are instances wherein a clinician may decide that the benefits of early treatment outweigh waiting for possible spontaneous clearance.”
Treatment of acute HCV
Dr. Terrault deems treatment of acute HCV warranted in circumstances in which there is significant danger of transmission from the acutely infected individual to others. For example, health care providers with a needlestick HCV infection, injecting drug users, and men with acute HCV/HIV coinfection. She also treats acute HCV in patients with underlying chronic liver disease.
“Clearly, I wouldn’t want those individuals to have any worsening of their liver function, so I would treat them acutely,” explained Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
She cited as particularly impressive the results of the SWIFT-C trial presented by Suzanna Naggie, MD, of Duke University, Durham, N.C., at the 2017 AASLD annual meeting. In this modest-size, National Institutes of Health–sponsored, multicenter study of HIV-infected men with acute HCV coinfection, the sustained viral response (SVR) rate with 8 weeks of ledipasvir/sofosbuvir (Harvoni) was 100%, regardless of their baseline HCV RNA level.
“I think this is remarkable. They cleared virus quite late and yet they went on to achieve HCV eradication. It highlights how little we really know about the treatment of individuals in this phase and that relying on HCV RNA levels may not tell the whole story. I think this is important data to suggest maybe when we treat acute hepatitis C we can use a shorter duration of treatment for that population. There are also other small studies testing 8 weeks of treatment in non–HIV-infected individuals with acute hepatitis C in which they also showed very high SVR rates,” the hepatologist said.
Copanelist Steven L. Flamm, MD, said that when he encounters a patient with acute HCV he, too, is prepared to offer treatment – he finds the available supporting evidence sufficiently compelling – but he often encounters a problem.
“Sometimes I’m blocked by insurance companies because this isn’t officially approved,” noted Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
“You’re right,” Dr. Terrault commented, “we have to make a pretty compelling argument to the insurer as to why we’re treating. But ‘treat to prevent transmission to others’ usually is successful in our hands.”
HCV in patients with end-stage renal disease
The product labeling for sofosbuvir (Sovaldi) says the drug’s safety and efficacy haven’t been established in patients with severe renal impairment or end-stage renal disease. However, a small multicenter study presented at the 2017 AASLD meeting demonstrated that 12 weeks of ledipasvir/sofosbuvir achieved a 100% SVR rate in patients with genotype 1 HCV and severe renal impairment, including some on dialysis, with no clinically meaningful change in estimated glomerular filtration rate or any signal of cardiac arrhythmia.
“The serum drug levels went up significantly, but reassuringly they saw no meaningful safety signals,” according to Dr. Terrault. “This, I think, is initial reassuring information that we were all very much waiting for.”
Still, as the AASLD/IDSA guidelines point out, ledipasvir/sofosbuvir is not a recommended option for HCV treatment in end-stage renal disease.
“In general, I think glecapravir/pibrentasvir [Mavyret] has become the go-to drug for patients who have renal dysfunction because it’s a pangenic regimen, it doesn’t require use of sofosbuvir, and there’s no dose adjustment. But I would say you could encounter situations where you might want to use sofosbuvir, and for me that situation is typically those direct-acting, antiviral-experienced patients who have failed other therapies and you really need to use sofosbuvir/velpatasvir/voxilaprevir [Vosevi] as your last or rescue therapy,” the hepatologist continued.
HCV in liver transplant recipients
“In the years before the direct-acting antivirals, treating transplant patients was always very challenging,” Dr. Terrault recalled. “They had very low response rates to therapy. That’s all gone away. Now we can say that liver transplant recipients who require treatment have response rates that are the same as in individuals who have not had a transplant. These patients are now being treated earlier and earlier after their transplant because you can do it safely.”
She pointed to a study presented at the 2017 AASLD meeting by Kosh Agarwal, MD, of Kings College London. It involved 79 adults with recurrent genotypes 1-4 HCV infection post–liver transplant who were treated with sofosbuvir/velpatasvir (Epclusa) for 12 weeks with a total SVR rate of 96%.
“The nice thing about sofosbuvir/velpatasvir is there are no drug-drug interactions with immunosuppressive drugs. Now it’s very easy to take care of these patients. The SVR rates are excellent,” Dr. Terrault observed.
The other combination that’s been studied specifically in liver transplant recipients, and in kidney transplant recipients as well, is glecapravir/pibrentasvir. In the MAGELLAN-2 study of 100 such patients with genotypes 1-6 HCV, the SVR rate was 99% with no drug-related adverse events leading to discontinuation.
Persons who inject drugs
The Centers for Disease Control and Prevention and the World Health Organization want HCV eradicated by 2030. If that’s going to happen, physicians will have to become more comfortable treating the disease in injectable drug users, a population with a high prevalence of HCV. Several studies have now shown that very high SVR rates can be achieved with direct-acting antiviral regimens as short as 8 weeks in these individuals, even if they are concurrently injecting drugs.
“There is increasing evidence that we should be doing more treatment in persons who inject drugs. Many of these individuals have very early disease and their response rates are excellent,” according to Dr. Terrault.
Moreover, their reinfection rates “are not outrageous,” she said: 1% or less in individuals who stopped injecting drugs decades prior to anti-HCV treatment, 5%-10% over the course of 3-5 years in those who continue injecting drugs after achieving SVR, and about 2% in those on methadone substitution therapy.
“These are very acceptable levels of reinfection if our goal is to move toward elimination of hepatitis C in this population,” she said.
She reported having no financial conflicts regarding her presentation.
MAUI, HAWAII – Treatment of acute rather than chronic hepatitis C infection is well worth considering in selected circumstances, Norah Terrault, MD, asserted at the Gastroenterology Updates, IBD, Liver Disease meeting.
This is not at present guideline-recommended therapy. Current American Association for the Study of Liver Disease/Infectious Diseases Society of America guidance states that while there is emerging data to support treatment of acute hepatitis C, the evidence isn’t yet sufficiently robust to support a particular regimen or duration. The guidelines currently recommend waiting 6 months to see if the acute infection resolves spontaneously, as happens in a minority of cases, or becomes chronic, at which point it becomes guideline-directed treatment time. But Dr. Terrault believes persuasive evidence to back treatment of acute hepatitis C infection (HCV) is forthcoming, and she noted that the guidelines leave the door ajar by stating, “There are instances wherein a clinician may decide that the benefits of early treatment outweigh waiting for possible spontaneous clearance.”
Treatment of acute HCV
Dr. Terrault deems treatment of acute HCV warranted in circumstances in which there is significant danger of transmission from the acutely infected individual to others. For example, health care providers with a needlestick HCV infection, injecting drug users, and men with acute HCV/HIV coinfection. She also treats acute HCV in patients with underlying chronic liver disease.
“Clearly, I wouldn’t want those individuals to have any worsening of their liver function, so I would treat them acutely,” explained Dr. Terrault, professor of medicine and director of the Viral Hepatitis Center at the University of California, San Francisco.
She cited as particularly impressive the results of the SWIFT-C trial presented by Suzanna Naggie, MD, of Duke University, Durham, N.C., at the 2017 AASLD annual meeting. In this modest-size, National Institutes of Health–sponsored, multicenter study of HIV-infected men with acute HCV coinfection, the sustained viral response (SVR) rate with 8 weeks of ledipasvir/sofosbuvir (Harvoni) was 100%, regardless of their baseline HCV RNA level.
“I think this is remarkable. They cleared virus quite late and yet they went on to achieve HCV eradication. It highlights how little we really know about the treatment of individuals in this phase and that relying on HCV RNA levels may not tell the whole story. I think this is important data to suggest maybe when we treat acute hepatitis C we can use a shorter duration of treatment for that population. There are also other small studies testing 8 weeks of treatment in non–HIV-infected individuals with acute hepatitis C in which they also showed very high SVR rates,” the hepatologist said.
Copanelist Steven L. Flamm, MD, said that when he encounters a patient with acute HCV he, too, is prepared to offer treatment – he finds the available supporting evidence sufficiently compelling – but he often encounters a problem.
“Sometimes I’m blocked by insurance companies because this isn’t officially approved,” noted Dr. Flamm, professor of medicine and chief of the hepatology program at Northwestern University, Chicago.
“You’re right,” Dr. Terrault commented, “we have to make a pretty compelling argument to the insurer as to why we’re treating. But ‘treat to prevent transmission to others’ usually is successful in our hands.”
HCV in patients with end-stage renal disease
The product labeling for sofosbuvir (Sovaldi) says the drug’s safety and efficacy haven’t been established in patients with severe renal impairment or end-stage renal disease. However, a small multicenter study presented at the 2017 AASLD meeting demonstrated that 12 weeks of ledipasvir/sofosbuvir achieved a 100% SVR rate in patients with genotype 1 HCV and severe renal impairment, including some on dialysis, with no clinically meaningful change in estimated glomerular filtration rate or any signal of cardiac arrhythmia.
“The serum drug levels went up significantly, but reassuringly they saw no meaningful safety signals,” according to Dr. Terrault. “This, I think, is initial reassuring information that we were all very much waiting for.”
Still, as the AASLD/IDSA guidelines point out, ledipasvir/sofosbuvir is not a recommended option for HCV treatment in end-stage renal disease.
“In general, I think glecapravir/pibrentasvir [Mavyret] has become the go-to drug for patients who have renal dysfunction because it’s a pangenic regimen, it doesn’t require use of sofosbuvir, and there’s no dose adjustment. But I would say you could encounter situations where you might want to use sofosbuvir, and for me that situation is typically those direct-acting, antiviral-experienced patients who have failed other therapies and you really need to use sofosbuvir/velpatasvir/voxilaprevir [Vosevi] as your last or rescue therapy,” the hepatologist continued.
HCV in liver transplant recipients
“In the years before the direct-acting antivirals, treating transplant patients was always very challenging,” Dr. Terrault recalled. “They had very low response rates to therapy. That’s all gone away. Now we can say that liver transplant recipients who require treatment have response rates that are the same as in individuals who have not had a transplant. These patients are now being treated earlier and earlier after their transplant because you can do it safely.”
She pointed to a study presented at the 2017 AASLD meeting by Kosh Agarwal, MD, of Kings College London. It involved 79 adults with recurrent genotypes 1-4 HCV infection post–liver transplant who were treated with sofosbuvir/velpatasvir (Epclusa) for 12 weeks with a total SVR rate of 96%.
“The nice thing about sofosbuvir/velpatasvir is there are no drug-drug interactions with immunosuppressive drugs. Now it’s very easy to take care of these patients. The SVR rates are excellent,” Dr. Terrault observed.
The other combination that’s been studied specifically in liver transplant recipients, and in kidney transplant recipients as well, is glecapravir/pibrentasvir. In the MAGELLAN-2 study of 100 such patients with genotypes 1-6 HCV, the SVR rate was 99% with no drug-related adverse events leading to discontinuation.
Persons who inject drugs
The Centers for Disease Control and Prevention and the World Health Organization want HCV eradicated by 2030. If that’s going to happen, physicians will have to become more comfortable treating the disease in injectable drug users, a population with a high prevalence of HCV. Several studies have now shown that very high SVR rates can be achieved with direct-acting antiviral regimens as short as 8 weeks in these individuals, even if they are concurrently injecting drugs.
“There is increasing evidence that we should be doing more treatment in persons who inject drugs. Many of these individuals have very early disease and their response rates are excellent,” according to Dr. Terrault.
Moreover, their reinfection rates “are not outrageous,” she said: 1% or less in individuals who stopped injecting drugs decades prior to anti-HCV treatment, 5%-10% over the course of 3-5 years in those who continue injecting drugs after achieving SVR, and about 2% in those on methadone substitution therapy.
“These are very acceptable levels of reinfection if our goal is to move toward elimination of hepatitis C in this population,” she said.
She reported having no financial conflicts regarding her presentation.
EXPERT ANALYSIS FROM GUILD 2018
Putting IBD medication risks into perspective
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
MAUI, HAWAII – Prolonged corticosteroid therapy for inflammatory bowel disease (IBD) was associated with a significantly increased mortality risk compared with anti–tumor necrosis factor therapy in a landmark study spotlighted by Edward V. Loftus Jr., MD, at the Gastroenterology Updates, IBD, Liver Disease meeting.
This was one of several key studies on safety issues involving IBD medications published in the past year. Others highlighted by Dr. Loftus and copanelist William J. Sandborn, MD, included a study that provided persuasive evidence that TNF inhibitors modestly increase lymphoma risk in IBD patients to a degree similar to that of thiopurines, and several reports addressing the question of whether preoperative use of vedolizumab in patients undergoing major abdominal operations for IBD boosts postoperative infection risk.
Mortality impact of prolonged steroids vs. anti-TNF therapy
That will come as an unpleasant surprise to many physicians. There is a widespread reluctance to turn to continuous chronic immunosuppression via anti-TNF therapy in patients with challenging IBD, particularly in elderly individuals with multiple comorbid conditions. Many physicians have heard and read so much about the biologics’ risks of serious adverse events that they opt instead for multiple courses of corticosteroids for disease control. This is a serious mistake, emphasized Dr. Loftus, professor of medicine and director of the IBD Interest Group at the Mayo Clinic in Rochester, Minn.
“When you say, ‘Oh, I’ll just give that patient another prednisone taper, he doesn’t want to start taking a TNF inhibitor,’ you’re actually doing the patient harm. You’re actually affecting the patient’s life expectancy when you do that,” he declared. “The message is, yes, steroids are cheap, steroids are easy, nobody’s afraid of steroids, but you should be afraid of steroids.”
The 1,879 Crohn’s disease patients who entered the cohort as new users of anti-TNF therapy had a subsequent mortality incidence rate of 21.4 per 1,000 person-years, compared with a rate of 30.1 per 1,000 person-years in the 7,694 who entered the study period as prolonged steroid users. In a multivariate analysis accounting for 57 potential confounding factors, this translated to a highly significant 22% relative risk reduction in mortality in the patients who went with anti-TNF therapy (Am J Gastroenterol. 2018 Jan 16. doi: 10.1038/ajg.2017.479).
A similar trend was seen in the ulcerative colitis cohort. The 459 ulcerative colitis patients who entered the cohort as new anti-TNF therapy users had a mortality incidence rate of 23.0 per 1,000 person-years, compared with a rate of 30.9 in the 3,224 who received more than 3,000 mg of prednisone in the next 12 months. This represented a 14% relative risk reduction, although this favorable trend did not achieve statistical significance, perhaps because of the smaller size of the ulcerative colitis cohort.
In addition to demonstrably greater life expectancy, anti-TNF therapy offered additional benefits: a 32% reduction in the risk of major adverse cardiovascular events and a 46% lower incidence of hip fracture.
Dr. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, spun the study data another way: “It shows the number needed to kill is 33. So for every 33 patients you put on prolonged corticosteroids, you’re killing one extra patient by doing that. Of course, you probably blame it on their age and comorbidities, but this is it. This is the data.”
TNF blockers, thiopurines, and lymphoma
The use of thiopurines for treatment of IBD is widely recognized to be associated with a small but real increased risk of lymphoma. Now a large French national study has demonstrated for the first time that anti-TNF therapy for IBD is also associated with an increased risk that needs to be discussed with patients. And in IBD patients on combination therapy with both classes of medication, that risk jumps to 6.1-fold greater than in unexposed IBD patients (JAMA 2017 Nov 7;318[17]:1679-86).
Dr. Loftus and Dr. Sandborn urged their colleagues to keep this increased risk in perspective in counseling patients by focusing on the modest absolute increase in risk rather than the scarier-sounding relative risk. Notably, two-thirds of lymphomas in the French study occurred in patients not on thiopurines or anti-TNF agents.
“The most interesting thing to me is that we worry and worry about lymphoma, and guess what? In this study and in multiple other studies, the majority of lymphomas occurring in IBD patients have nothing to do with their medications. They’re due to the usual risk factors for lymphoma, which include age and male gender,” Dr. Loftus observed.
The French study included more than 189,000 IBD patients followed for a median of 6.7 years, during which 336 cases of lymphoma occurred. The incidence rate was 0.26 cases per 1,000 person-years in unexposed patients. The rate was significantly higher at 0.54 per 1,000 person-years in those on thiopurine monotherapy, increased to a similar extent at 0.41 cases per 1,000 person-years in patients on anti-TNF monotherapy, and 0.95 per 1,000 person-years in those on combination therapy.
In a multivariate analysis, the lymphoma risk was an adjusted 2.6-fold greater in patients exposed to thiopurine monotherapy than in unexposed patients, 2.41-fold greater in patients exposed to anti-TNF monotherapy, and 6.1-fold greater in those exposed to combination therapy.
“The point I want to make is the lymphoma rates in the thiopurine monotherapy and anti-TNF monotherapy groups are not significantly different. So the claim that’s been out there that the increased lymphoma risk in IBD patients can be completely explained by thiopurines is wrong. This study is showing us that with anti-TNF monotherapy there is still a low-level risk of lymphoma,” Dr. Loftus said.
“It is somewhat eyebrow-raising when you see that relative risk of 6.1, and that’s what patients are going to focus on, but when you counsel patients you have to redirect them to the absolute risk. You can say, ‘Even on combination therapy, your risk is 1 in 1,000,’ ” the gastroenterologist said.
Dr. Sandborn said the lymphoma signal hadn’t been spotted previously because the individual registries of IBD patients on anti-TNF agents are too small to allow for identification of a small increase in risk. The French investigators overcame that limitation by tapping into the country’s national health care system.
“This is a huge dataset and I think the message is unequivocal,” Dr. Sandborn said.
He noted that strongly risk-averse patients may find ustekinumab (Stelara) and vedolizumab (Entyvio) to be attractive treatment options. Neither has any link to lymphoma.
Preoperative vedolizumab and postoperative infection risk
“The overall safety profile of vedolizumab is pretty good,” Dr. Loftus observed. “The one unanswered question is its safety when used within 8-12 weeks of a major abdominal operation.”
It’s a clinically relevant question because vedolizumab selectively inhibits leukocyte migration into the intestinal tract, which could provide a mechanism for impaired postoperative wound healing in patients undergoing major abdominal surgery. And sooner or later a high proportion of IBD patients have a major abdominal operation.
Dr. Loftus and his coinvestigators kicked off a controversy by reporting a 37% incidence of surgical site infections in IBD patients who received vedolizumab within 30 days of a major abdominal operation in a retrospective chart review of the Mayo Clinic experience, a postoperative infection rate strikingly higher than in their patients on anti-TNF or nonbiologic therapy (J Crohns Colitis. 2017 Feb;11[2]:185-90).
This prompted investigators at the University of Chicago to look retrospectively at their institutional experience. They reported no increased risk in IBD patients on vedolizumab (Am J Gastroenterol. 2017 Sep;112[9]:1423-9). Neither did Belgian gastroenterologists at the Catholic University of Leuven (J Crohns Colitis. 2017 Oct 27;11[11]:1353-61).
Most recently, the Mayo Clinic group along with gastroenterologists at three other U.S. centers collaborated in a multicenter retrospective review of 146 adult IBD patients who received vedolizumab within 12 weeks before major abdominal surgery and 289 who received anti-TNF therapy. In a multivariate analysis, perioperative use of vedolizumab was independently associated with a 5.8-fold increased risk of developing a surgical site infection (J Inflamm Bowel Dis. 2018 Mar 19. doi: 10.1093/ibd/izx076).
Dr. Sandborn, who like Dr. Loftus was a coauthor of the multicenter study, drew back to look at the big picture.
“Is vedolizumab really causal? I doubt it, although it’s remotely possible. But I bet vedolizumab therapy is a really good marker for sick patients, and sick patients have worse operative outcomes, so we ought to be conservative with their surgery. My read of this is this [postoperative infection risk] isn’t unique to vedolizumab. Just be careful with sick patients when you’re operating and do more conservative surgeries,” he said.
Both gastroenterologists reported serving as consultants to and receiving research grants from numerous pharmaceutical companies.
EXPERT ANALYSIS FROM GUILD 2018
Management of IBD in older patients
MAUI, HAWAII – Misconceptions abound regarding inflammatory bowel disease (IBD) in the elderly, Uma Mahadevan, MD, said at the Gastroenterology, IBD, Liver Disease meeting.
In addition to dispelling these notions, she outlined her favored treatment strategies in older IBD patients.
IBD in older individuals is actually very common
A Swedish national registry study of all 27,834 patients diagnosed with IBD in that country during 2006-2013 showed that 23% were first diagnosed at age 60 or older, with an incidence rate of 35 per 100,000 person-years for Crohn’s disease and 19 per 100,000 person-years for ulcerative colitis (Gastroenterology. 2018 Feb;154[3]:518-528e15.
“One in four to one in five of your new IBD patients are going to be over the age of 60. That’s pretty impressive,” Dr. Mahadevan said.
Genetics is less important in the pathophysiology of older-onset IBD. In one study, a positive family history of Crohn’s disease was present in 16% of affected patients under age 17 but in only 7% of those with disease onset after age 60. Similarly, a positive family history was present in 13% of ulcerative colitis patients under age 17 but in just 3% of those with onset after 60.
If genetics plays a minimal role in elderly-onset IBD, then what are the drivers? Two contributors are immunosenescence and age-related changes in the gut microbiota. Aging is accompanied by diminished T-cell responses marked by impaired memory T cells and a reduction in naive T-cell precursors.
“As the rest of you starts to age and sag, so do your T cells,” the gastroenterologist quipped.
Aging also brings physiologic alterations in gastrointestinal motility and transit. Together with changes in diet and an increase in comorbid conditions, with consequent need for a raft of medications, the end result is reduced abundance and diversity of anaerobes in the microbiota. This has immunologic implications.
Elderly IBD isn’t less severe
During a median of 4.2 years of follow-up in the Swedish national study, patients diagnosed with IBD after age 60 had more IBD-related hospitalizations and overall health care utilization than those diagnosed at ages 18-59. The incidence of extraintestinal disease manifestations was similar in the elderly and younger-adult patients; however, bowel surgery was significantly more common in the elderly patients, with a 13% rate after 5 years versus 10% in patients diagnosed as younger adults.
Moreover, elderly patients were less likely to use biologic agents and received much more systemic corticosteroid therapy than younger adults. These findings suggest that the reason elderly patients aren’t using biologics isn’t because their disease is milder, but rather because their physicians are afraid of using biologics. Due to their overconcern about risks of malignancy and serious infections, many physicians opt instead for repeated courses of corticosteroids, which is an inappropriate treatment strategy, Dr. Mahadevan said.
A cross-sectional U.S. study utilizing data from the National Inpatient Sample demonstrated that 25% of all patients hospitalized for IBD were above age 65. The study by investigators at the Medical College of Wisconsin, Milwaukee, found that age greater than 65 was an independent risk factor for in-hospital mortality. Indeed, even after adjustment for comorbidity in a multivariate logistic regression analysis, IBD patients above age 65 had a sobering 3.9-fold greater risk of in-hospital mortality (Inflamm Bowel Dis. 2009 Feb;15[2]182-9).
Another piece of evidence that elderly-onset IBD isn’t less severe comes from a Canadian cohort study of all newly diagnosed cases of IBD in Ontario during 1999-2008. The elderly-onset ulcerative colitis patients were one-third more likely to undergo IBD-related surgery than those diagnosed at ages 18-40. Older-onset Crohn’s disease patients weren’t more likely to have IBD-related operations than younger-onset patients; however, IBD-specific mortality was significantly greater in elderly-onset Crohn’s disease patients than in those diagnosed in middle age or as young adults, by a margin of 33.1 cases to 5.6 cases to 1.0 case per 10,000 person-years (Inflamm Bowel Dis. 2017 Feb;23[2]:218-23).
Treatment of IBD in the elderly
Dr. Mahadevan emphasized that, if elderly patients need biologic therapy because their disease isn’t being adequately controlled with more conservative management strategies, then they should get it. The higher rates of IBD-related surgery and in-hospital mortality in elderly IBD patients argue in favor of that strategy in order to keep them out of the hospital and optimize quality of life.
Her go-to biologics in elderly IBD patients are vedolizumab (Entyvio) and ustekinumab (Stelara): “In my older patients I reach for these two first.”
This is because of the well-documented, excellent safety profiles of those two biologics, which are particularly relevant in an elderly population at increased background risk for lymphoma and serious infections. A pooled analysis of three clinical trials of ustekinumab in induction therapy for Crohn’s disease showed an adverse event risk no different from placebo (J Comp Eff Res. 2017 Oct;6[7]:601-12). Vedolizumab, like ustekinumab, doesn’t carry a black box warning for lymphoma, and the biologic had no increase in any infections in an analysis of six clinical trials entailing more than 4,800 person-years of vedolizumab exposure (Gut. 2017 May;66[5]:839-51).
She provided three illustrative clinical scenarios, each involving a 62-year-old fit and active patient. If that patient had newly diagnosed moderate to severe ulcerative colitis, had failed on 5-aminosalicylic acid, and had good symptomatic control on prednisone, that’s someone who needs a steroid-sparing drug, and she would choose vedolizumab based upon its track record. If that active 62-year-old had moderate to severe ileal and perianal Crohn’s disease, she would opt for ustekinumab or a tumor necrosis factor inhibitor. But if that older patient was hospitalized with newly diagnosed severe ulcerative colitis that was only partially responsive to intravenous steroids, she would eschew vedolizumab and ustekinumab and turn to infliximab (Remicade).
“That patient should get infliximab just like a 32-year-old would. You need to give this patient the best shot [at avoiding colectomy], and to this day the data still supports infliximab in that population,” Dr. Mahadevan said.
Complicating management in the elderly are the commonly encountered challenges posed by polypharmacy, frailty, history of skin cancer or solid organ tumors, and heart failure. In one study, older patients with Crohn’s disease were on an average of 10 medications, ulcerative colitis patients on nine. Forty percent of the patients had potential drug-drug interactions involving their IBD medications (Inflamm Bowel Dis. 2015 Jun;21[6]:1392-400). These are situations that require individually tailored immunosuppressive decision-making.
Dr. Mahadevan reported receiving research support from the Crohn’s and Colitis Foundation, Celgene, and Pfizer and serving as a consultant to those pharmaceutical companies as well as AbbVie, Janssen, and Takeda.
MAUI, HAWAII – Misconceptions abound regarding inflammatory bowel disease (IBD) in the elderly, Uma Mahadevan, MD, said at the Gastroenterology, IBD, Liver Disease meeting.
In addition to dispelling these notions, she outlined her favored treatment strategies in older IBD patients.
IBD in older individuals is actually very common
A Swedish national registry study of all 27,834 patients diagnosed with IBD in that country during 2006-2013 showed that 23% were first diagnosed at age 60 or older, with an incidence rate of 35 per 100,000 person-years for Crohn’s disease and 19 per 100,000 person-years for ulcerative colitis (Gastroenterology. 2018 Feb;154[3]:518-528e15.
“One in four to one in five of your new IBD patients are going to be over the age of 60. That’s pretty impressive,” Dr. Mahadevan said.
Genetics is less important in the pathophysiology of older-onset IBD. In one study, a positive family history of Crohn’s disease was present in 16% of affected patients under age 17 but in only 7% of those with disease onset after age 60. Similarly, a positive family history was present in 13% of ulcerative colitis patients under age 17 but in just 3% of those with onset after 60.
If genetics plays a minimal role in elderly-onset IBD, then what are the drivers? Two contributors are immunosenescence and age-related changes in the gut microbiota. Aging is accompanied by diminished T-cell responses marked by impaired memory T cells and a reduction in naive T-cell precursors.
“As the rest of you starts to age and sag, so do your T cells,” the gastroenterologist quipped.
Aging also brings physiologic alterations in gastrointestinal motility and transit. Together with changes in diet and an increase in comorbid conditions, with consequent need for a raft of medications, the end result is reduced abundance and diversity of anaerobes in the microbiota. This has immunologic implications.
Elderly IBD isn’t less severe
During a median of 4.2 years of follow-up in the Swedish national study, patients diagnosed with IBD after age 60 had more IBD-related hospitalizations and overall health care utilization than those diagnosed at ages 18-59. The incidence of extraintestinal disease manifestations was similar in the elderly and younger-adult patients; however, bowel surgery was significantly more common in the elderly patients, with a 13% rate after 5 years versus 10% in patients diagnosed as younger adults.
Moreover, elderly patients were less likely to use biologic agents and received much more systemic corticosteroid therapy than younger adults. These findings suggest that the reason elderly patients aren’t using biologics isn’t because their disease is milder, but rather because their physicians are afraid of using biologics. Due to their overconcern about risks of malignancy and serious infections, many physicians opt instead for repeated courses of corticosteroids, which is an inappropriate treatment strategy, Dr. Mahadevan said.
A cross-sectional U.S. study utilizing data from the National Inpatient Sample demonstrated that 25% of all patients hospitalized for IBD were above age 65. The study by investigators at the Medical College of Wisconsin, Milwaukee, found that age greater than 65 was an independent risk factor for in-hospital mortality. Indeed, even after adjustment for comorbidity in a multivariate logistic regression analysis, IBD patients above age 65 had a sobering 3.9-fold greater risk of in-hospital mortality (Inflamm Bowel Dis. 2009 Feb;15[2]182-9).
Another piece of evidence that elderly-onset IBD isn’t less severe comes from a Canadian cohort study of all newly diagnosed cases of IBD in Ontario during 1999-2008. The elderly-onset ulcerative colitis patients were one-third more likely to undergo IBD-related surgery than those diagnosed at ages 18-40. Older-onset Crohn’s disease patients weren’t more likely to have IBD-related operations than younger-onset patients; however, IBD-specific mortality was significantly greater in elderly-onset Crohn’s disease patients than in those diagnosed in middle age or as young adults, by a margin of 33.1 cases to 5.6 cases to 1.0 case per 10,000 person-years (Inflamm Bowel Dis. 2017 Feb;23[2]:218-23).
Treatment of IBD in the elderly
Dr. Mahadevan emphasized that, if elderly patients need biologic therapy because their disease isn’t being adequately controlled with more conservative management strategies, then they should get it. The higher rates of IBD-related surgery and in-hospital mortality in elderly IBD patients argue in favor of that strategy in order to keep them out of the hospital and optimize quality of life.
Her go-to biologics in elderly IBD patients are vedolizumab (Entyvio) and ustekinumab (Stelara): “In my older patients I reach for these two first.”
This is because of the well-documented, excellent safety profiles of those two biologics, which are particularly relevant in an elderly population at increased background risk for lymphoma and serious infections. A pooled analysis of three clinical trials of ustekinumab in induction therapy for Crohn’s disease showed an adverse event risk no different from placebo (J Comp Eff Res. 2017 Oct;6[7]:601-12). Vedolizumab, like ustekinumab, doesn’t carry a black box warning for lymphoma, and the biologic had no increase in any infections in an analysis of six clinical trials entailing more than 4,800 person-years of vedolizumab exposure (Gut. 2017 May;66[5]:839-51).
She provided three illustrative clinical scenarios, each involving a 62-year-old fit and active patient. If that patient had newly diagnosed moderate to severe ulcerative colitis, had failed on 5-aminosalicylic acid, and had good symptomatic control on prednisone, that’s someone who needs a steroid-sparing drug, and she would choose vedolizumab based upon its track record. If that active 62-year-old had moderate to severe ileal and perianal Crohn’s disease, she would opt for ustekinumab or a tumor necrosis factor inhibitor. But if that older patient was hospitalized with newly diagnosed severe ulcerative colitis that was only partially responsive to intravenous steroids, she would eschew vedolizumab and ustekinumab and turn to infliximab (Remicade).
“That patient should get infliximab just like a 32-year-old would. You need to give this patient the best shot [at avoiding colectomy], and to this day the data still supports infliximab in that population,” Dr. Mahadevan said.
Complicating management in the elderly are the commonly encountered challenges posed by polypharmacy, frailty, history of skin cancer or solid organ tumors, and heart failure. In one study, older patients with Crohn’s disease were on an average of 10 medications, ulcerative colitis patients on nine. Forty percent of the patients had potential drug-drug interactions involving their IBD medications (Inflamm Bowel Dis. 2015 Jun;21[6]:1392-400). These are situations that require individually tailored immunosuppressive decision-making.
Dr. Mahadevan reported receiving research support from the Crohn’s and Colitis Foundation, Celgene, and Pfizer and serving as a consultant to those pharmaceutical companies as well as AbbVie, Janssen, and Takeda.
MAUI, HAWAII – Misconceptions abound regarding inflammatory bowel disease (IBD) in the elderly, Uma Mahadevan, MD, said at the Gastroenterology, IBD, Liver Disease meeting.
In addition to dispelling these notions, she outlined her favored treatment strategies in older IBD patients.
IBD in older individuals is actually very common
A Swedish national registry study of all 27,834 patients diagnosed with IBD in that country during 2006-2013 showed that 23% were first diagnosed at age 60 or older, with an incidence rate of 35 per 100,000 person-years for Crohn’s disease and 19 per 100,000 person-years for ulcerative colitis (Gastroenterology. 2018 Feb;154[3]:518-528e15.
“One in four to one in five of your new IBD patients are going to be over the age of 60. That’s pretty impressive,” Dr. Mahadevan said.
Genetics is less important in the pathophysiology of older-onset IBD. In one study, a positive family history of Crohn’s disease was present in 16% of affected patients under age 17 but in only 7% of those with disease onset after age 60. Similarly, a positive family history was present in 13% of ulcerative colitis patients under age 17 but in just 3% of those with onset after 60.
If genetics plays a minimal role in elderly-onset IBD, then what are the drivers? Two contributors are immunosenescence and age-related changes in the gut microbiota. Aging is accompanied by diminished T-cell responses marked by impaired memory T cells and a reduction in naive T-cell precursors.
“As the rest of you starts to age and sag, so do your T cells,” the gastroenterologist quipped.
Aging also brings physiologic alterations in gastrointestinal motility and transit. Together with changes in diet and an increase in comorbid conditions, with consequent need for a raft of medications, the end result is reduced abundance and diversity of anaerobes in the microbiota. This has immunologic implications.
Elderly IBD isn’t less severe
During a median of 4.2 years of follow-up in the Swedish national study, patients diagnosed with IBD after age 60 had more IBD-related hospitalizations and overall health care utilization than those diagnosed at ages 18-59. The incidence of extraintestinal disease manifestations was similar in the elderly and younger-adult patients; however, bowel surgery was significantly more common in the elderly patients, with a 13% rate after 5 years versus 10% in patients diagnosed as younger adults.
Moreover, elderly patients were less likely to use biologic agents and received much more systemic corticosteroid therapy than younger adults. These findings suggest that the reason elderly patients aren’t using biologics isn’t because their disease is milder, but rather because their physicians are afraid of using biologics. Due to their overconcern about risks of malignancy and serious infections, many physicians opt instead for repeated courses of corticosteroids, which is an inappropriate treatment strategy, Dr. Mahadevan said.
A cross-sectional U.S. study utilizing data from the National Inpatient Sample demonstrated that 25% of all patients hospitalized for IBD were above age 65. The study by investigators at the Medical College of Wisconsin, Milwaukee, found that age greater than 65 was an independent risk factor for in-hospital mortality. Indeed, even after adjustment for comorbidity in a multivariate logistic regression analysis, IBD patients above age 65 had a sobering 3.9-fold greater risk of in-hospital mortality (Inflamm Bowel Dis. 2009 Feb;15[2]182-9).
Another piece of evidence that elderly-onset IBD isn’t less severe comes from a Canadian cohort study of all newly diagnosed cases of IBD in Ontario during 1999-2008. The elderly-onset ulcerative colitis patients were one-third more likely to undergo IBD-related surgery than those diagnosed at ages 18-40. Older-onset Crohn’s disease patients weren’t more likely to have IBD-related operations than younger-onset patients; however, IBD-specific mortality was significantly greater in elderly-onset Crohn’s disease patients than in those diagnosed in middle age or as young adults, by a margin of 33.1 cases to 5.6 cases to 1.0 case per 10,000 person-years (Inflamm Bowel Dis. 2017 Feb;23[2]:218-23).
Treatment of IBD in the elderly
Dr. Mahadevan emphasized that, if elderly patients need biologic therapy because their disease isn’t being adequately controlled with more conservative management strategies, then they should get it. The higher rates of IBD-related surgery and in-hospital mortality in elderly IBD patients argue in favor of that strategy in order to keep them out of the hospital and optimize quality of life.
Her go-to biologics in elderly IBD patients are vedolizumab (Entyvio) and ustekinumab (Stelara): “In my older patients I reach for these two first.”
This is because of the well-documented, excellent safety profiles of those two biologics, which are particularly relevant in an elderly population at increased background risk for lymphoma and serious infections. A pooled analysis of three clinical trials of ustekinumab in induction therapy for Crohn’s disease showed an adverse event risk no different from placebo (J Comp Eff Res. 2017 Oct;6[7]:601-12). Vedolizumab, like ustekinumab, doesn’t carry a black box warning for lymphoma, and the biologic had no increase in any infections in an analysis of six clinical trials entailing more than 4,800 person-years of vedolizumab exposure (Gut. 2017 May;66[5]:839-51).
She provided three illustrative clinical scenarios, each involving a 62-year-old fit and active patient. If that patient had newly diagnosed moderate to severe ulcerative colitis, had failed on 5-aminosalicylic acid, and had good symptomatic control on prednisone, that’s someone who needs a steroid-sparing drug, and she would choose vedolizumab based upon its track record. If that active 62-year-old had moderate to severe ileal and perianal Crohn’s disease, she would opt for ustekinumab or a tumor necrosis factor inhibitor. But if that older patient was hospitalized with newly diagnosed severe ulcerative colitis that was only partially responsive to intravenous steroids, she would eschew vedolizumab and ustekinumab and turn to infliximab (Remicade).
“That patient should get infliximab just like a 32-year-old would. You need to give this patient the best shot [at avoiding colectomy], and to this day the data still supports infliximab in that population,” Dr. Mahadevan said.
Complicating management in the elderly are the commonly encountered challenges posed by polypharmacy, frailty, history of skin cancer or solid organ tumors, and heart failure. In one study, older patients with Crohn’s disease were on an average of 10 medications, ulcerative colitis patients on nine. Forty percent of the patients had potential drug-drug interactions involving their IBD medications (Inflamm Bowel Dis. 2015 Jun;21[6]:1392-400). These are situations that require individually tailored immunosuppressive decision-making.
Dr. Mahadevan reported receiving research support from the Crohn’s and Colitis Foundation, Celgene, and Pfizer and serving as a consultant to those pharmaceutical companies as well as AbbVie, Janssen, and Takeda.
EXPERT ANALYSIS FROM GUILD 2018