Red blood cells

Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.

The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.

The researchers described the model in PNAS.

Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.

More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.

In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.

Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.

“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.

“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”

In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.

A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.

The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.

Red blood cells

Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.

The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.

The researchers described the model in PNAS.

Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.

More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.

In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.

Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.

“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.

“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”

In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.

A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.

The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.

Red blood cells

Researchers have created a computer model that shows how tiny slits in the spleen prevent old, diseased, or misshapen red blood cells from re-entering the bloodstream.

The team says the model can be used to study the spleen’s role in controlling diseases that affect the size and structure of red blood cells—such as sickle cell anemia, thalassemia, and malaria—and to develop new diagnostics and therapeutics for these diseases.

The researchers described the model in PNAS.

Previous studies have shown that part of the spleen’s filtration process relies on having red blood cells squeeze through tiny slits between the endothelial cells that line the spleen’s blood vessels. These “interendothelial slits” are no larger than 1.2 µm tall, 4 µm wide, and 1.9 µm deep.

More rigid and misshapen blood cells might not be able to pass through these narrow passages. And this process cannot be observed in vivo because of the minute size of the slits.

In order to “see” how the interendothelial slits regulate red blood cell circulation, the researchers created a computer simulation based on dissipative particle dynamics, a modeling method.

Their model allowed the team to determine the range of cell sizes and shapes that could fit through the slits. The range closely mirrored the range of sizes and shapes for healthy red blood cells, indicating that only healthy cells should be able to pass through the slits.

“The computational and analytical models from this work, along with a variety of experimental observations, point to a more detailed picture of how the physiology of the human spleen likely influences several key geometrical characteristics of red blood cells,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.

“They also offer better understanding of how the circulatory bottleneck for the red blood cell in the spleen could affect a variety of acute and chronic disease states arising from hereditary disorders, human cancers, and infectious diseases, with implications for therapeutic interventions and drug efficacy assays.”

In addition to giving researchers a better picture of how the spleen functions, the findings provide new insights into drug treatments.

A class of drugs currently in development for treating malaria alters the shape of red blood cells infected with malaria, theoretically preventing them from passing through interendothelial slits. One such drug, spiroindoline KAE609, is in clinical trials.

The researchers’ results might also explain why artemisinin-based antimalarial drugs, which stiffen healthy and malaria-infected red blood cells, can lead to severe anemia.

T cells

Image courtesy of NIAID

Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.

The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.

There was 1 adverse event considered possibly related to the treatment.

The researchers reported these results in The Journal of Clinical Investigation.

The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.

“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.

He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).

The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.

Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×10⁸ to 2×10⁸ κ.CAR T cells/m²).

“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.

One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.

Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.

Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.

“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.

T cells

Image courtesy of NIAID

Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.

The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.

There was 1 adverse event considered possibly related to the treatment.

The researchers reported these results in The Journal of Clinical Investigation.

The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.

“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.

He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).

The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.

Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×10⁸ to 2×10⁸ κ.CAR T cells/m²).

“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.

One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.

Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.

Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.

“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.

T cells

Image courtesy of NIAID

Results of a phase 1 study suggest that chimeric antigen receptor T cells specific for the κ light chain (κ.CAR T cells) can produce responses in patients with relapsed or refractory B-cell malignancies, largely without side effects.

The therapy induced complete and partial responses in some patients with non-Hodgkin lymphoma (NHL), and it allowed other patients with chronic lymphocytic leukemia (CLL) or multiple myeloma (MM) to maintain stable disease.

There was 1 adverse event considered possibly related to the treatment.

The researchers reported these results in The Journal of Clinical Investigation.

The κ.CAR T cells were designed to recognize κ-restricted cells and spare normal B cells expressing the nontargeted λ light chain.

“We reasoned that targeting the light chain expressed by malignant B cells should efficiently kill tumor cells while sparing normal B cells expressing the other type of light chain,” said study author Carlos Ramos, MD, of Baylor College of Medicine in Houston, Texas.

He and his colleagues tested the κ.CAR T cells in 16 patients with relapsed or refractory κ+ NHL (n=7), CLL (n=2), or MM (n=7).

The team isolated T cells from these patients and modified the cells so they could target the κ light chain on the surface of malignant B cells. The modified T cells were infused back into the patients, and each patient was monitored for disease progression and side effects.

Eleven patients stopped receiving other treatments at least 4 weeks prior to T-cell infusion. Six patients without lymphopenia received cyclophosphamide at 12.5 mg/kg 4 days before κ.CAR T-cell infusion (0.2×10⁸ to 2×10⁸ κ.CAR T cells/m²).

“We found the treatment to be feasible and safe at all the dose levels studied,” Dr Ramos said.

One MM patient had grade 3 lymphopenia that was deemed possibly related to treatment, but none of the other adverse events were thought to result from the κ.CAR T cells.

Two patients with NHL achieved a complete response to treatment, 1 lasting more than 32 months and the other lasting 6 weeks. A third NHL patient had a partial response lasting 3 months, and a CLL patient had stable disease lasting 6 weeks.

Five of the 7 MM patients had stable disease, 3 lasting 6 weeks, 1 lasting 17 months, and 1 lasting 24 months.

“Our approach, although we are still optimizing it, offers a new possibility for patients in whom other treatments have not been successful,” Dr Ramos concluded.

Daratumumab (Darzalex)

Photo courtesy of Janssen

Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.

The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.

An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Studies of daratumumab

The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.

Daratumumab (Darzalex)

Photo courtesy of Janssen

Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.

The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.

An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Studies of daratumumab

The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.

Daratumumab (Darzalex)

Photo courtesy of Janssen

Health Canada has granted conditional approval, or a Notice of Compliance with Conditions (NOC/c), for daratumumab (Darzalex), a monoclonal antibody (mAb) targeting CD38.

The mAb is now approved to treat patients with multiple myeloma (MM) who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or MM patients who are refractory to both a PI and an IMiD.

An NOC/c is authorization to market a drug with the condition that the sponsor—in this case, Janssen Inc.—undertake additional studies to verify a clinical benefit.

The NOC/c policy is designed to provide access to:

• Drugs that can treat serious, life-threatening, or severely debilitating diseases
• Drugs that can treat conditions for which no drug is currently marketed in Canada
• Drugs that provide a significant increase in efficacy or significant decrease in risk when compared to existing drugs marketed in Canada.

Studies of daratumumab

The NOC/c for daratumumab was based on a review of data from the phase 2 SIRIUS study, the phase 1/2 GEN501 study, and additional supportive studies.

The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.

The results suggested daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%. Most adverse events in this study were grade 1 or 2, although serious events did occur.

The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 patients received the drug at 16 mg/kg.

Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.

Findings from a combined efficacy analysis of the GEN501 and SIRIUS trials demonstrated that, after a mean follow-up of 14.8 months, the estimated median overall survival for patients who received single-agent daratumumab at 16 mg/kg was 20 months.

Five phase 3 clinical studies with daratumumab in MM patients—in relapsed and frontline settings—are ongoing. Additional studies are ongoing or planned to assess the mAb’s potential in other malignant and pre-malignant diseases in which CD38 is expressed.

Janssen has exclusive worldwide rights to the development, manufacturing, and commercialization of daratumumab for all potential indications. The company licensed daratumumab from Genmab A/S in August 2012.

Click here to access the July 2016 Digital Edition. 

Table of Contents

• What is the VA? The Largest Educator of Health Care Professionals in the U.S.
• The Relationship Between Sustained Gripping and the Development of Carpal Tunnel Syndrome
• Efficacy and Safety Outcomes for Patients Taking Warfarin Who Were Switched From Face-to-Face to Telephone Anticoagulation Clinic
• The Most Expensive Drug in the World: To Continue or Discontinue, That Is the Question
• The Unique Value of Externships to Nursing Education and Health Care Organizations
• The Cost of Oncology Drugs: A Pharmacy Perspective, Part 2
• Diabetic Peripheral Neuropathy: The Learning Curve
• Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

Click here to access the July 2016 Digital Edition. 

Table of Contents

• What is the VA? The Largest Educator of Health Care Professionals in the U.S.
• The Relationship Between Sustained Gripping and the Development of Carpal Tunnel Syndrome
• Efficacy and Safety Outcomes for Patients Taking Warfarin Who Were Switched From Face-to-Face to Telephone Anticoagulation Clinic
• The Most Expensive Drug in the World: To Continue or Discontinue, That Is the Question
• The Unique Value of Externships to Nursing Education and Health Care Organizations
• The Cost of Oncology Drugs: A Pharmacy Perspective, Part 2
• Diabetic Peripheral Neuropathy: The Learning Curve
• Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

Click here to access the July 2016 Digital Edition. 

Table of Contents

• What is the VA? The Largest Educator of Health Care Professionals in the U.S.
• The Relationship Between Sustained Gripping and the Development of Carpal Tunnel Syndrome
• Efficacy and Safety Outcomes for Patients Taking Warfarin Who Were Switched From Face-to-Face to Telephone Anticoagulation Clinic
• The Most Expensive Drug in the World: To Continue or Discontinue, That Is the Question
• The Unique Value of Externships to Nursing Education and Health Care Organizations
• The Cost of Oncology Drugs: A Pharmacy Perspective, Part 2
• Diabetic Peripheral Neuropathy: The Learning Curve
• Let’s Dance: A Holistic Approach to Treating Veterans With Posttraumatic Stress Disorder

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

Integrins that bind arginine-glycine-aspartic acid (RGD) activated stellate cells in the pancreas, inducing pancreatic fibrogenesis in mice, researchers reported in the July issue of Cellular and Molecular Gastroenterology and Hepatology.

“Small-molecule antagonists of this interaction might be developed for the treatment of pancreatic fibrotic diseases,” wrote Dr. Barbara Ulmasov and her associates at Saint Louis University.

Cytokine transforming growth factor beta, or TGFB, plays a “central” role in the activation of pancreatic stellate cells and the promotion of fibrogenesis, both in the pancreas and in other organs, the investigators noted. Because latent TGFB is “abundantly present” in the pancreas and most other tissues, it might be more important to control the activation of TGFB than its expression, they added. Studies of other organs have shown that TGFB is activated when integrins of the av family bind the RGD sequence, but no one had determined whether this was true for pancreatic fibrogenesis, Dr. Ulmasov and her associates asserted (Cell Mol Gastroenterol Hepatol. 2016 Mar 16. doi: 10.1016/j.jcmgh.2016.03.004).

Therefore, they repeatedly injected female C57BL/6 mice with cerulein to induce pancreatic fibrogenesis, and gave a group of control mice sterile saline instead. The mice then received continuous infusions of a small molecule called CWHM-12, which is an antagonist of RGD-integrin that is known to prevent both pulmonary and hepatic fibrosis in mice. After euthanizing the mice, the researchers measured pancreatic parenchymal atrophy, fibrosis, and activation of pancreatic stellate cells. They also studied TGFB activation in an established line of pancreatic stellate cells from rats.

Pancreatic stellate cells expressed messenger RNAs encoding RGD-binding integrins, the investigators found. The mice that received cerulein had higher levels of these integrins than the mice that received saline, and the cerulein group also had more disrupted acinar cell architecture, tubular complexes, and infiltrations of inflammatory cells. Mice that received prophylactic CWHM-12 had only somewhat less acinar cell loss and atrophy than the control mice, and had similar levels of inflammatory cell infiltration, but had “dramatically” lower levels of pancreatic fibrosis, the researchers said. Even if mice received CWHM-12 several days after starting cerulein, they still had less fibrosis and activation of TGFB than if they received saline, they noted.

The established line of pancreatic stellate cells “could robustly activate endogenously produced TGFB,” the investigators also reported. Furthermore, CWHM-12 “potently blocked TGFB activation,” unlike the control compound. Taken together, the findings illustrate the “critical role of RGD-binding integrins in chronic pancreatitis, and the promising potential to arrest or possibly even reverse pancreatic fibrosis using a pharmacologic approach to inhibiting integrin-mediated TGFB activation,” the researchers concluded.

The National Pancreas Foundation and the Frank R. Burton Memorial Fund supported the study. Dr. Ulmasov had no disclosures. Three coinvestigators reported being consultants and/or holding equity in Integrin Therapeutics, Nimbus Therapeutics, Bristol-Myers Squibb, Janssen, Mitsubishi Tanabe, Conatus, and Scholar Rock.

Among patients with hepatitis C virus infection who were in compensated cirrhosis, sustained viral response was associated with significantly lower rates of liver decompensation, hepatocellular carcinoma, and liver-related death, even in the presence of clinically meaningful portal hypertension.

But patients in stage 2 cirrhosis were more likely than were stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR, said Dr. Vito Di Marco and his associates at the University of Palermo, Italy. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” they wrote. The report is in the July issue of Gastroenterology.

Clinically significant portal hypertension causes esophageal varices, a “landmark” indicator of stage 2 cirrhosis, the researchers noted. To parse the effects of SVR by cirrhosis stage, they followed all 444 HCV patients with compensated cirrhosis who were treated with pegylated interferon a2b and ribavirin at their tertiary liver centers between 2001 and 2009 (Gastroenterology 2016 March 31. doi: 10.1053/j.gastro.2016.03.036).

The cohort included 218 patients without esophageal varices (that is, patients in stage 1 cirrhosis) and 226 patients with esophageal varices (stage 2 cirrhosis), the researchers said. The groups were demographically similar at baseline, and had similar body mass indices and rates of comorbidities. Rates of SVR were 31% for patients in stage 1 cirrhosis and 18% for patients in stage 2 cirrhosis (P = .003).

Among stage 1 patients, achieving SVR was associated with a lower risk of liver decompensation (0% versus 7%; P = .009), a lower annual rate of hepatocellular carcinoma (0.7% versus 2.9%; P = .002), and a lower risk of liver-related death (3% versus 12%; P = .03). Stage 1 cirrhosis patients also were about 75% less likely to develop esophageal varices if they achieved SVR than if they did not (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11 to 0.48; P less than .001).

Eradicating HCV infection also was associated with better clinical outcomes among patients in stage 2 cirrhosis, according to the investigators. For example, those who achieved SVR had a 0.9% annual rate of hepatocellular carcinoma, compared with 3.6% for those who did not (P = .002). And only 2% of stage 2 patients who achieved SVR died from hepatocellular carcinoma, compared to 18% of those who did not (P = .003).

But regardless of SVR, patients with stage 2 cirrhosis were nearly three times more likely to develop liver compensation (HR, 2.8; 95% CI, 1.73 to 4.59) and about 1.75 times more likely to die of liver-related causes (HR, 1.77; 95% CI, 1.12 to 2.80) compared with patients in stage 1 cirrhosis, the investigators emphasized. Also, achieving SVR did not prevent stage 2 patients from developing more esophageal varices (HR, 1.58; 95% CI, 0.33 to 1.03).

The researchers acknowledged several study limitations. “We have performed many comparisons with respect to multiple endpoints, which could have increased the likelihood of inference errors that can result from multiple comparisons,” they wrote. “Furthermore, we cannot exclude the lack of power as an explanation for some of our results.” In addition, pegylated interferon–based therapies have low rates of SVR, and the study was limited to patients who could tolerate the regimen, they added. Nonetheless, the results indicate that eradicating HCV is clinically beneficial even in advanced compensated cirrhosis, but that early treatment helps maximize these outcomes, they concluded. “Pegylated interferon–free direct-acting antiviral combo regimens will ultimately increase the rate of virological cure to almost universal effectiveness,” they added. “It remains to be assessed whether the effectiveness of these new regimens will be automatically translated into a universal clinical benefit.”

The Italian Ministry of Health funded the study. The investigators had no disclosures.

Among patients with hepatitis C virus infection who were in compensated cirrhosis, sustained viral response was associated with significantly lower rates of liver decompensation, hepatocellular carcinoma, and liver-related death, even in the presence of clinically meaningful portal hypertension.

But patients in stage 2 cirrhosis were more likely than were stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR, said Dr. Vito Di Marco and his associates at the University of Palermo, Italy. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” they wrote. The report is in the July issue of Gastroenterology.

Clinically significant portal hypertension causes esophageal varices, a “landmark” indicator of stage 2 cirrhosis, the researchers noted. To parse the effects of SVR by cirrhosis stage, they followed all 444 HCV patients with compensated cirrhosis who were treated with pegylated interferon a2b and ribavirin at their tertiary liver centers between 2001 and 2009 (Gastroenterology 2016 March 31. doi: 10.1053/j.gastro.2016.03.036).

The cohort included 218 patients without esophageal varices (that is, patients in stage 1 cirrhosis) and 226 patients with esophageal varices (stage 2 cirrhosis), the researchers said. The groups were demographically similar at baseline, and had similar body mass indices and rates of comorbidities. Rates of SVR were 31% for patients in stage 1 cirrhosis and 18% for patients in stage 2 cirrhosis (P = .003).

Among stage 1 patients, achieving SVR was associated with a lower risk of liver decompensation (0% versus 7%; P = .009), a lower annual rate of hepatocellular carcinoma (0.7% versus 2.9%; P = .002), and a lower risk of liver-related death (3% versus 12%; P = .03). Stage 1 cirrhosis patients also were about 75% less likely to develop esophageal varices if they achieved SVR than if they did not (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11 to 0.48; P less than .001).

Eradicating HCV infection also was associated with better clinical outcomes among patients in stage 2 cirrhosis, according to the investigators. For example, those who achieved SVR had a 0.9% annual rate of hepatocellular carcinoma, compared with 3.6% for those who did not (P = .002). And only 2% of stage 2 patients who achieved SVR died from hepatocellular carcinoma, compared to 18% of those who did not (P = .003).

But regardless of SVR, patients with stage 2 cirrhosis were nearly three times more likely to develop liver compensation (HR, 2.8; 95% CI, 1.73 to 4.59) and about 1.75 times more likely to die of liver-related causes (HR, 1.77; 95% CI, 1.12 to 2.80) compared with patients in stage 1 cirrhosis, the investigators emphasized. Also, achieving SVR did not prevent stage 2 patients from developing more esophageal varices (HR, 1.58; 95% CI, 0.33 to 1.03).

The researchers acknowledged several study limitations. “We have performed many comparisons with respect to multiple endpoints, which could have increased the likelihood of inference errors that can result from multiple comparisons,” they wrote. “Furthermore, we cannot exclude the lack of power as an explanation for some of our results.” In addition, pegylated interferon–based therapies have low rates of SVR, and the study was limited to patients who could tolerate the regimen, they added. Nonetheless, the results indicate that eradicating HCV is clinically beneficial even in advanced compensated cirrhosis, but that early treatment helps maximize these outcomes, they concluded. “Pegylated interferon–free direct-acting antiviral combo regimens will ultimately increase the rate of virological cure to almost universal effectiveness,” they added. “It remains to be assessed whether the effectiveness of these new regimens will be automatically translated into a universal clinical benefit.”

The Italian Ministry of Health funded the study. The investigators had no disclosures.

Among patients with hepatitis C virus infection who were in compensated cirrhosis, sustained viral response was associated with significantly lower rates of liver decompensation, hepatocellular carcinoma, and liver-related death, even in the presence of clinically meaningful portal hypertension.

But patients in stage 2 cirrhosis were more likely than were stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR, said Dr. Vito Di Marco and his associates at the University of Palermo, Italy. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” they wrote. The report is in the July issue of Gastroenterology.

Clinically significant portal hypertension causes esophageal varices, a “landmark” indicator of stage 2 cirrhosis, the researchers noted. To parse the effects of SVR by cirrhosis stage, they followed all 444 HCV patients with compensated cirrhosis who were treated with pegylated interferon a2b and ribavirin at their tertiary liver centers between 2001 and 2009 (Gastroenterology 2016 March 31. doi: 10.1053/j.gastro.2016.03.036).

The cohort included 218 patients without esophageal varices (that is, patients in stage 1 cirrhosis) and 226 patients with esophageal varices (stage 2 cirrhosis), the researchers said. The groups were demographically similar at baseline, and had similar body mass indices and rates of comorbidities. Rates of SVR were 31% for patients in stage 1 cirrhosis and 18% for patients in stage 2 cirrhosis (P = .003).

Among stage 1 patients, achieving SVR was associated with a lower risk of liver decompensation (0% versus 7%; P = .009), a lower annual rate of hepatocellular carcinoma (0.7% versus 2.9%; P = .002), and a lower risk of liver-related death (3% versus 12%; P = .03). Stage 1 cirrhosis patients also were about 75% less likely to develop esophageal varices if they achieved SVR than if they did not (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11 to 0.48; P less than .001).

Eradicating HCV infection also was associated with better clinical outcomes among patients in stage 2 cirrhosis, according to the investigators. For example, those who achieved SVR had a 0.9% annual rate of hepatocellular carcinoma, compared with 3.6% for those who did not (P = .002). And only 2% of stage 2 patients who achieved SVR died from hepatocellular carcinoma, compared to 18% of those who did not (P = .003).

But regardless of SVR, patients with stage 2 cirrhosis were nearly three times more likely to develop liver compensation (HR, 2.8; 95% CI, 1.73 to 4.59) and about 1.75 times more likely to die of liver-related causes (HR, 1.77; 95% CI, 1.12 to 2.80) compared with patients in stage 1 cirrhosis, the investigators emphasized. Also, achieving SVR did not prevent stage 2 patients from developing more esophageal varices (HR, 1.58; 95% CI, 0.33 to 1.03).

The researchers acknowledged several study limitations. “We have performed many comparisons with respect to multiple endpoints, which could have increased the likelihood of inference errors that can result from multiple comparisons,” they wrote. “Furthermore, we cannot exclude the lack of power as an explanation for some of our results.” In addition, pegylated interferon–based therapies have low rates of SVR, and the study was limited to patients who could tolerate the regimen, they added. Nonetheless, the results indicate that eradicating HCV is clinically beneficial even in advanced compensated cirrhosis, but that early treatment helps maximize these outcomes, they concluded. “Pegylated interferon–free direct-acting antiviral combo regimens will ultimately increase the rate of virological cure to almost universal effectiveness,” they added. “It remains to be assessed whether the effectiveness of these new regimens will be automatically translated into a universal clinical benefit.”

The Italian Ministry of Health funded the study. The investigators had no disclosures.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

Among patients with immune-mediated diseases and a history of malignancy, cancer recurrence rates were similar regardless of whether they received tumor necrosis factor inhibitors, traditional immunosuppressants, or no immunosuppression, according to a meta-analysis of 16 cohort and case-control studies.

“However, there is a need for larger studies to prospectively monitor for cancer recurrence and new malignancies in this population to better inform our practice,” wrote Dr. Edward Shelton of Massachusetts General Hospital in Boston, and his associates. The report is in the July issue of Gastroenterology.

Patients with immune-mediated diseases often have a history of malignancy, raising questions about the effects of therapies that target the immune system, the researchers noted. However, relevant studies have been “small with few events, preventing robust estimates of risk,” they said. They searched Medline, Embase, and conference proceedings through April 2015 for studies of the risk of primary or recurrent cancer among patients with a history of malignancy who were exposed to thiopurines, methotrexate, or anti-TNF agents, or no immunosuppression. Among the 16 studies meeting these criteria, seven included patients with rheumatoid arthritis, seven included patients with inflammatory bowel disease, one included both diseases, and one included patients with psoriasis. Twelve were cohort studies, one was a case-control study, and three were case series. The resulting meta-analysis comprised 11,702 patients who contributed a total of 31,258 person-years of follow-up (Gastroenterology 2016 May 13. doi: 10.1053/j.gastro.2016.03.037).

Rates of cancer recurrence were statistically similar among patients who received no immunosuppression, anti-TNF therapy, traditional immune modulators, or combination regimens (P greater than .1 for differences among groups). Numerically, however, the risk of recurrent cancer was highest with combination immunotherapy (54.5 cases per 1,000 person-years of follow-up), compared with 37.5 cases per 1,000 person-years for patients who did not receive immunosuppressive treatment, 36.2 cases per 1,000 person-years for patients who received traditional immunomodulator monotherapy, and 33.8 cases per 1,000 person-years for patients who received anti-TNF agents. Analyses of subgroups of patients with new or recurrent cancers, or various types of therapies, and of specific immune-mediated diseases yielded “similar results, with no increase in risk,” said the researchers. Furthermore, rates of cancer recurrence did not statistically differ depending on whether patients started immunosuppression less than or more than 6 years after their index cancer (P = .43).

“Treatment decisions after a cancer diagnosis are complex, and must take into account the natural history of cancer, histologic type and stage, time from diagnosis, and course of underlying chronic inflammatory disease,” the researchers noted. “Our findings suggest that anti-TNF therapy, conventional immunosuppressant therapy, or combination immunosuppression are not associated with an increased risk of cancer recurrence in this population.”

The researchers cited several limitations. Notably, three of the studies included only 20 patients, and the studies included variable index cancers and methods for detecting recurrent cancers. “It also is possible, and likely, that patients who were at high risk for recurrence were not recommenced on immunosuppression, and consequently our findings may be more applicable to a population in which the patient and physicians were comfortable with re-initiation of therapy,” they said.

The National Institutes of Health supported several of the study investigators. Dr. Shelton had no disclosures. Five coinvestigators disclosed relationships with a number of pharmaceutical companies.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

Adults with irritable bowel syndrome (IBS) who underwent psychotherapy improved more than about 75% of controls, and the effect “remained significant and medium in magnitude” for at least 6-12 months, according to a meta-analysis of 41 randomized, controlled trials reported in the July issue of Clinical Gastroenterology and Hepatology.

The finding “is particularly noteworthy because of the typically recurrent, persistent nature of IBS symptoms,” said Kelsey Laird, a doctoral student of clinical psychology at Vanderbilt University in Nashville, Tenn., together with her associates there. “Future research is needed to compare the longevity of treatment effects for psychotherapy with pharmacologic therapies, such as antidepressants,” they added. “Although it is beyond the scope of this review, it is also important to consider the mechanisms by which psychotherapies improve GI symptoms and to determine the ‘active ingredients’ responsible for this effect.”

©MacXever/Thinkstock

Up to 16% of individuals in the United States have IBS, and treating it costs anywhere from $950 million to $1.35 billion per year, the researchers noted. Other meta-analyses found psychotherapy about as effective as antidepressants for treating IBS-related GI symptoms over the short term, but its long-term efficacy was unknown, they added. Therefore, they searched PubMed, PsycINFO, Science Direct, and ProQuest through Aug. 15, 2015, identifying randomized controlled trials of psychological therapy and active or nonactive comparators. Psychotherapy included not only traditional psychodynamic and cognitive-behavioral therapies, but also mind-body approaches, such as relaxation training, biofeedback, and yoga, “which can be conceptualized as mindful movement,” Ms. Laird and her associates said. Comparators included support groups, education, sham treatments for hypnosis or biofeedback, online discussion forums, enhanced medical care, treatment as usual, symptom monitoring, and being wait-listed for psychological treatment (Clin Gastroenterol Hepatol. 2016 Jan 21. doi: 10.1016/j.cgh.2015.11.020). The 41 trials included 2,290 patients, comprising 1,183 assigned to the psychological modalities and 1,107 assigned to the various comparators. Taken together, the psychological modalities were associated with greater improvements in GI symptoms immediately after treatment, as compared with the grouped comparators. The Cohen’s d value was 0.69 (95% confidence interval, 0.52-0.86; P less than .001), indicating a medium effect size, the researchers said. Moreover, Cohen’s d values were 0.76 and 0.73, respectively, at short-term follow-up (1-6 months) and long-term follow-up (6-12 months). “On average, individuals who received psychotherapy had a greater reduction in GI symptoms after treatment than 75% of individuals assigned to a control condition,” the researchers concluded.

Effect sizes were similar among cognitive, cognitive-behavioral, and relaxation and hypnosis interventions, and between interventions delivered online and in person, the investigators also reported. Furthermore, longer durations or sessions of psychotherapy did not appear to further improve symptoms.

Study limitations included substantial variability between trials, and the fact that none of the 41 trials could be seen as having a low risk of bias in every domain assessed, the investigators said. “This was partially a result of the difficulty in blinding participants in psychological trials,” they noted. “However, even after excluding this domain, only nine trials were rated as low risk of bias in all remaining domains. Future studies should follow the CONSORT guidelines for [randomized controlled trials], use [intention-to-treat] designs, use active control conditions to control for nonspecific treatment effects, and assess treatment credibility and expectancy.”

The authors reported no funding sources and had no disclosures.

State Medicaid programs denied nearly half of requests to cover direct-acting antiviral drugs for patients with chronic hepatitis C virus (HCV) infection, according to a prospective study of beneficiaries in Delaware, Maryland, New Jersey, and Pennsylvania reported in the July issue of Clinical Gastroenterology and Hepatology.

In contrast, only 5% of Medicare patients and 10% of privately insured patients were denied coverage, said Dr. Vincent Lo Re III of the University of Pennsylvania, Philadelphia, together with his associates. “Notably, nearly one-quarter of Medicaid recipients with cirrhosis experienced treatment denial. Medicaid patients from these states also experienced a longer time to prescription fill than those with Medicare or commercial insurance,” the researchers said.

©roxanabalint/Thinkstock

Their study included 2,321 HCV patients prescribed a direct-acting antiviral regimen between November 1, 2014 and April 30, 2015. All prescriptions were submitted to a specialty pharmacy that serves HCV patients in Maryland, Pennsylvania, Delaware, and New Jersey, the investigators noted. They focused on “absolute denial,” meaning that the prescription was never filled because the insurer denied coverage, regardless of appeals. “Data are lacking on the incidence of absolute denial of direct-acting antiviral prescriptions and factors associated with this outcome,” the investigators said. “These data are important because absolute denial of HCV treatment by insurers might have adverse outcomes on patients and could harm patient-provider relationships” (Clin Gastroenterol Hepatol. 2016 Apr 5. doi: 10.1016/j.cgh.2016.03.040).

Source: American Gastroenterological Association

A total of 1,023 study patients were privately insured, 795 were enrolled in Medicare, and 503 were Medicaid patients, according to the researchers. In all, 377 patients (16%) received absolute denials, most often because of “insufficient information to assess medical need” (36% of denials) and “lack of medical necessity” (35%). Medicaid patients faced an absolute denial rate of 46% – significantly higher than rates for private insurers (10.5%) or Medicare (5%; P less than .001 for both comparisons). After adjusting for potential confounders, Medicaid patients were more than four times as likely to be denied coverage for direct-acting antivirals, compared with privately insured patients (relative risk, 4.1; 95% confidence interval, 3.4-5.1). Delaware’s Medicaid program had the highest rate of absolute denial (57%), followed by Pennsylvania (48%), Maryland (47%), and New Jersey (37%).

Medicaid programs even refused to cover direct-acting antiviral prescriptions for 25% of patients who had cirrhosis, compared with absolute denial rates of only 1% for Medicare and 3% of private insurers (P less than .001 for both comparisons), according to the researchers. The implications of these denials “remain unknown,” but lack of treatment increases the risk of end-stage liver disease, hepatocellular carcinoma, extrahepatic disease, HCV transmission, and “anxiety and stress about HCV disease progression, [which can] provoke distrust among patients of the health care system and their providers,” they added. “Clinicians then are challenged to explain the denial, and important opportunities for patient engagement, education, and cure could be irrevocably lost.”

Medicaid programs also initially denied about 25% of prescriptions before eventually approving them, despite the fact that “patients had complete prior authorization requests that should have contained the materials needed to justify approval,” said the investigators. Furthermore, denial letters usually did not specify the information that was needed, “making it difficult [for clinicians] to appeal the decision.” In contrast, only about 8% of privately insured patients and 13% of Medicare enrollees were initially denied coverage.

Prescriptions as a whole were more likely to be filled in the last 3 months of the study than earlier, perhaps because insurers are starting to relax their reimbursement criteria, said the investigators. Indeed, in October 2015, the American Association for the Study of Liver Diseases and the Infectious Disease Society of America stopped triaging groups of patients for direct-acting antiviral therapy, they noted.

The research was supported by the Penn Center for AIDS Research, which is funded by the National Institutes of Health. Dr. Lo Re received investigator-initiated research support from AstraZeneca. Five coinvestigators reported relationships with a number of pharmaceutical companies. Four coinvestigators reported employment by the study site, Burman’s Specialty Pharmacy. The other four coauthors had no disclosures.

State Medicaid programs denied nearly half of requests to cover direct-acting antiviral drugs for patients with chronic hepatitis C virus (HCV) infection, according to a prospective study of beneficiaries in Delaware, Maryland, New Jersey, and Pennsylvania reported in the July issue of Clinical Gastroenterology and Hepatology.

In contrast, only 5% of Medicare patients and 10% of privately insured patients were denied coverage, said Dr. Vincent Lo Re III of the University of Pennsylvania, Philadelphia, together with his associates. “Notably, nearly one-quarter of Medicaid recipients with cirrhosis experienced treatment denial. Medicaid patients from these states also experienced a longer time to prescription fill than those with Medicare or commercial insurance,” the researchers said.

©roxanabalint/Thinkstock

Their study included 2,321 HCV patients prescribed a direct-acting antiviral regimen between November 1, 2014 and April 30, 2015. All prescriptions were submitted to a specialty pharmacy that serves HCV patients in Maryland, Pennsylvania, Delaware, and New Jersey, the investigators noted. They focused on “absolute denial,” meaning that the prescription was never filled because the insurer denied coverage, regardless of appeals. “Data are lacking on the incidence of absolute denial of direct-acting antiviral prescriptions and factors associated with this outcome,” the investigators said. “These data are important because absolute denial of HCV treatment by insurers might have adverse outcomes on patients and could harm patient-provider relationships” (Clin Gastroenterol Hepatol. 2016 Apr 5. doi: 10.1016/j.cgh.2016.03.040).

Source: American Gastroenterological Association

A total of 1,023 study patients were privately insured, 795 were enrolled in Medicare, and 503 were Medicaid patients, according to the researchers. In all, 377 patients (16%) received absolute denials, most often because of “insufficient information to assess medical need” (36% of denials) and “lack of medical necessity” (35%). Medicaid patients faced an absolute denial rate of 46% – significantly higher than rates for private insurers (10.5%) or Medicare (5%; P less than .001 for both comparisons). After adjusting for potential confounders, Medicaid patients were more than four times as likely to be denied coverage for direct-acting antivirals, compared with privately insured patients (relative risk, 4.1; 95% confidence interval, 3.4-5.1). Delaware’s Medicaid program had the highest rate of absolute denial (57%), followed by Pennsylvania (48%), Maryland (47%), and New Jersey (37%).

Medicaid programs even refused to cover direct-acting antiviral prescriptions for 25% of patients who had cirrhosis, compared with absolute denial rates of only 1% for Medicare and 3% of private insurers (P less than .001 for both comparisons), according to the researchers. The implications of these denials “remain unknown,” but lack of treatment increases the risk of end-stage liver disease, hepatocellular carcinoma, extrahepatic disease, HCV transmission, and “anxiety and stress about HCV disease progression, [which can] provoke distrust among patients of the health care system and their providers,” they added. “Clinicians then are challenged to explain the denial, and important opportunities for patient engagement, education, and cure could be irrevocably lost.”

Medicaid programs also initially denied about 25% of prescriptions before eventually approving them, despite the fact that “patients had complete prior authorization requests that should have contained the materials needed to justify approval,” said the investigators. Furthermore, denial letters usually did not specify the information that was needed, “making it difficult [for clinicians] to appeal the decision.” In contrast, only about 8% of privately insured patients and 13% of Medicare enrollees were initially denied coverage.

Prescriptions as a whole were more likely to be filled in the last 3 months of the study than earlier, perhaps because insurers are starting to relax their reimbursement criteria, said the investigators. Indeed, in October 2015, the American Association for the Study of Liver Diseases and the Infectious Disease Society of America stopped triaging groups of patients for direct-acting antiviral therapy, they noted.

The research was supported by the Penn Center for AIDS Research, which is funded by the National Institutes of Health. Dr. Lo Re received investigator-initiated research support from AstraZeneca. Five coinvestigators reported relationships with a number of pharmaceutical companies. Four coinvestigators reported employment by the study site, Burman’s Specialty Pharmacy. The other four coauthors had no disclosures.

State Medicaid programs denied nearly half of requests to cover direct-acting antiviral drugs for patients with chronic hepatitis C virus (HCV) infection, according to a prospective study of beneficiaries in Delaware, Maryland, New Jersey, and Pennsylvania reported in the July issue of Clinical Gastroenterology and Hepatology.

In contrast, only 5% of Medicare patients and 10% of privately insured patients were denied coverage, said Dr. Vincent Lo Re III of the University of Pennsylvania, Philadelphia, together with his associates. “Notably, nearly one-quarter of Medicaid recipients with cirrhosis experienced treatment denial. Medicaid patients from these states also experienced a longer time to prescription fill than those with Medicare or commercial insurance,” the researchers said.

©roxanabalint/Thinkstock

Their study included 2,321 HCV patients prescribed a direct-acting antiviral regimen between November 1, 2014 and April 30, 2015. All prescriptions were submitted to a specialty pharmacy that serves HCV patients in Maryland, Pennsylvania, Delaware, and New Jersey, the investigators noted. They focused on “absolute denial,” meaning that the prescription was never filled because the insurer denied coverage, regardless of appeals. “Data are lacking on the incidence of absolute denial of direct-acting antiviral prescriptions and factors associated with this outcome,” the investigators said. “These data are important because absolute denial of HCV treatment by insurers might have adverse outcomes on patients and could harm patient-provider relationships” (Clin Gastroenterol Hepatol. 2016 Apr 5. doi: 10.1016/j.cgh.2016.03.040).

Source: American Gastroenterological Association

A total of 1,023 study patients were privately insured, 795 were enrolled in Medicare, and 503 were Medicaid patients, according to the researchers. In all, 377 patients (16%) received absolute denials, most often because of “insufficient information to assess medical need” (36% of denials) and “lack of medical necessity” (35%). Medicaid patients faced an absolute denial rate of 46% – significantly higher than rates for private insurers (10.5%) or Medicare (5%; P less than .001 for both comparisons). After adjusting for potential confounders, Medicaid patients were more than four times as likely to be denied coverage for direct-acting antivirals, compared with privately insured patients (relative risk, 4.1; 95% confidence interval, 3.4-5.1). Delaware’s Medicaid program had the highest rate of absolute denial (57%), followed by Pennsylvania (48%), Maryland (47%), and New Jersey (37%).

Medicaid programs even refused to cover direct-acting antiviral prescriptions for 25% of patients who had cirrhosis, compared with absolute denial rates of only 1% for Medicare and 3% of private insurers (P less than .001 for both comparisons), according to the researchers. The implications of these denials “remain unknown,” but lack of treatment increases the risk of end-stage liver disease, hepatocellular carcinoma, extrahepatic disease, HCV transmission, and “anxiety and stress about HCV disease progression, [which can] provoke distrust among patients of the health care system and their providers,” they added. “Clinicians then are challenged to explain the denial, and important opportunities for patient engagement, education, and cure could be irrevocably lost.”

Medicaid programs also initially denied about 25% of prescriptions before eventually approving them, despite the fact that “patients had complete prior authorization requests that should have contained the materials needed to justify approval,” said the investigators. Furthermore, denial letters usually did not specify the information that was needed, “making it difficult [for clinicians] to appeal the decision.” In contrast, only about 8% of privately insured patients and 13% of Medicare enrollees were initially denied coverage.

Prescriptions as a whole were more likely to be filled in the last 3 months of the study than earlier, perhaps because insurers are starting to relax their reimbursement criteria, said the investigators. Indeed, in October 2015, the American Association for the Study of Liver Diseases and the Infectious Disease Society of America stopped triaging groups of patients for direct-acting antiviral therapy, they noted.

The research was supported by the Penn Center for AIDS Research, which is funded by the National Institutes of Health. Dr. Lo Re received investigator-initiated research support from AstraZeneca. Five coinvestigators reported relationships with a number of pharmaceutical companies. Four coinvestigators reported employment by the study site, Burman’s Specialty Pharmacy. The other four coauthors had no disclosures.