Liver Disease

A newly identified interferon gene known as IFNL4 is associated with impaired clearance of hepatitis C virus, results from a novel study demonstrated.

In an article published online Jan. 6 in Nature Genetics, the results of the study suggest that therapeutic inhibition of IFNL4 "might represent a novel biological strategy for the treatment of HCV and HBV infection and possibly other diseases, and IFNL4 genotype could be used to select patients for this therapy," wrote Ludmila Prokunina-Olsson, Ph.D., and her colleagues.

Courtesy US. Dept of Veterans Affairs

They described IFNL4 as "related to but distinct from known IFNs and other class 2 cytokines. The 179 amino acid open reading frame of the IFNL4 transcript is created by a common deletion frameshift allele of ss469415590, which is a dinucleotide variant strongly linked with rs12979860" – a genetic marker strongly associated with HCV clearance. The gene is located upstream of IFNL3 on chromosome 19q13.13.

Dr. Prokunina-Olsson, of the Laboratory of Translational Genomics in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her associates performed the RNA sequencing experiment in a sample of primary human hepatocytes treated with polyinosinic:polycytidylic acid, a synthetic mimic of double-stranded HCV RNA. The sample was taken from a liver donor who was heterozygous for rs12979860 and uninfected with HCV (Nature Genetics 2013 Jan. 6 [doi: 10.1038/ng.2521]).

The researchers found that compared with rs12979860, ss469415590 was more strongly associated with HCV clearance in individuals of African ancestry (P = .015), while these variants behaved similarly in individuals of European ancestry.

They also discovered that IFNL4 "induces STAT1 and STAT2 phosphorylation, activates ISRE-Luc reporter and ISGs, and generates antiviral response in hepatoma cells," they wrote. "The mechanisms by which IFNL4 induces these responses but nevertheless impairs HCV clearance are currently under investigation."

The study was funded by grants from the National Cancer Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases.

[email protected]

A newly identified interferon gene known as IFNL4 is associated with impaired clearance of hepatitis C virus, results from a novel study demonstrated.

In an article published online Jan. 6 in Nature Genetics, the results of the study suggest that therapeutic inhibition of IFNL4 "might represent a novel biological strategy for the treatment of HCV and HBV infection and possibly other diseases, and IFNL4 genotype could be used to select patients for this therapy," wrote Ludmila Prokunina-Olsson, Ph.D., and her colleagues.

Courtesy US. Dept of Veterans Affairs

They described IFNL4 as "related to but distinct from known IFNs and other class 2 cytokines. The 179 amino acid open reading frame of the IFNL4 transcript is created by a common deletion frameshift allele of ss469415590, which is a dinucleotide variant strongly linked with rs12979860" – a genetic marker strongly associated with HCV clearance. The gene is located upstream of IFNL3 on chromosome 19q13.13.

Dr. Prokunina-Olsson, of the Laboratory of Translational Genomics in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her associates performed the RNA sequencing experiment in a sample of primary human hepatocytes treated with polyinosinic:polycytidylic acid, a synthetic mimic of double-stranded HCV RNA. The sample was taken from a liver donor who was heterozygous for rs12979860 and uninfected with HCV (Nature Genetics 2013 Jan. 6 [doi: 10.1038/ng.2521]).

The researchers found that compared with rs12979860, ss469415590 was more strongly associated with HCV clearance in individuals of African ancestry (P = .015), while these variants behaved similarly in individuals of European ancestry.

They also discovered that IFNL4 "induces STAT1 and STAT2 phosphorylation, activates ISRE-Luc reporter and ISGs, and generates antiviral response in hepatoma cells," they wrote. "The mechanisms by which IFNL4 induces these responses but nevertheless impairs HCV clearance are currently under investigation."

The study was funded by grants from the National Cancer Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases.

[email protected]

A newly identified interferon gene known as IFNL4 is associated with impaired clearance of hepatitis C virus, results from a novel study demonstrated.

In an article published online Jan. 6 in Nature Genetics, the results of the study suggest that therapeutic inhibition of IFNL4 "might represent a novel biological strategy for the treatment of HCV and HBV infection and possibly other diseases, and IFNL4 genotype could be used to select patients for this therapy," wrote Ludmila Prokunina-Olsson, Ph.D., and her colleagues.

Courtesy US. Dept of Veterans Affairs

They described IFNL4 as "related to but distinct from known IFNs and other class 2 cytokines. The 179 amino acid open reading frame of the IFNL4 transcript is created by a common deletion frameshift allele of ss469415590, which is a dinucleotide variant strongly linked with rs12979860" – a genetic marker strongly associated with HCV clearance. The gene is located upstream of IFNL3 on chromosome 19q13.13.

Dr. Prokunina-Olsson, of the Laboratory of Translational Genomics in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her associates performed the RNA sequencing experiment in a sample of primary human hepatocytes treated with polyinosinic:polycytidylic acid, a synthetic mimic of double-stranded HCV RNA. The sample was taken from a liver donor who was heterozygous for rs12979860 and uninfected with HCV (Nature Genetics 2013 Jan. 6 [doi: 10.1038/ng.2521]).

The researchers found that compared with rs12979860, ss469415590 was more strongly associated with HCV clearance in individuals of African ancestry (P = .015), while these variants behaved similarly in individuals of European ancestry.

They also discovered that IFNL4 "induces STAT1 and STAT2 phosphorylation, activates ISRE-Luc reporter and ISGs, and generates antiviral response in hepatoma cells," they wrote. "The mechanisms by which IFNL4 induces these responses but nevertheless impairs HCV clearance are currently under investigation."

The study was funded by grants from the National Cancer Institute and the National Institute of Diabetes, Digestive, and Kidney Diseases.

[email protected]

Therapy with telaprevir, peginterferon, and ribavirin should be stopped in both treatment-naive and treatment-experienced patients with hepatitis C virus infection if HCV RNA levels are greater than 1,000 IU/mL at week 4 or 12 of treatment, according to new futility rules developed using phase II and III trial data.

The rules are important for preventing needless drug exposure and to minimize the development of drug-resistant variants in patients with little or no chance of achieving sustained virologic response, reported Dr. Nathalie Adda of Vertex Pharmaceuticals Inc., Cambridge, Mass., and her colleagues.

Courtesy US Dept. Of Veteran Affairs

The futility rules were initially developed during clinical trials of telaprevir combination therapy and were instituted along with standard peginterferon/ribavirin (Peg-IFN/RBV) futility rules; phase II trial data were analyzed to determine whether the telaprevir rules could differentiate patients likely to experience viral breakthrough and patients likely to achieve sustained virologic response, and it was found that the majority of viral breakthroughs occurred within the first 4 weeks of treatment. Thus, a futility rule was implemented at week 4 in studies of telaprevir combination therapy as has long been the case for studies of Peg-IFN/RBV therapy (Clin. Gastroenterol. Hepatol. 2012 Nov. 16 [doi: 10.1016/j.cgh.2012.10.045]).

For treatment-naive patients, a level of 1,000 IU/mL at week 4 was used; for treatment-experienced patients, a more conservative level of 100 IU/mL at week 4 (and at weeks 6 and 8) was used.

These rules were further analyzed based on phase III studies of patients who were treated with 12 weeks of telaprevir, Peg-IFN/RBV followed by 12 or 36 weeks of Peg-IFN/RBV alone. This allowed for refinement of the optimal thresholds and time points for identifying patients unlikely to achieve sustained virologic response.

"In this analysis, we also sought to harmonize the futility rules for all patient populations (treatment-naive and -experienced)," the investigators wrote.

They found that 1.7% of 844 treatment-naive patients, 0.7% of 138 prior relapsers, and 0% of 46 prior partial responders had HCV RNA levels greater than 1,000 IU/mL at week 4, compared with 14% of 70 prior nonresponders. None of the 25 patients with HCV RNA levels above the 1,000 IU/mL level at week 4 achieved sustained virologic response with continued therapy. Among those who had HCV RNA levels between 100 and 1,000 IU/mL at week 4, a small subset achieved sustained virologic response with continued treatment: 25% of treatment-naive and 14% of treatment-experienced patients.

The 1,000 IU/mL threshold was retained, as it was found to maximize the likelihood of achieving sustained virologic response, they said.

"Furthermore, 13/14 (93%) treatment-naive and 10/11 (91%) treatment-experienced patients with HCV RNA levels greater than 1,000 IU/mL at week 4 reached their HCV RNA nadir prior to week 4, typically by week 2, with subsequent increase in HCV RNA by week 4, meeting the definition of viral breakthrough," they wrote.

Additionally, the investigators reassessed previously-established Peg-IFN/RBV treatment futility rule of a 2 log₁₀ decrease or greater in HCV RNA at week 12 in the context of a telaprevir-based regimen, and implemented a futility rule for treatment-naive patients of greater than 1,000 IU/mL HCV RNA at the end of the telaprevir dosing period to avoid unnecessary Peg-IFN/RBV exposure in those unlikely to achieve SVR.

This rule was met by 1.5% of 605 treatment naive patients who completed week 12. Similar rules were implemented at weeks 6, 8, and 12 for treatment-experienced patients, but few patients met the week 6 and 8 futility rules (5 and 2 of 266 patients, respectively), and the HCV RNA assessment at these time points was replaced by the week 12 assessment.

"In conclusion, data from phase II and III trials confirmed that a futility rule of greater than 1,000 IU/mL at week 4 accurately and specifically identified patients unlikely to achieve sustained virologic response. Less than 2% of treatment-naive, prior relapse, and prior partial response, and 14% of prior null response patients met the above criterion, and none achieved sustained virologic response after stopping telaprevir, with continued Peg-IFN/RBV," the investigators wrote, noting that the vast majority of these patients were already experiencing viral breakthrough by week 4.

The new rules prevent unnecessary drug exposure in those unlikely to achieve sustained virologic response, and, importantly, they minimize additional HCV RNA testing, because the futility time points coincide with those used to guide total treatment duration.

"This strategy will avoid additional adverse effects of continued treatment and will help minimize the evolution, enrichment, or protracted persistence of resistant variants, which could adversely impact patient candidacy for potential treatment with subsequent antiviral regimens," they concluded.

Several authors are employees of Janssen Pharmaceuticals and stock owners of Johnson and Johnson. One author reported receiving consulting fees, lecture fees, and/or grant/research support from many companies involved in hepatitis C virus therapeutics.

Therapy with telaprevir, peginterferon, and ribavirin should be stopped in both treatment-naive and treatment-experienced patients with hepatitis C virus infection if HCV RNA levels are greater than 1,000 IU/mL at week 4 or 12 of treatment, according to new futility rules developed using phase II and III trial data.

The rules are important for preventing needless drug exposure and to minimize the development of drug-resistant variants in patients with little or no chance of achieving sustained virologic response, reported Dr. Nathalie Adda of Vertex Pharmaceuticals Inc., Cambridge, Mass., and her colleagues.

Courtesy US Dept. Of Veteran Affairs

The futility rules were initially developed during clinical trials of telaprevir combination therapy and were instituted along with standard peginterferon/ribavirin (Peg-IFN/RBV) futility rules; phase II trial data were analyzed to determine whether the telaprevir rules could differentiate patients likely to experience viral breakthrough and patients likely to achieve sustained virologic response, and it was found that the majority of viral breakthroughs occurred within the first 4 weeks of treatment. Thus, a futility rule was implemented at week 4 in studies of telaprevir combination therapy as has long been the case for studies of Peg-IFN/RBV therapy (Clin. Gastroenterol. Hepatol. 2012 Nov. 16 [doi: 10.1016/j.cgh.2012.10.045]).

For treatment-naive patients, a level of 1,000 IU/mL at week 4 was used; for treatment-experienced patients, a more conservative level of 100 IU/mL at week 4 (and at weeks 6 and 8) was used.

These rules were further analyzed based on phase III studies of patients who were treated with 12 weeks of telaprevir, Peg-IFN/RBV followed by 12 or 36 weeks of Peg-IFN/RBV alone. This allowed for refinement of the optimal thresholds and time points for identifying patients unlikely to achieve sustained virologic response.

"In this analysis, we also sought to harmonize the futility rules for all patient populations (treatment-naive and -experienced)," the investigators wrote.

They found that 1.7% of 844 treatment-naive patients, 0.7% of 138 prior relapsers, and 0% of 46 prior partial responders had HCV RNA levels greater than 1,000 IU/mL at week 4, compared with 14% of 70 prior nonresponders. None of the 25 patients with HCV RNA levels above the 1,000 IU/mL level at week 4 achieved sustained virologic response with continued therapy. Among those who had HCV RNA levels between 100 and 1,000 IU/mL at week 4, a small subset achieved sustained virologic response with continued treatment: 25% of treatment-naive and 14% of treatment-experienced patients.

The 1,000 IU/mL threshold was retained, as it was found to maximize the likelihood of achieving sustained virologic response, they said.

"Furthermore, 13/14 (93%) treatment-naive and 10/11 (91%) treatment-experienced patients with HCV RNA levels greater than 1,000 IU/mL at week 4 reached their HCV RNA nadir prior to week 4, typically by week 2, with subsequent increase in HCV RNA by week 4, meeting the definition of viral breakthrough," they wrote.

Additionally, the investigators reassessed previously-established Peg-IFN/RBV treatment futility rule of a 2 log₁₀ decrease or greater in HCV RNA at week 12 in the context of a telaprevir-based regimen, and implemented a futility rule for treatment-naive patients of greater than 1,000 IU/mL HCV RNA at the end of the telaprevir dosing period to avoid unnecessary Peg-IFN/RBV exposure in those unlikely to achieve SVR.

This rule was met by 1.5% of 605 treatment naive patients who completed week 12. Similar rules were implemented at weeks 6, 8, and 12 for treatment-experienced patients, but few patients met the week 6 and 8 futility rules (5 and 2 of 266 patients, respectively), and the HCV RNA assessment at these time points was replaced by the week 12 assessment.

"In conclusion, data from phase II and III trials confirmed that a futility rule of greater than 1,000 IU/mL at week 4 accurately and specifically identified patients unlikely to achieve sustained virologic response. Less than 2% of treatment-naive, prior relapse, and prior partial response, and 14% of prior null response patients met the above criterion, and none achieved sustained virologic response after stopping telaprevir, with continued Peg-IFN/RBV," the investigators wrote, noting that the vast majority of these patients were already experiencing viral breakthrough by week 4.

The new rules prevent unnecessary drug exposure in those unlikely to achieve sustained virologic response, and, importantly, they minimize additional HCV RNA testing, because the futility time points coincide with those used to guide total treatment duration.

"This strategy will avoid additional adverse effects of continued treatment and will help minimize the evolution, enrichment, or protracted persistence of resistant variants, which could adversely impact patient candidacy for potential treatment with subsequent antiviral regimens," they concluded.

Several authors are employees of Janssen Pharmaceuticals and stock owners of Johnson and Johnson. One author reported receiving consulting fees, lecture fees, and/or grant/research support from many companies involved in hepatitis C virus therapeutics.

Therapy with telaprevir, peginterferon, and ribavirin should be stopped in both treatment-naive and treatment-experienced patients with hepatitis C virus infection if HCV RNA levels are greater than 1,000 IU/mL at week 4 or 12 of treatment, according to new futility rules developed using phase II and III trial data.

The rules are important for preventing needless drug exposure and to minimize the development of drug-resistant variants in patients with little or no chance of achieving sustained virologic response, reported Dr. Nathalie Adda of Vertex Pharmaceuticals Inc., Cambridge, Mass., and her colleagues.

Courtesy US Dept. Of Veteran Affairs

The futility rules were initially developed during clinical trials of telaprevir combination therapy and were instituted along with standard peginterferon/ribavirin (Peg-IFN/RBV) futility rules; phase II trial data were analyzed to determine whether the telaprevir rules could differentiate patients likely to experience viral breakthrough and patients likely to achieve sustained virologic response, and it was found that the majority of viral breakthroughs occurred within the first 4 weeks of treatment. Thus, a futility rule was implemented at week 4 in studies of telaprevir combination therapy as has long been the case for studies of Peg-IFN/RBV therapy (Clin. Gastroenterol. Hepatol. 2012 Nov. 16 [doi: 10.1016/j.cgh.2012.10.045]).

For treatment-naive patients, a level of 1,000 IU/mL at week 4 was used; for treatment-experienced patients, a more conservative level of 100 IU/mL at week 4 (and at weeks 6 and 8) was used.

These rules were further analyzed based on phase III studies of patients who were treated with 12 weeks of telaprevir, Peg-IFN/RBV followed by 12 or 36 weeks of Peg-IFN/RBV alone. This allowed for refinement of the optimal thresholds and time points for identifying patients unlikely to achieve sustained virologic response.

"In this analysis, we also sought to harmonize the futility rules for all patient populations (treatment-naive and -experienced)," the investigators wrote.

They found that 1.7% of 844 treatment-naive patients, 0.7% of 138 prior relapsers, and 0% of 46 prior partial responders had HCV RNA levels greater than 1,000 IU/mL at week 4, compared with 14% of 70 prior nonresponders. None of the 25 patients with HCV RNA levels above the 1,000 IU/mL level at week 4 achieved sustained virologic response with continued therapy. Among those who had HCV RNA levels between 100 and 1,000 IU/mL at week 4, a small subset achieved sustained virologic response with continued treatment: 25% of treatment-naive and 14% of treatment-experienced patients.

The 1,000 IU/mL threshold was retained, as it was found to maximize the likelihood of achieving sustained virologic response, they said.

"Furthermore, 13/14 (93%) treatment-naive and 10/11 (91%) treatment-experienced patients with HCV RNA levels greater than 1,000 IU/mL at week 4 reached their HCV RNA nadir prior to week 4, typically by week 2, with subsequent increase in HCV RNA by week 4, meeting the definition of viral breakthrough," they wrote.

Additionally, the investigators reassessed previously-established Peg-IFN/RBV treatment futility rule of a 2 log₁₀ decrease or greater in HCV RNA at week 12 in the context of a telaprevir-based regimen, and implemented a futility rule for treatment-naive patients of greater than 1,000 IU/mL HCV RNA at the end of the telaprevir dosing period to avoid unnecessary Peg-IFN/RBV exposure in those unlikely to achieve SVR.

This rule was met by 1.5% of 605 treatment naive patients who completed week 12. Similar rules were implemented at weeks 6, 8, and 12 for treatment-experienced patients, but few patients met the week 6 and 8 futility rules (5 and 2 of 266 patients, respectively), and the HCV RNA assessment at these time points was replaced by the week 12 assessment.

"In conclusion, data from phase II and III trials confirmed that a futility rule of greater than 1,000 IU/mL at week 4 accurately and specifically identified patients unlikely to achieve sustained virologic response. Less than 2% of treatment-naive, prior relapse, and prior partial response, and 14% of prior null response patients met the above criterion, and none achieved sustained virologic response after stopping telaprevir, with continued Peg-IFN/RBV," the investigators wrote, noting that the vast majority of these patients were already experiencing viral breakthrough by week 4.

The new rules prevent unnecessary drug exposure in those unlikely to achieve sustained virologic response, and, importantly, they minimize additional HCV RNA testing, because the futility time points coincide with those used to guide total treatment duration.

"This strategy will avoid additional adverse effects of continued treatment and will help minimize the evolution, enrichment, or protracted persistence of resistant variants, which could adversely impact patient candidacy for potential treatment with subsequent antiviral regimens," they concluded.

Several authors are employees of Janssen Pharmaceuticals and stock owners of Johnson and Johnson. One author reported receiving consulting fees, lecture fees, and/or grant/research support from many companies involved in hepatitis C virus therapeutics.

BOSTON – Adding pegylated interferon alfa-2a to entecavir increased the likelihood of long-term viral suppression of chronic hepatitis B infections in a randomized trial of 160 patients with chronic hepatitis B virus infections.

Loss of the hepatitis B e antigen (HBeAg) and hepatitis B viral (HBV) DNA levels below 200 IU/mL after 48 weeks of therapy occurred in 18% of patients who were randomized to entecavir (Baraclude) and pegylated interferon alfa-2a (Pegasys), compared with 8% of patients on entecavir monotherapy, but this difference was not significant, Dr. Milan J. Sonneveld reported at the annual meeting of the American Association for the Study of Liver Diseases.

However, after adjustment for baseline HBV serum antigen levels, analysis showed that pegylated interferon alfa-2a (PEG IFN) as an add-on was independently associated with response at 48 weeks (P = .01).

"Adding peginterferon alfa-2a to a potent nucleoside analogue appears to be a possibility to increase the probability of finite treatment in e-antigen–positive chronic hepatitis B patients," said Dr. Sonneveld of the department of gastroenterology and hepatology at Erasmus University Medical Center in Rotterdam, the Netherlands.

Investigators at 15 sites in Europe and China enrolled 184 patients with HBeAg-positive infections with compensated liver disease. The patients were randomized to either entecavir alone at a dose of 0.5 mg daily for 48 weeks, or 24 weeks of entecavir monotherapy, after which 24 weeks of PEG IFN alfa-2a 180 mcg weekly were added.

All patients were assessed at weeks 12, 24, 36, and 48. Those with a response – a loss of the HBeAg with HBV DNA less than 200 IU/mL at 48 weeks – received an additional 24 weeks of consolidation therapy with entecavir and then discontinued therapy, whereas those without a response were continued on entecavir through week 72.

At week 48, there were 77 patients assigned to entecavir and PEG IFN and 83 assigned to entecavir alone.

There were no significant differences in response rates between the treatment arms, but patients who received the PEG IFN add-on had a greater decline of HBV DNA (6.33 vs. 5.91 log IU/mL; P = .05), HBeAg (1.99 vs. 1.56 log IU/mL; P = .01) and HBV serum antigen (0.84 vs. 0.32 log IU/mL; P less than .001) at week 48.

HBV serum antigen clearance was seen in only one patient at week 48; he had been assigned to the PEG IFN add-on group.

In a multivariate analysis adjusted for differences in baseline serum antigen levels, the addition of PEG IFN was independently associated with response at week 48 (adjusted odds ratio, 3.78; P = .012).

There were no differences in anemia between the two groups, but patients on the entecavir plus PEG IFN combination had significantly more leukopenia (8% vs. 0%; P = .01), neutropenia (23% vs. 0%; P = .001), and thrombocytopenia (P = .01).

The study was supported by Bristol-Myers Squibb, which manufactures entecavir, and Roche, which manufactures pegylated interferon alfa-2a. Dr. Sonneveld reported receiving speakers fees and educational support from Roche.

BOSTON – Adding pegylated interferon alfa-2a to entecavir increased the likelihood of long-term viral suppression of chronic hepatitis B infections in a randomized trial of 160 patients with chronic hepatitis B virus infections.

Loss of the hepatitis B e antigen (HBeAg) and hepatitis B viral (HBV) DNA levels below 200 IU/mL after 48 weeks of therapy occurred in 18% of patients who were randomized to entecavir (Baraclude) and pegylated interferon alfa-2a (Pegasys), compared with 8% of patients on entecavir monotherapy, but this difference was not significant, Dr. Milan J. Sonneveld reported at the annual meeting of the American Association for the Study of Liver Diseases.

However, after adjustment for baseline HBV serum antigen levels, analysis showed that pegylated interferon alfa-2a (PEG IFN) as an add-on was independently associated with response at 48 weeks (P = .01).

"Adding peginterferon alfa-2a to a potent nucleoside analogue appears to be a possibility to increase the probability of finite treatment in e-antigen–positive chronic hepatitis B patients," said Dr. Sonneveld of the department of gastroenterology and hepatology at Erasmus University Medical Center in Rotterdam, the Netherlands.

Investigators at 15 sites in Europe and China enrolled 184 patients with HBeAg-positive infections with compensated liver disease. The patients were randomized to either entecavir alone at a dose of 0.5 mg daily for 48 weeks, or 24 weeks of entecavir monotherapy, after which 24 weeks of PEG IFN alfa-2a 180 mcg weekly were added.

All patients were assessed at weeks 12, 24, 36, and 48. Those with a response – a loss of the HBeAg with HBV DNA less than 200 IU/mL at 48 weeks – received an additional 24 weeks of consolidation therapy with entecavir and then discontinued therapy, whereas those without a response were continued on entecavir through week 72.

At week 48, there were 77 patients assigned to entecavir and PEG IFN and 83 assigned to entecavir alone.

There were no significant differences in response rates between the treatment arms, but patients who received the PEG IFN add-on had a greater decline of HBV DNA (6.33 vs. 5.91 log IU/mL; P = .05), HBeAg (1.99 vs. 1.56 log IU/mL; P = .01) and HBV serum antigen (0.84 vs. 0.32 log IU/mL; P less than .001) at week 48.

HBV serum antigen clearance was seen in only one patient at week 48; he had been assigned to the PEG IFN add-on group.

In a multivariate analysis adjusted for differences in baseline serum antigen levels, the addition of PEG IFN was independently associated with response at week 48 (adjusted odds ratio, 3.78; P = .012).

There were no differences in anemia between the two groups, but patients on the entecavir plus PEG IFN combination had significantly more leukopenia (8% vs. 0%; P = .01), neutropenia (23% vs. 0%; P = .001), and thrombocytopenia (P = .01).

The study was supported by Bristol-Myers Squibb, which manufactures entecavir, and Roche, which manufactures pegylated interferon alfa-2a. Dr. Sonneveld reported receiving speakers fees and educational support from Roche.

BOSTON – Adding pegylated interferon alfa-2a to entecavir increased the likelihood of long-term viral suppression of chronic hepatitis B infections in a randomized trial of 160 patients with chronic hepatitis B virus infections.

Loss of the hepatitis B e antigen (HBeAg) and hepatitis B viral (HBV) DNA levels below 200 IU/mL after 48 weeks of therapy occurred in 18% of patients who were randomized to entecavir (Baraclude) and pegylated interferon alfa-2a (Pegasys), compared with 8% of patients on entecavir monotherapy, but this difference was not significant, Dr. Milan J. Sonneveld reported at the annual meeting of the American Association for the Study of Liver Diseases.

However, after adjustment for baseline HBV serum antigen levels, analysis showed that pegylated interferon alfa-2a (PEG IFN) as an add-on was independently associated with response at 48 weeks (P = .01).

"Adding peginterferon alfa-2a to a potent nucleoside analogue appears to be a possibility to increase the probability of finite treatment in e-antigen–positive chronic hepatitis B patients," said Dr. Sonneveld of the department of gastroenterology and hepatology at Erasmus University Medical Center in Rotterdam, the Netherlands.

Investigators at 15 sites in Europe and China enrolled 184 patients with HBeAg-positive infections with compensated liver disease. The patients were randomized to either entecavir alone at a dose of 0.5 mg daily for 48 weeks, or 24 weeks of entecavir monotherapy, after which 24 weeks of PEG IFN alfa-2a 180 mcg weekly were added.

All patients were assessed at weeks 12, 24, 36, and 48. Those with a response – a loss of the HBeAg with HBV DNA less than 200 IU/mL at 48 weeks – received an additional 24 weeks of consolidation therapy with entecavir and then discontinued therapy, whereas those without a response were continued on entecavir through week 72.

At week 48, there were 77 patients assigned to entecavir and PEG IFN and 83 assigned to entecavir alone.

There were no significant differences in response rates between the treatment arms, but patients who received the PEG IFN add-on had a greater decline of HBV DNA (6.33 vs. 5.91 log IU/mL; P = .05), HBeAg (1.99 vs. 1.56 log IU/mL; P = .01) and HBV serum antigen (0.84 vs. 0.32 log IU/mL; P less than .001) at week 48.

HBV serum antigen clearance was seen in only one patient at week 48; he had been assigned to the PEG IFN add-on group.

In a multivariate analysis adjusted for differences in baseline serum antigen levels, the addition of PEG IFN was independently associated with response at week 48 (adjusted odds ratio, 3.78; P = .012).

There were no differences in anemia between the two groups, but patients on the entecavir plus PEG IFN combination had significantly more leukopenia (8% vs. 0%; P = .01), neutropenia (23% vs. 0%; P = .001), and thrombocytopenia (P = .01).

The study was supported by Bristol-Myers Squibb, which manufactures entecavir, and Roche, which manufactures pegylated interferon alfa-2a. Dr. Sonneveld reported receiving speakers fees and educational support from Roche.

BOSTON  – Anemia developed significantly more often among patients with hepatitis C virus infection and compensated cirrhosis than among noncirrhotic patients during triple therapy in a randomized, open-label trial of treatment-naive patients, but in most instances the anemia was effectively treated.

In an anemia management subanalysis of a study comparing sustained virologic response (SVR) rates in cirrhotic and noncirrhotic patients treated with boceprevir (Victrelis), pegylated interferon alfa-2b (Peg-Intron), and ribavirin (RBV), 57% of patients with cirrhosis and anemia treated with a ribavirin dose reduction had an SVR, compared with 64% of those treated with erythropoietin. Among noncirrhotic patients with anemia, the respective SVR rates were 73% and 72%; none of the differences was significant, Dr. Eric J. Lawitz reported at the annual meeting of the American Association for the Study of Liver Diseases.

Courtesy US. Dept of Veterans Affairs

"Sustained viral responses are comparable in cirrhotic patients when anemia is managed by ribavirin dose reduction or erythropoietin," said Dr. Lawitz, medical director and principal investigator at Alamo Medical Research in San Antonio, Tex., adding that ribavirin dose reductions should be the initial strategy for managing anemia, followed, if necessary, by erythropoietin.

In the trial, 687 treatment-naive patients with hepatitis C virus (HCV) infections were treated for 4 weeks with pegylated interferon (PEG-IFN) alfa-2b and RBV, then 24 or 44 weeks of boceprevir added in. Baseline hemoglobin levels ranged from 12 g/dL to15 g/dL for women, and from 13 g/dL to15 g/dL for men.

Patients with a hemoglobin level approaching 10 g/dL or less (tested from baseline through week 48) were randomized to either ribavirin dose reduction (249 patients) in 200-mg increments (first increment of 400 mg for initial 1,400-mg daily doses) at the investigators’ discretion, or to erythropoietin (251 patients) at 40,000 U/wk, modifiable to 20,000 U/wk or 60,000 U/wk at the investigator’s discretion. The remaining patients received anemia prophylaxis but were not randomized.

If the hemoglobin level dropped to 8.5 g/dL, patients could receive the other treatment as a secondary intervention, and patients with a hemoglobin level of 7.5 g/dL were discontinued from all study drugs.

Primary efficacy measures for all patients (cirrhotic and noncirrhotic) in each anemia strategy group were identical, with 82% having an end-of-treatment response, 71% having an SVR, and 10% experiencing relapse.

Among cirrhotic vs. noncirrhotic patients, rates were 68% vs. 76% for end-of-treatment response , 55% vs. 64% for SVR, and 18% vs. 11% for relapse.

Patients with cirrhosis were significantly more likely to require a secondary anemia intervention (44% vs. 26%, P = .009). Among noncirrhotic patients (but not cirrhotic patients), a secondary anemia intervention was associated with a greater likelihood of SVR (80% vs. 70% for only one intervention, P = .05).

Serious adverse events occurred in 20% of cirrhotic patients and 12% of noncirrhotic patients, but only one study death occurred. The noncirrhotic patient died of a cardiac arrest, which was considered to be unrelated to therapy.

Treatment-emergent adverse events occurred in 3% of patients with cirrhosis and 2% of those without cirrhosis. Drug discontinuation for adverse events occurred in 17% of cirrhotic patients, and 16% of noncirrhotic patients.

Cirrhotic patients were more likely to have hemoglobin concentrations ranging from 6.5 to 8.0 g/dL than were noncirrhotic patients, but no patient in either group had a hemoglobin concentration below 6.5 g/dL.

Neutrophil counts in the range of 500-749/mm³ occurred in 24% of cirrhotic patients and 27% of noncirrhotic patients, and counts below 500/mm³ were seen in 20% and 12%.

Platelet counts from 25,000 to 49,999/mm³ occurred in 22% of cirrhotic patients and 2% of noncirrhotic patients. Counts below 25,000/mm³ were seen in 3% vs. less than 1%, respectively. Transfusion rates were similar between the groups.

The study was funded by Merck Sharp & Dohme, which manufactures boceprevir. Dr. Lawitz disclosed receiving grant and research support from the company.

BOSTON  – Anemia developed significantly more often among patients with hepatitis C virus infection and compensated cirrhosis than among noncirrhotic patients during triple therapy in a randomized, open-label trial of treatment-naive patients, but in most instances the anemia was effectively treated.

In an anemia management subanalysis of a study comparing sustained virologic response (SVR) rates in cirrhotic and noncirrhotic patients treated with boceprevir (Victrelis), pegylated interferon alfa-2b (Peg-Intron), and ribavirin (RBV), 57% of patients with cirrhosis and anemia treated with a ribavirin dose reduction had an SVR, compared with 64% of those treated with erythropoietin. Among noncirrhotic patients with anemia, the respective SVR rates were 73% and 72%; none of the differences was significant, Dr. Eric J. Lawitz reported at the annual meeting of the American Association for the Study of Liver Diseases.

Courtesy US. Dept of Veterans Affairs

"Sustained viral responses are comparable in cirrhotic patients when anemia is managed by ribavirin dose reduction or erythropoietin," said Dr. Lawitz, medical director and principal investigator at Alamo Medical Research in San Antonio, Tex., adding that ribavirin dose reductions should be the initial strategy for managing anemia, followed, if necessary, by erythropoietin.

In the trial, 687 treatment-naive patients with hepatitis C virus (HCV) infections were treated for 4 weeks with pegylated interferon (PEG-IFN) alfa-2b and RBV, then 24 or 44 weeks of boceprevir added in. Baseline hemoglobin levels ranged from 12 g/dL to15 g/dL for women, and from 13 g/dL to15 g/dL for men.

Patients with a hemoglobin level approaching 10 g/dL or less (tested from baseline through week 48) were randomized to either ribavirin dose reduction (249 patients) in 200-mg increments (first increment of 400 mg for initial 1,400-mg daily doses) at the investigators’ discretion, or to erythropoietin (251 patients) at 40,000 U/wk, modifiable to 20,000 U/wk or 60,000 U/wk at the investigator’s discretion. The remaining patients received anemia prophylaxis but were not randomized.

If the hemoglobin level dropped to 8.5 g/dL, patients could receive the other treatment as a secondary intervention, and patients with a hemoglobin level of 7.5 g/dL were discontinued from all study drugs.

Primary efficacy measures for all patients (cirrhotic and noncirrhotic) in each anemia strategy group were identical, with 82% having an end-of-treatment response, 71% having an SVR, and 10% experiencing relapse.

Among cirrhotic vs. noncirrhotic patients, rates were 68% vs. 76% for end-of-treatment response , 55% vs. 64% for SVR, and 18% vs. 11% for relapse.

Patients with cirrhosis were significantly more likely to require a secondary anemia intervention (44% vs. 26%, P = .009). Among noncirrhotic patients (but not cirrhotic patients), a secondary anemia intervention was associated with a greater likelihood of SVR (80% vs. 70% for only one intervention, P = .05).

Serious adverse events occurred in 20% of cirrhotic patients and 12% of noncirrhotic patients, but only one study death occurred. The noncirrhotic patient died of a cardiac arrest, which was considered to be unrelated to therapy.

Treatment-emergent adverse events occurred in 3% of patients with cirrhosis and 2% of those without cirrhosis. Drug discontinuation for adverse events occurred in 17% of cirrhotic patients, and 16% of noncirrhotic patients.

Cirrhotic patients were more likely to have hemoglobin concentrations ranging from 6.5 to 8.0 g/dL than were noncirrhotic patients, but no patient in either group had a hemoglobin concentration below 6.5 g/dL.

Neutrophil counts in the range of 500-749/mm³ occurred in 24% of cirrhotic patients and 27% of noncirrhotic patients, and counts below 500/mm³ were seen in 20% and 12%.

Platelet counts from 25,000 to 49,999/mm³ occurred in 22% of cirrhotic patients and 2% of noncirrhotic patients. Counts below 25,000/mm³ were seen in 3% vs. less than 1%, respectively. Transfusion rates were similar between the groups.

The study was funded by Merck Sharp & Dohme, which manufactures boceprevir. Dr. Lawitz disclosed receiving grant and research support from the company.

BOSTON  – Anemia developed significantly more often among patients with hepatitis C virus infection and compensated cirrhosis than among noncirrhotic patients during triple therapy in a randomized, open-label trial of treatment-naive patients, but in most instances the anemia was effectively treated.

In an anemia management subanalysis of a study comparing sustained virologic response (SVR) rates in cirrhotic and noncirrhotic patients treated with boceprevir (Victrelis), pegylated interferon alfa-2b (Peg-Intron), and ribavirin (RBV), 57% of patients with cirrhosis and anemia treated with a ribavirin dose reduction had an SVR, compared with 64% of those treated with erythropoietin. Among noncirrhotic patients with anemia, the respective SVR rates were 73% and 72%; none of the differences was significant, Dr. Eric J. Lawitz reported at the annual meeting of the American Association for the Study of Liver Diseases.

Courtesy US. Dept of Veterans Affairs

"Sustained viral responses are comparable in cirrhotic patients when anemia is managed by ribavirin dose reduction or erythropoietin," said Dr. Lawitz, medical director and principal investigator at Alamo Medical Research in San Antonio, Tex., adding that ribavirin dose reductions should be the initial strategy for managing anemia, followed, if necessary, by erythropoietin.

In the trial, 687 treatment-naive patients with hepatitis C virus (HCV) infections were treated for 4 weeks with pegylated interferon (PEG-IFN) alfa-2b and RBV, then 24 or 44 weeks of boceprevir added in. Baseline hemoglobin levels ranged from 12 g/dL to15 g/dL for women, and from 13 g/dL to15 g/dL for men.

Patients with a hemoglobin level approaching 10 g/dL or less (tested from baseline through week 48) were randomized to either ribavirin dose reduction (249 patients) in 200-mg increments (first increment of 400 mg for initial 1,400-mg daily doses) at the investigators’ discretion, or to erythropoietin (251 patients) at 40,000 U/wk, modifiable to 20,000 U/wk or 60,000 U/wk at the investigator’s discretion. The remaining patients received anemia prophylaxis but were not randomized.

If the hemoglobin level dropped to 8.5 g/dL, patients could receive the other treatment as a secondary intervention, and patients with a hemoglobin level of 7.5 g/dL were discontinued from all study drugs.

Primary efficacy measures for all patients (cirrhotic and noncirrhotic) in each anemia strategy group were identical, with 82% having an end-of-treatment response, 71% having an SVR, and 10% experiencing relapse.

Among cirrhotic vs. noncirrhotic patients, rates were 68% vs. 76% for end-of-treatment response , 55% vs. 64% for SVR, and 18% vs. 11% for relapse.

Patients with cirrhosis were significantly more likely to require a secondary anemia intervention (44% vs. 26%, P = .009). Among noncirrhotic patients (but not cirrhotic patients), a secondary anemia intervention was associated with a greater likelihood of SVR (80% vs. 70% for only one intervention, P = .05).

Serious adverse events occurred in 20% of cirrhotic patients and 12% of noncirrhotic patients, but only one study death occurred. The noncirrhotic patient died of a cardiac arrest, which was considered to be unrelated to therapy.

Treatment-emergent adverse events occurred in 3% of patients with cirrhosis and 2% of those without cirrhosis. Drug discontinuation for adverse events occurred in 17% of cirrhotic patients, and 16% of noncirrhotic patients.

Cirrhotic patients were more likely to have hemoglobin concentrations ranging from 6.5 to 8.0 g/dL than were noncirrhotic patients, but no patient in either group had a hemoglobin concentration below 6.5 g/dL.

Neutrophil counts in the range of 500-749/mm³ occurred in 24% of cirrhotic patients and 27% of noncirrhotic patients, and counts below 500/mm³ were seen in 20% and 12%.

Platelet counts from 25,000 to 49,999/mm³ occurred in 22% of cirrhotic patients and 2% of noncirrhotic patients. Counts below 25,000/mm³ were seen in 3% vs. less than 1%, respectively. Transfusion rates were similar between the groups.

The study was funded by Merck Sharp & Dohme, which manufactures boceprevir. Dr. Lawitz disclosed receiving grant and research support from the company.

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.

BOSTON  – In patients who had chronic hepatitis B infections and documented lamivudine resistance, tenofovir with or without emtricitabine produced high rates of viral suppression with no detectable resistance over 2 years.

In a phase IIIb randomized study, 89% of lamivudine-resistant patients with HBV who were randomly assigned to receive tenofovir (Viread) alone met the primary end point of HBV DNA below 400 copies/mL, compared with 86% of those assigned to a tenofovir/emtricitabine (Emtriva) combination, in an intention-to-treat analysis, Dr. Scott Fung, assistant professor of hepatology at the University of Toronto, reported at the annual meeting of the American Association for the Study of Liver Diseases.

©CDC/ Dr. Erskine Palmer

"Tenofovir monotherapy was just as safe and effective as combination therapy, suggesting that monotherapy alone was sufficient for treatment of hepatitis B," Dr. Fung said.

In addition to the high rate of viral resistance, tenofovir was associated with normalization of ALT levels in a majority of patients, and with no emergent viral resistance, he said.

The investigators enrolled 280 patients who carried virus with lamivudine-resistant mutations, were viremic (HBV DNA greater than 10³/IU per mL), and were still on lamivudine until the day of randomization. Current or prior treatment with adefovir (Hepsera) was allowed as long as the patient had received less than 48 total weeks of therapy.

A total of 133 patients who were assigned to receive tenofovir 300 mg daily completed 96 weeks of treatment and were thus available for analysis, as were 125 of those assigned to emtricitabine/tenofovir in a fixed-dose combination.

As noted before, the rates of HBV DNA below 400 copies/mL were 89% for the monotherapy arm and 86% for the combination in an analysis that considered missing data as treatment failure. When missing data were excluded from an on-treatment analysis, however, the respective rates were 96% and 95%.

Using a lower cutoff point, less than 169 copies/mL, the respective rates at 96 weeks were 86% and 84%.

In all, 70% of patients in each group had normal ALT levels at 96 weeks, and among patients with abnormally high levels at baseline nearly two-thirds in each group had normalization of ALT during the study.

The HBV e-antigen loss rate was modest, at 15% of patients on tenofovir alone and 13% on the combination. HBeAg seroconversion occurred in 11% and 10%, respectively.

Among 18 patients who qualified for genotypic resistance testing at their last on-treatment visit, there were no viral isolates demonstrating tenofovir resistance, Dr. Fung said.

There were three deaths during the study: one from gastrointestinal hemorrhage in a patient in the monotherapy group and two – one from cardiac arrest and sepsis in a patient with hepatocellular carcinoma and one from bronchopneumonia – in the combination group. The deaths were judged to be unrelated to study treatment.

There was only one serious treatment-related adverse event, occurring in the combination group (the event was unspecified), and only three patients discontinued because of adverse events – one in the monotherapy arm and two in the combination group. Five patients on tenofovir alone and four on the combination had creatinine clearance less than 50 mL/min at study end; these patients all had low baseline creatinine clearance levels, ranging from 41 to 69 mL/min, Dr. Fung noted.

The authors also looked at bone mineral density levels at baseline and at study end in 239 patients for who dual-energy x-ray absorptiometry data were available. At baseline, 33% of patients were determined to have osteopenia and 7% to have osteoporosis on spine scans and 22% and 1.3%, respectively, on hip scans. Repeat scans at 96 weeks showed that the majority of patients had a reduction in bone mineral density of about 22%, a decline that was considered not clinically significant, he said.

The study was funded by Gilead Sciences. Dr. Fung disclosed receiving grant/research support and speaking/teaching fees from the company.

BOSTON  – In patients who had chronic hepatitis B infections and documented lamivudine resistance, tenofovir with or without emtricitabine produced high rates of viral suppression with no detectable resistance over 2 years.

In a phase IIIb randomized study, 89% of lamivudine-resistant patients with HBV who were randomly assigned to receive tenofovir (Viread) alone met the primary end point of HBV DNA below 400 copies/mL, compared with 86% of those assigned to a tenofovir/emtricitabine (Emtriva) combination, in an intention-to-treat analysis, Dr. Scott Fung, assistant professor of hepatology at the University of Toronto, reported at the annual meeting of the American Association for the Study of Liver Diseases.

©CDC/ Dr. Erskine Palmer

"Tenofovir monotherapy was just as safe and effective as combination therapy, suggesting that monotherapy alone was sufficient for treatment of hepatitis B," Dr. Fung said.

In addition to the high rate of viral resistance, tenofovir was associated with normalization of ALT levels in a majority of patients, and with no emergent viral resistance, he said.

The investigators enrolled 280 patients who carried virus with lamivudine-resistant mutations, were viremic (HBV DNA greater than 10³/IU per mL), and were still on lamivudine until the day of randomization. Current or prior treatment with adefovir (Hepsera) was allowed as long as the patient had received less than 48 total weeks of therapy.

A total of 133 patients who were assigned to receive tenofovir 300 mg daily completed 96 weeks of treatment and were thus available for analysis, as were 125 of those assigned to emtricitabine/tenofovir in a fixed-dose combination.

As noted before, the rates of HBV DNA below 400 copies/mL were 89% for the monotherapy arm and 86% for the combination in an analysis that considered missing data as treatment failure. When missing data were excluded from an on-treatment analysis, however, the respective rates were 96% and 95%.

Using a lower cutoff point, less than 169 copies/mL, the respective rates at 96 weeks were 86% and 84%.

In all, 70% of patients in each group had normal ALT levels at 96 weeks, and among patients with abnormally high levels at baseline nearly two-thirds in each group had normalization of ALT during the study.

The HBV e-antigen loss rate was modest, at 15% of patients on tenofovir alone and 13% on the combination. HBeAg seroconversion occurred in 11% and 10%, respectively.

Among 18 patients who qualified for genotypic resistance testing at their last on-treatment visit, there were no viral isolates demonstrating tenofovir resistance, Dr. Fung said.

There were three deaths during the study: one from gastrointestinal hemorrhage in a patient in the monotherapy group and two – one from cardiac arrest and sepsis in a patient with hepatocellular carcinoma and one from bronchopneumonia – in the combination group. The deaths were judged to be unrelated to study treatment.

There was only one serious treatment-related adverse event, occurring in the combination group (the event was unspecified), and only three patients discontinued because of adverse events – one in the monotherapy arm and two in the combination group. Five patients on tenofovir alone and four on the combination had creatinine clearance less than 50 mL/min at study end; these patients all had low baseline creatinine clearance levels, ranging from 41 to 69 mL/min, Dr. Fung noted.

The authors also looked at bone mineral density levels at baseline and at study end in 239 patients for who dual-energy x-ray absorptiometry data were available. At baseline, 33% of patients were determined to have osteopenia and 7% to have osteoporosis on spine scans and 22% and 1.3%, respectively, on hip scans. Repeat scans at 96 weeks showed that the majority of patients had a reduction in bone mineral density of about 22%, a decline that was considered not clinically significant, he said.

The study was funded by Gilead Sciences. Dr. Fung disclosed receiving grant/research support and speaking/teaching fees from the company.

BOSTON  – In patients who had chronic hepatitis B infections and documented lamivudine resistance, tenofovir with or without emtricitabine produced high rates of viral suppression with no detectable resistance over 2 years.

In a phase IIIb randomized study, 89% of lamivudine-resistant patients with HBV who were randomly assigned to receive tenofovir (Viread) alone met the primary end point of HBV DNA below 400 copies/mL, compared with 86% of those assigned to a tenofovir/emtricitabine (Emtriva) combination, in an intention-to-treat analysis, Dr. Scott Fung, assistant professor of hepatology at the University of Toronto, reported at the annual meeting of the American Association for the Study of Liver Diseases.

©CDC/ Dr. Erskine Palmer

"Tenofovir monotherapy was just as safe and effective as combination therapy, suggesting that monotherapy alone was sufficient for treatment of hepatitis B," Dr. Fung said.

In addition to the high rate of viral resistance, tenofovir was associated with normalization of ALT levels in a majority of patients, and with no emergent viral resistance, he said.

The investigators enrolled 280 patients who carried virus with lamivudine-resistant mutations, were viremic (HBV DNA greater than 10³/IU per mL), and were still on lamivudine until the day of randomization. Current or prior treatment with adefovir (Hepsera) was allowed as long as the patient had received less than 48 total weeks of therapy.

A total of 133 patients who were assigned to receive tenofovir 300 mg daily completed 96 weeks of treatment and were thus available for analysis, as were 125 of those assigned to emtricitabine/tenofovir in a fixed-dose combination.

As noted before, the rates of HBV DNA below 400 copies/mL were 89% for the monotherapy arm and 86% for the combination in an analysis that considered missing data as treatment failure. When missing data were excluded from an on-treatment analysis, however, the respective rates were 96% and 95%.

Using a lower cutoff point, less than 169 copies/mL, the respective rates at 96 weeks were 86% and 84%.

In all, 70% of patients in each group had normal ALT levels at 96 weeks, and among patients with abnormally high levels at baseline nearly two-thirds in each group had normalization of ALT during the study.

The HBV e-antigen loss rate was modest, at 15% of patients on tenofovir alone and 13% on the combination. HBeAg seroconversion occurred in 11% and 10%, respectively.

Among 18 patients who qualified for genotypic resistance testing at their last on-treatment visit, there were no viral isolates demonstrating tenofovir resistance, Dr. Fung said.

There were three deaths during the study: one from gastrointestinal hemorrhage in a patient in the monotherapy group and two – one from cardiac arrest and sepsis in a patient with hepatocellular carcinoma and one from bronchopneumonia – in the combination group. The deaths were judged to be unrelated to study treatment.

There was only one serious treatment-related adverse event, occurring in the combination group (the event was unspecified), and only three patients discontinued because of adverse events – one in the monotherapy arm and two in the combination group. Five patients on tenofovir alone and four on the combination had creatinine clearance less than 50 mL/min at study end; these patients all had low baseline creatinine clearance levels, ranging from 41 to 69 mL/min, Dr. Fung noted.

The authors also looked at bone mineral density levels at baseline and at study end in 239 patients for who dual-energy x-ray absorptiometry data were available. At baseline, 33% of patients were determined to have osteopenia and 7% to have osteoporosis on spine scans and 22% and 1.3%, respectively, on hip scans. Repeat scans at 96 weeks showed that the majority of patients had a reduction in bone mineral density of about 22%, a decline that was considered not clinically significant, he said.

The study was funded by Gilead Sciences. Dr. Fung disclosed receiving grant/research support and speaking/teaching fees from the company.

BOSTON – Patients with HIV and hepatitis C coinfection had high levels of sustained viral response with regimens combining select antiretroviral agents with telaprevir, pegylated interferon, and ribavirin, said investigators at the annual meeting of the American Association for the Study of Liver Diseases.

The key to avoiding adverse drug interactions between telaprevir (Incivek) and highly active antiretroviral therapy (HAART) regimens is careful selection of HIV therapy, said Dr. Mark Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University in Baltimore.

Dr. Sulkowski and his colleagues showed in a randomized phase III study that a combination of specific antiretroviral agents with telaprevir and pegylated interferon alfa-2a (PEG-IFN) and ribavirin (RBV) was associated with a 74% SVR₂₄ rate, compared with HAART and PEG-IFN only.

"Overall, 74% of patients treated with telaprevir in combination with peg-interferon and ribavirin achieved SVR [sustained virological response], compared to 45% of those treated with placebo. Drug interactions with telaprevir and selected antiretroviral therapies, specifically atazanavir/ritonavir and efavirenz, were not clinically meaningful," Dr. Sulkowski said.

A separate study by European investigators showed that the likelihood that patients with HIV/HCV coinfection will clear HCV from serum may depend on the presence of ribavirin in a regimen, and on HCV genotype.

"Ribavirin is important in the management of acute hepatitis C in HIV-positive patients. Almost all patients with genotype 2 and 3 infections were able to clear virus with combination therapy [PEG-IFN and RBV]," said lead investigator Dr. Christoph Boesecke of the University of Bonn, Germany.

Safety Concerns

Some infectious disease specialists have expressed concern that the addition of a direct-acting antiviral agent in combination with PEG-IFN/RBV could compromise the efficacy and/or safety of a HAART regimen.

To test the HAART/direct-acting antiviral agent combination, Dr. Sulkowski and his colleagues enrolled patients with HIV/HCV coinfection in a two-part study. In part A, patients were assigned on a 1:1 ratio to receive either telaprevir or placebo, each with PEG-IFN/RBV.

In part B, patients on a HAART regimen (either a combination of efavirenz, tenofovir, and emtricitabine or ritonavir-boosted atazanavir, tenofovir, and emtricitabine or lamivudine) were assigned on a 2:1 basis to receive telaprevir or placebo plus PEG-IFN/RBV. All patients were treated for 48 weeks, with an additional 24 weeks of follow-up.

HCV RNA levels on study were measured at various time points, and the investigators looked for drug interactions, adverse events, viral breakthrough, and other clinical measures.

At 24 weeks post treatment, the HCV sustained virologic response rate (SVR₂₄) among patients treated with telaprevir and PEG-IFN/RBV but not an antiretroviral therapy was 71%, compared with 33% among those treated with placebo and PEG-IFN/RBV.

Among patients on the HAART regimen containing efavirenz plus telaprevir and PEG-IFN/RBV, 69% had an SVR₂₄, compared with 38% of those who received the same HAART regimen without telaprevir. Among those on the atazanavir-containing regimen, 73% had an SVR₂₄, compared with 50% of controls who received only PEG-IFN/RBV plus HAART.

The serum concentrations of both atazanavir and efavirenz were similar whether the patients had received telaprevir or not, and there were no cases of HIV viral breakthrough, although CD4 cell counts decreased among patients taking PEG-IFN/RBV and either telaprevir or placebo. Nonetheless, investigators did not see HIV-related adverse events, Dr. Sulkowski said.

Patients on efavirenz did require a telaprevir dose increase, but the required increase was adequate for maintaining exposure to the direct-acting antiviral agent, he added.

Genotype Matters

Dr. Boesecke and his colleagues in the European AIDS Treatment Network looked at the effect of HCV genotype and ribavirin on SVR rates in the treatment of coinfected patients. They reported on 303 HIV-infected men from the Austria, France, Germany, and the United Kingdom who had been diagnosed with acute HCV infections. Of this group, 273 were treated with PEG-IFN/RBV, and 30 were treated with PEG-IFN alone. In all, 88% of the patients who received ribavirin had weight-based doses (1,000 mg for those 75 kg and under, and 1,200 mg for those over 75 kg).

A majority of the patients (69%) were infected with genotype 1; 4% had genotype 2; 11% had genotype 3; and 16% had genotype 4 infections. About one-third of patients had 24 weeks of therapy, and the remaining third had 48 weeks. Median time from HCV diagnosis to the start of treatment was about 10 weeks.

Among all patients, 52% of those received PEG-IFN alone, and 52% of those who also received ribavirin had a rapid virologic response (RVR), defined as HCV RNA negative at 4 weeks. Respective SVR₂₄ rates were 66.7% and 69.6%.

When the investigators broke it out by genotype, however, they found that while the addition of ribavirin did not significantly change either RVR or SVR₂₄ rates among patients with genotype 1 or 3 infections, 60% of patients with genotype 2 or 3 infections on PEG-IFN monotherapy had a 60% SVR^24,, whereas those on PEG-IFN/RBV had a 94% SVR₂₄. indicating a significant benefit to adding RBV (P = .016). The RVR rates were not significantly different in these patients, however.

There were no significant differences in either the total number or severity of adverse events among the various genotypes. In 10% of all cases a ribavirin dose reduction was required, and interferon dose reductions were required in 6% of cases.

Toxicities required stopping HCV therapy in 17 patients (6%).

"We saw high sustained virologic response rates if you treat hepatitis C early on, when it’s still acute, compared to when the disease is left to a chronic course in HIV patients," said Dr. Boesecke

Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Boesecke’s study was supported by the European AIDS Treatment Network. He reported no conflict of interest.

BOSTON – Patients with HIV and hepatitis C coinfection had high levels of sustained viral response with regimens combining select antiretroviral agents with telaprevir, pegylated interferon, and ribavirin, said investigators at the annual meeting of the American Association for the Study of Liver Diseases.

The key to avoiding adverse drug interactions between telaprevir (Incivek) and highly active antiretroviral therapy (HAART) regimens is careful selection of HIV therapy, said Dr. Mark Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University in Baltimore.

Dr. Sulkowski and his colleagues showed in a randomized phase III study that a combination of specific antiretroviral agents with telaprevir and pegylated interferon alfa-2a (PEG-IFN) and ribavirin (RBV) was associated with a 74% SVR₂₄ rate, compared with HAART and PEG-IFN only.

"Overall, 74% of patients treated with telaprevir in combination with peg-interferon and ribavirin achieved SVR [sustained virological response], compared to 45% of those treated with placebo. Drug interactions with telaprevir and selected antiretroviral therapies, specifically atazanavir/ritonavir and efavirenz, were not clinically meaningful," Dr. Sulkowski said.

A separate study by European investigators showed that the likelihood that patients with HIV/HCV coinfection will clear HCV from serum may depend on the presence of ribavirin in a regimen, and on HCV genotype.

"Ribavirin is important in the management of acute hepatitis C in HIV-positive patients. Almost all patients with genotype 2 and 3 infections were able to clear virus with combination therapy [PEG-IFN and RBV]," said lead investigator Dr. Christoph Boesecke of the University of Bonn, Germany.

Safety Concerns

Some infectious disease specialists have expressed concern that the addition of a direct-acting antiviral agent in combination with PEG-IFN/RBV could compromise the efficacy and/or safety of a HAART regimen.

To test the HAART/direct-acting antiviral agent combination, Dr. Sulkowski and his colleagues enrolled patients with HIV/HCV coinfection in a two-part study. In part A, patients were assigned on a 1:1 ratio to receive either telaprevir or placebo, each with PEG-IFN/RBV.

In part B, patients on a HAART regimen (either a combination of efavirenz, tenofovir, and emtricitabine or ritonavir-boosted atazanavir, tenofovir, and emtricitabine or lamivudine) were assigned on a 2:1 basis to receive telaprevir or placebo plus PEG-IFN/RBV. All patients were treated for 48 weeks, with an additional 24 weeks of follow-up.

HCV RNA levels on study were measured at various time points, and the investigators looked for drug interactions, adverse events, viral breakthrough, and other clinical measures.

At 24 weeks post treatment, the HCV sustained virologic response rate (SVR₂₄) among patients treated with telaprevir and PEG-IFN/RBV but not an antiretroviral therapy was 71%, compared with 33% among those treated with placebo and PEG-IFN/RBV.

Among patients on the HAART regimen containing efavirenz plus telaprevir and PEG-IFN/RBV, 69% had an SVR₂₄, compared with 38% of those who received the same HAART regimen without telaprevir. Among those on the atazanavir-containing regimen, 73% had an SVR₂₄, compared with 50% of controls who received only PEG-IFN/RBV plus HAART.

The serum concentrations of both atazanavir and efavirenz were similar whether the patients had received telaprevir or not, and there were no cases of HIV viral breakthrough, although CD4 cell counts decreased among patients taking PEG-IFN/RBV and either telaprevir or placebo. Nonetheless, investigators did not see HIV-related adverse events, Dr. Sulkowski said.

Patients on efavirenz did require a telaprevir dose increase, but the required increase was adequate for maintaining exposure to the direct-acting antiviral agent, he added.

Genotype Matters

Dr. Boesecke and his colleagues in the European AIDS Treatment Network looked at the effect of HCV genotype and ribavirin on SVR rates in the treatment of coinfected patients. They reported on 303 HIV-infected men from the Austria, France, Germany, and the United Kingdom who had been diagnosed with acute HCV infections. Of this group, 273 were treated with PEG-IFN/RBV, and 30 were treated with PEG-IFN alone. In all, 88% of the patients who received ribavirin had weight-based doses (1,000 mg for those 75 kg and under, and 1,200 mg for those over 75 kg).

A majority of the patients (69%) were infected with genotype 1; 4% had genotype 2; 11% had genotype 3; and 16% had genotype 4 infections. About one-third of patients had 24 weeks of therapy, and the remaining third had 48 weeks. Median time from HCV diagnosis to the start of treatment was about 10 weeks.

Among all patients, 52% of those received PEG-IFN alone, and 52% of those who also received ribavirin had a rapid virologic response (RVR), defined as HCV RNA negative at 4 weeks. Respective SVR₂₄ rates were 66.7% and 69.6%.

When the investigators broke it out by genotype, however, they found that while the addition of ribavirin did not significantly change either RVR or SVR₂₄ rates among patients with genotype 1 or 3 infections, 60% of patients with genotype 2 or 3 infections on PEG-IFN monotherapy had a 60% SVR^24,, whereas those on PEG-IFN/RBV had a 94% SVR₂₄. indicating a significant benefit to adding RBV (P = .016). The RVR rates were not significantly different in these patients, however.

There were no significant differences in either the total number or severity of adverse events among the various genotypes. In 10% of all cases a ribavirin dose reduction was required, and interferon dose reductions were required in 6% of cases.

Toxicities required stopping HCV therapy in 17 patients (6%).

"We saw high sustained virologic response rates if you treat hepatitis C early on, when it’s still acute, compared to when the disease is left to a chronic course in HIV patients," said Dr. Boesecke

Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Boesecke’s study was supported by the European AIDS Treatment Network. He reported no conflict of interest.

BOSTON – Patients with HIV and hepatitis C coinfection had high levels of sustained viral response with regimens combining select antiretroviral agents with telaprevir, pegylated interferon, and ribavirin, said investigators at the annual meeting of the American Association for the Study of Liver Diseases.

The key to avoiding adverse drug interactions between telaprevir (Incivek) and highly active antiretroviral therapy (HAART) regimens is careful selection of HIV therapy, said Dr. Mark Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University in Baltimore.

Dr. Sulkowski and his colleagues showed in a randomized phase III study that a combination of specific antiretroviral agents with telaprevir and pegylated interferon alfa-2a (PEG-IFN) and ribavirin (RBV) was associated with a 74% SVR₂₄ rate, compared with HAART and PEG-IFN only.

"Overall, 74% of patients treated with telaprevir in combination with peg-interferon and ribavirin achieved SVR [sustained virological response], compared to 45% of those treated with placebo. Drug interactions with telaprevir and selected antiretroviral therapies, specifically atazanavir/ritonavir and efavirenz, were not clinically meaningful," Dr. Sulkowski said.

A separate study by European investigators showed that the likelihood that patients with HIV/HCV coinfection will clear HCV from serum may depend on the presence of ribavirin in a regimen, and on HCV genotype.

"Ribavirin is important in the management of acute hepatitis C in HIV-positive patients. Almost all patients with genotype 2 and 3 infections were able to clear virus with combination therapy [PEG-IFN and RBV]," said lead investigator Dr. Christoph Boesecke of the University of Bonn, Germany.

Safety Concerns

Some infectious disease specialists have expressed concern that the addition of a direct-acting antiviral agent in combination with PEG-IFN/RBV could compromise the efficacy and/or safety of a HAART regimen.

To test the HAART/direct-acting antiviral agent combination, Dr. Sulkowski and his colleagues enrolled patients with HIV/HCV coinfection in a two-part study. In part A, patients were assigned on a 1:1 ratio to receive either telaprevir or placebo, each with PEG-IFN/RBV.

In part B, patients on a HAART regimen (either a combination of efavirenz, tenofovir, and emtricitabine or ritonavir-boosted atazanavir, tenofovir, and emtricitabine or lamivudine) were assigned on a 2:1 basis to receive telaprevir or placebo plus PEG-IFN/RBV. All patients were treated for 48 weeks, with an additional 24 weeks of follow-up.

HCV RNA levels on study were measured at various time points, and the investigators looked for drug interactions, adverse events, viral breakthrough, and other clinical measures.

At 24 weeks post treatment, the HCV sustained virologic response rate (SVR₂₄) among patients treated with telaprevir and PEG-IFN/RBV but not an antiretroviral therapy was 71%, compared with 33% among those treated with placebo and PEG-IFN/RBV.

Among patients on the HAART regimen containing efavirenz plus telaprevir and PEG-IFN/RBV, 69% had an SVR₂₄, compared with 38% of those who received the same HAART regimen without telaprevir. Among those on the atazanavir-containing regimen, 73% had an SVR₂₄, compared with 50% of controls who received only PEG-IFN/RBV plus HAART.

The serum concentrations of both atazanavir and efavirenz were similar whether the patients had received telaprevir or not, and there were no cases of HIV viral breakthrough, although CD4 cell counts decreased among patients taking PEG-IFN/RBV and either telaprevir or placebo. Nonetheless, investigators did not see HIV-related adverse events, Dr. Sulkowski said.

Patients on efavirenz did require a telaprevir dose increase, but the required increase was adequate for maintaining exposure to the direct-acting antiviral agent, he added.

Genotype Matters

Dr. Boesecke and his colleagues in the European AIDS Treatment Network looked at the effect of HCV genotype and ribavirin on SVR rates in the treatment of coinfected patients. They reported on 303 HIV-infected men from the Austria, France, Germany, and the United Kingdom who had been diagnosed with acute HCV infections. Of this group, 273 were treated with PEG-IFN/RBV, and 30 were treated with PEG-IFN alone. In all, 88% of the patients who received ribavirin had weight-based doses (1,000 mg for those 75 kg and under, and 1,200 mg for those over 75 kg).

A majority of the patients (69%) were infected with genotype 1; 4% had genotype 2; 11% had genotype 3; and 16% had genotype 4 infections. About one-third of patients had 24 weeks of therapy, and the remaining third had 48 weeks. Median time from HCV diagnosis to the start of treatment was about 10 weeks.

Among all patients, 52% of those received PEG-IFN alone, and 52% of those who also received ribavirin had a rapid virologic response (RVR), defined as HCV RNA negative at 4 weeks. Respective SVR₂₄ rates were 66.7% and 69.6%.

When the investigators broke it out by genotype, however, they found that while the addition of ribavirin did not significantly change either RVR or SVR₂₄ rates among patients with genotype 1 or 3 infections, 60% of patients with genotype 2 or 3 infections on PEG-IFN monotherapy had a 60% SVR^24,, whereas those on PEG-IFN/RBV had a 94% SVR₂₄. indicating a significant benefit to adding RBV (P = .016). The RVR rates were not significantly different in these patients, however.

There were no significant differences in either the total number or severity of adverse events among the various genotypes. In 10% of all cases a ribavirin dose reduction was required, and interferon dose reductions were required in 6% of cases.

Toxicities required stopping HCV therapy in 17 patients (6%).

"We saw high sustained virologic response rates if you treat hepatitis C early on, when it’s still acute, compared to when the disease is left to a chronic course in HIV patients," said Dr. Boesecke

Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Boesecke’s study was supported by the European AIDS Treatment Network. He reported no conflict of interest.

BOSTON – In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial looking at the safety of the regimen.

Although the efficacy of direct-acting antiviral regimens involving the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) combined with pegylated interferon alfa-2a or -2b in combination with ribavirin (PEG-IFN/RBV) in cirrhotic nonresponders to prior therapy was good , their safety was "poor," according to Dr. Christophe Hézode of the Hôpital Henri Mondor in Créteil, France.

Virologic response at 16 weeks in a per-protocol analysis was associated with a virologic response rate of 92% with telaprevir and 77% with boceprevir.

However, there were increased rates of serious adverse events and more difficult-to-manage anemia than in phase III trials for telaprevir and boceprevir, which included only a few patients with cirrhosis, Dr. Hézode said at the annual meeting of the American Association for the Study of Liver Diseases.

In treatment-experienced cirrhotic patients with platelet counts of 100,000/mm³ or serum albumin levels below 35 g/L, clinicians should weigh the risks and benefits of such regimens, with patients treated on a case-by-case basis because of the high risk for severe complications, Dr. Hézode said.

"However, cirrhotic experienced patients without predictors of severe complications clearly should be treated, but cautiously and carefully monitored," he added.

Dr. Hézode and his coinvestigators in the French Cohort of Therapeutic Failure and Resistances in Patients Treated With a Protease Inhibitor (telaprevir or boceprevir), Pegylated Interferon, and Ribavirin (CUPIC) trial studied two cohorts of patients with chronic hepatitis C virus (HCV) infections, and compensated cirrhosis (Child Pugh class A) who had either relapsed or had only a partial response to prior therapy, with partial response defined as at least a 2 log₁₀ decline inV RNA but failure to clear virus by week 24.

He presented data on 497 patients who had completed 16 weeks of therapy on one of two regimens. In one cohort, 292 patients received 12 weeks of telaprevir 750 mg every 8 hours, and PEG-IFN alfa-2a (Pegasys) 180 mcg/wk with ribavirin 1,000-1,200 mg/day, followed by PEG-IFN/RBV through 48 weeks. In the second cohort, patients received a 4-week initiation phase with PEG-IFN alfa-2b (PegIntron) and ribavirin, followed by 44 weeks of boceprevir 800 mg every 8 hours, PEG-IFN 1.5 mcg/kg per wk, and ribavirin 800-1,400 mg/day.

At week 16, 45% of patients on telaprevir had had at least one serious adverse event, with 14.7% terminating therapy because of a serious side effect. In all, nearly one-fourth (22.6%) discontinued therapy, and there were five deaths: from septicemia, septic shock, pneumopathy, endocarditis, and bleeding esophageal varices. Other complications in this group included grade 3 or 4 infections in 6.5%, grade 3 or 4 hepatic decompensation in 2%, grade 3/4 asthenia in 5.5%, and renal failure in 1.7%.

Hematologic adverse events included anemia of grade 2 or greater in 30.4%, erythropoietin use in 53.8%, blood transfusion in 16.1%, and ribavirin dose reduction in 13%. In addition, 2.7% of patients had grade 3 or 4 neutropenia, and 1.7% had grade 3 or 4 thrombocytopenia.

In the boceprevir group, 32.7% had at least one serious adverse event, 26.3% discontinued prematurely, and 7.3% discontinued because of serious events. The cause of one death was described as pneumopathy. Grade 3/4 adverse events involved infections in 2.4%, hepatic decompensation in 2.9%, and asthenia in 5.8%. There were no cases of renal failure in this group.

Hematologic events in patients on boceprevir included grade 2 or greater anemia in 27.8%, erythropoietin use in 46.3%, blood transfusion in 6.3%, and ribavirin dose reduction in 10.7%.

Grade 3/4 neutropenia was seen in 4.4%, and grade 3/4 thrombocytopenia in 5.4%. Two patients (1%) in this cohort received thrombopoietin.

In a multivariate analysis, significant baseline predictors of severe complications (death, severe infection, and hepatic decompensation) included platelet counts of 100,000/mm³ or lower (odds ratio, 3.11; P = .0098) and a serum albumin level below 35 g/L (OR, 6.33; P less than .0001).

Baseline predictors for severe anemia (hemoglobin less than 8 g/dL) or blood transfusion included female gender (OR, 2.19; P = .023), no lead-in phase (OR, 2.25; P = .018), age 65 years or older (OR, 3.04; P = .0014), and hemoglobin 12 g/dL or lower for women and 13 g/dL or lower for men (OR, 5.30; P less than .0001),

The study was sponsored by ANRS, the French National Agency for Research in AIDS and Viral Hepatitis, with support from INSERM, the French National Institute for Health and Medical Research. Dr. Hézode said that he has no financial conflicts of interest, but disclosed serving as a speaker and adviser for Abbott, BMS, Gilead, Janssen, Merck, and Roche.

BOSTON – In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial looking at the safety of the regimen.

Although the efficacy of direct-acting antiviral regimens involving the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) combined with pegylated interferon alfa-2a or -2b in combination with ribavirin (PEG-IFN/RBV) in cirrhotic nonresponders to prior therapy was good , their safety was "poor," according to Dr. Christophe Hézode of the Hôpital Henri Mondor in Créteil, France.

Virologic response at 16 weeks in a per-protocol analysis was associated with a virologic response rate of 92% with telaprevir and 77% with boceprevir.

However, there were increased rates of serious adverse events and more difficult-to-manage anemia than in phase III trials for telaprevir and boceprevir, which included only a few patients with cirrhosis, Dr. Hézode said at the annual meeting of the American Association for the Study of Liver Diseases.

In treatment-experienced cirrhotic patients with platelet counts of 100,000/mm³ or serum albumin levels below 35 g/L, clinicians should weigh the risks and benefits of such regimens, with patients treated on a case-by-case basis because of the high risk for severe complications, Dr. Hézode said.

"However, cirrhotic experienced patients without predictors of severe complications clearly should be treated, but cautiously and carefully monitored," he added.

Dr. Hézode and his coinvestigators in the French Cohort of Therapeutic Failure and Resistances in Patients Treated With a Protease Inhibitor (telaprevir or boceprevir), Pegylated Interferon, and Ribavirin (CUPIC) trial studied two cohorts of patients with chronic hepatitis C virus (HCV) infections, and compensated cirrhosis (Child Pugh class A) who had either relapsed or had only a partial response to prior therapy, with partial response defined as at least a 2 log₁₀ decline inV RNA but failure to clear virus by week 24.

He presented data on 497 patients who had completed 16 weeks of therapy on one of two regimens. In one cohort, 292 patients received 12 weeks of telaprevir 750 mg every 8 hours, and PEG-IFN alfa-2a (Pegasys) 180 mcg/wk with ribavirin 1,000-1,200 mg/day, followed by PEG-IFN/RBV through 48 weeks. In the second cohort, patients received a 4-week initiation phase with PEG-IFN alfa-2b (PegIntron) and ribavirin, followed by 44 weeks of boceprevir 800 mg every 8 hours, PEG-IFN 1.5 mcg/kg per wk, and ribavirin 800-1,400 mg/day.

At week 16, 45% of patients on telaprevir had had at least one serious adverse event, with 14.7% terminating therapy because of a serious side effect. In all, nearly one-fourth (22.6%) discontinued therapy, and there were five deaths: from septicemia, septic shock, pneumopathy, endocarditis, and bleeding esophageal varices. Other complications in this group included grade 3 or 4 infections in 6.5%, grade 3 or 4 hepatic decompensation in 2%, grade 3/4 asthenia in 5.5%, and renal failure in 1.7%.

Hematologic adverse events included anemia of grade 2 or greater in 30.4%, erythropoietin use in 53.8%, blood transfusion in 16.1%, and ribavirin dose reduction in 13%. In addition, 2.7% of patients had grade 3 or 4 neutropenia, and 1.7% had grade 3 or 4 thrombocytopenia.

In the boceprevir group, 32.7% had at least one serious adverse event, 26.3% discontinued prematurely, and 7.3% discontinued because of serious events. The cause of one death was described as pneumopathy. Grade 3/4 adverse events involved infections in 2.4%, hepatic decompensation in 2.9%, and asthenia in 5.8%. There were no cases of renal failure in this group.

Hematologic events in patients on boceprevir included grade 2 or greater anemia in 27.8%, erythropoietin use in 46.3%, blood transfusion in 6.3%, and ribavirin dose reduction in 10.7%.

Grade 3/4 neutropenia was seen in 4.4%, and grade 3/4 thrombocytopenia in 5.4%. Two patients (1%) in this cohort received thrombopoietin.

In a multivariate analysis, significant baseline predictors of severe complications (death, severe infection, and hepatic decompensation) included platelet counts of 100,000/mm³ or lower (odds ratio, 3.11; P = .0098) and a serum albumin level below 35 g/L (OR, 6.33; P less than .0001).

Baseline predictors for severe anemia (hemoglobin less than 8 g/dL) or blood transfusion included female gender (OR, 2.19; P = .023), no lead-in phase (OR, 2.25; P = .018), age 65 years or older (OR, 3.04; P = .0014), and hemoglobin 12 g/dL or lower for women and 13 g/dL or lower for men (OR, 5.30; P less than .0001),

The study was sponsored by ANRS, the French National Agency for Research in AIDS and Viral Hepatitis, with support from INSERM, the French National Institute for Health and Medical Research. Dr. Hézode said that he has no financial conflicts of interest, but disclosed serving as a speaker and adviser for Abbott, BMS, Gilead, Janssen, Merck, and Roche.

BOSTON – In patients with chronic hepatitis C virus infections and compensated cirrhosis, a combination of a direct-acting antiviral agent, pegylated interferon, and ribavirin produced high on-treatment virologic response rates, but at the cost of significantly increased toxicities in an interim analysis of a French multicenter trial looking at the safety of the regimen.

Although the efficacy of direct-acting antiviral regimens involving the protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) combined with pegylated interferon alfa-2a or -2b in combination with ribavirin (PEG-IFN/RBV) in cirrhotic nonresponders to prior therapy was good , their safety was "poor," according to Dr. Christophe Hézode of the Hôpital Henri Mondor in Créteil, France.

Virologic response at 16 weeks in a per-protocol analysis was associated with a virologic response rate of 92% with telaprevir and 77% with boceprevir.

However, there were increased rates of serious adverse events and more difficult-to-manage anemia than in phase III trials for telaprevir and boceprevir, which included only a few patients with cirrhosis, Dr. Hézode said at the annual meeting of the American Association for the Study of Liver Diseases.

In treatment-experienced cirrhotic patients with platelet counts of 100,000/mm³ or serum albumin levels below 35 g/L, clinicians should weigh the risks and benefits of such regimens, with patients treated on a case-by-case basis because of the high risk for severe complications, Dr. Hézode said.

"However, cirrhotic experienced patients without predictors of severe complications clearly should be treated, but cautiously and carefully monitored," he added.

Dr. Hézode and his coinvestigators in the French Cohort of Therapeutic Failure and Resistances in Patients Treated With a Protease Inhibitor (telaprevir or boceprevir), Pegylated Interferon, and Ribavirin (CUPIC) trial studied two cohorts of patients with chronic hepatitis C virus (HCV) infections, and compensated cirrhosis (Child Pugh class A) who had either relapsed or had only a partial response to prior therapy, with partial response defined as at least a 2 log₁₀ decline inV RNA but failure to clear virus by week 24.

He presented data on 497 patients who had completed 16 weeks of therapy on one of two regimens. In one cohort, 292 patients received 12 weeks of telaprevir 750 mg every 8 hours, and PEG-IFN alfa-2a (Pegasys) 180 mcg/wk with ribavirin 1,000-1,200 mg/day, followed by PEG-IFN/RBV through 48 weeks. In the second cohort, patients received a 4-week initiation phase with PEG-IFN alfa-2b (PegIntron) and ribavirin, followed by 44 weeks of boceprevir 800 mg every 8 hours, PEG-IFN 1.5 mcg/kg per wk, and ribavirin 800-1,400 mg/day.

At week 16, 45% of patients on telaprevir had had at least one serious adverse event, with 14.7% terminating therapy because of a serious side effect. In all, nearly one-fourth (22.6%) discontinued therapy, and there were five deaths: from septicemia, septic shock, pneumopathy, endocarditis, and bleeding esophageal varices. Other complications in this group included grade 3 or 4 infections in 6.5%, grade 3 or 4 hepatic decompensation in 2%, grade 3/4 asthenia in 5.5%, and renal failure in 1.7%.

Hematologic adverse events included anemia of grade 2 or greater in 30.4%, erythropoietin use in 53.8%, blood transfusion in 16.1%, and ribavirin dose reduction in 13%. In addition, 2.7% of patients had grade 3 or 4 neutropenia, and 1.7% had grade 3 or 4 thrombocytopenia.

In the boceprevir group, 32.7% had at least one serious adverse event, 26.3% discontinued prematurely, and 7.3% discontinued because of serious events. The cause of one death was described as pneumopathy. Grade 3/4 adverse events involved infections in 2.4%, hepatic decompensation in 2.9%, and asthenia in 5.8%. There were no cases of renal failure in this group.

Hematologic events in patients on boceprevir included grade 2 or greater anemia in 27.8%, erythropoietin use in 46.3%, blood transfusion in 6.3%, and ribavirin dose reduction in 10.7%.

Grade 3/4 neutropenia was seen in 4.4%, and grade 3/4 thrombocytopenia in 5.4%. Two patients (1%) in this cohort received thrombopoietin.

In a multivariate analysis, significant baseline predictors of severe complications (death, severe infection, and hepatic decompensation) included platelet counts of 100,000/mm³ or lower (odds ratio, 3.11; P = .0098) and a serum albumin level below 35 g/L (OR, 6.33; P less than .0001).

Baseline predictors for severe anemia (hemoglobin less than 8 g/dL) or blood transfusion included female gender (OR, 2.19; P = .023), no lead-in phase (OR, 2.25; P = .018), age 65 years or older (OR, 3.04; P = .0014), and hemoglobin 12 g/dL or lower for women and 13 g/dL or lower for men (OR, 5.30; P less than .0001),

The study was sponsored by ANRS, the French National Agency for Research in AIDS and Viral Hepatitis, with support from INSERM, the French National Institute for Health and Medical Research. Dr. Hézode said that he has no financial conflicts of interest, but disclosed serving as a speaker and adviser for Abbott, BMS, Gilead, Janssen, Merck, and Roche.

BOSTON  – Liver transplant recipients with hepatitis C virus infection who underwent triple-drug therapy achieved a high extended rapid virologic response rate but often contended with treatment complications in a retrospective multicenter cohort study.

The extended rapid virologic response (eRVR) rate seen in 57% of patients was "encouraging, given a very difficult-to-cure population," Dr. James R. Burton, Jr., said at the annual meeting of the American Association for the Study of Liver Diseases. He noted, however, that it’s not clear if the encouraging eRVR rate will predict sustained virologic response (SVR) as it does in non-liver transplant patients.

The use of peginteferon plus ribavirin in liver transplant recipients with hepatitis C virus infection has an SVR of only 30%. While triple therapy with peginterferon, ribavirin, and a protease inhibitor (boceprevir or telaprevir) has significantly improved rates of SVR in patients infected with genotype 1 hepatitis C virus, its safety and efficacy in liver transplant recipients is unknown, said Dr. Burton, medical director of liver transplantation at the University of Colorado Hospital, Aurora.

With 101 patients, the five-center study is the largest involving triple therapy in liver transplant recipients with hepatitis C virus infection.

Telaprevir was the protease inhibitor used most often in patients (90% vs. 10% with boceprevir). Nearly all patients (96%) had a lead-in treatment phase with peginterferon plus ribavirin. A minority of patients (14%) had an extended lead-in phase of at least 90 days (median of 189 days) and were excluded from efficacy, but not safety, analyses. The other patients had a lead-in lasting a median of 29 days. The patients with a long lead-in phase had a median of 398 total treatment days, compared with a median of 154 days for those with a shorter lead-in time.

The efficacy study population involved genotype 1–infected patients (54% genotype 1a, 39% 1b, and 7% mixed) from five medical centers. Most patients were men (76%); they had a median age of 58 years and a median duration of 54 months from their liver transplant to starting a protease inhibitor. An unfavorable IL28B genotype was found in 69% of 45 patients tested. In the 60% of patients who had undergone previous antiviral therapy, 29% had a partial response. On liver biopsy, another 47% of patients had either bridging fibrosis or cirrhosis.

The immunosuppressive agents used by the patients included cyclosporine (66%) and tacrolimus (23%). A small percentage did not receive a calcineurin inhibitor or rapamycin. Another 27% were taking corticosteroids, and 72% were taking mycophenolate mofetil or mycophenolic acid.

On treatment, the percentage of patients who had an HCV RNA level less than the limit of detection increased from 55% at 4 weeks to 63% at 8 weeks. At 12 weeks the percentage was 71%. An eRVR, defined as negative HCV RNA tests at 4 and 12 weeks, occurred in 57%. An eRVR occurred significantly more often among patients who had at least a 1 log drop in HCV RNA levels during the lead-in phase than did those with less than a 1 log drop (76% vs. 35%).

Overall, 12% of patients experienced virologic breakthrough, and treatment was stopped. This occurred more often among those with a long lead-in vs. those with a short lead-in (21% vs. 10%, respectively). Another 14% discontinued treatment early because of an adverse event; discontinuations occurred more often among patients with a long lead-in (40% vs. 11%).

Protease inhibitors are known to inhibit the metabolism of calcineurin inhibitors, which was reflected in the study by the need to reduce the median daily doses of cyclosporine (from 200 mg to 50 mg) and tacrolimus (from 1.0 mg to 0.06 mg) after protease inhibitor therapy began.

Many patients (49%) required blood transfusions during triple therapy. During the first 16 weeks of therapy, these patients used a median of 2.5 units. The majority of patients (86%) used growth factors, including granulocyte-colony stimulating factor in 44% and erythropoietin in 79%. Medication dose reductions were most frequent for ribavirin (in 78%). A total of 7% were hospitalized for anemia, Dr. Burton said.

Renal insufficiency, defined as an increase in creatinine of greater than 0.5 mg/dL from baseline, developed in 32%. Of two rejection episodes in the study, one involved a patient coming off a protease inhibitor.

Dr. Burton suggested that future studies should focus on identifying predictors for nonresponse to avoid unnecessary treatment and associated toxicities such as complications of anemia and adverse events related to significant protease inhibitor–calcineurin inhibitor interactions, such as worsening renal function and graft rejection when transitioning off a protease inhibitor.

Dr. Burton disclosed that he is an investigator in a clinical trial sponsored by Vertex Pharmaceuticals, which makes telaprevir.☐

BOSTON  – Liver transplant recipients with hepatitis C virus infection who underwent triple-drug therapy achieved a high extended rapid virologic response rate but often contended with treatment complications in a retrospective multicenter cohort study.

The extended rapid virologic response (eRVR) rate seen in 57% of patients was "encouraging, given a very difficult-to-cure population," Dr. James R. Burton, Jr., said at the annual meeting of the American Association for the Study of Liver Diseases. He noted, however, that it’s not clear if the encouraging eRVR rate will predict sustained virologic response (SVR) as it does in non-liver transplant patients.

The use of peginteferon plus ribavirin in liver transplant recipients with hepatitis C virus infection has an SVR of only 30%. While triple therapy with peginterferon, ribavirin, and a protease inhibitor (boceprevir or telaprevir) has significantly improved rates of SVR in patients infected with genotype 1 hepatitis C virus, its safety and efficacy in liver transplant recipients is unknown, said Dr. Burton, medical director of liver transplantation at the University of Colorado Hospital, Aurora.

With 101 patients, the five-center study is the largest involving triple therapy in liver transplant recipients with hepatitis C virus infection.

Telaprevir was the protease inhibitor used most often in patients (90% vs. 10% with boceprevir). Nearly all patients (96%) had a lead-in treatment phase with peginterferon plus ribavirin. A minority of patients (14%) had an extended lead-in phase of at least 90 days (median of 189 days) and were excluded from efficacy, but not safety, analyses. The other patients had a lead-in lasting a median of 29 days. The patients with a long lead-in phase had a median of 398 total treatment days, compared with a median of 154 days for those with a shorter lead-in time.

The efficacy study population involved genotype 1–infected patients (54% genotype 1a, 39% 1b, and 7% mixed) from five medical centers. Most patients were men (76%); they had a median age of 58 years and a median duration of 54 months from their liver transplant to starting a protease inhibitor. An unfavorable IL28B genotype was found in 69% of 45 patients tested. In the 60% of patients who had undergone previous antiviral therapy, 29% had a partial response. On liver biopsy, another 47% of patients had either bridging fibrosis or cirrhosis.

The immunosuppressive agents used by the patients included cyclosporine (66%) and tacrolimus (23%). A small percentage did not receive a calcineurin inhibitor or rapamycin. Another 27% were taking corticosteroids, and 72% were taking mycophenolate mofetil or mycophenolic acid.

On treatment, the percentage of patients who had an HCV RNA level less than the limit of detection increased from 55% at 4 weeks to 63% at 8 weeks. At 12 weeks the percentage was 71%. An eRVR, defined as negative HCV RNA tests at 4 and 12 weeks, occurred in 57%. An eRVR occurred significantly more often among patients who had at least a 1 log drop in HCV RNA levels during the lead-in phase than did those with less than a 1 log drop (76% vs. 35%).

Overall, 12% of patients experienced virologic breakthrough, and treatment was stopped. This occurred more often among those with a long lead-in vs. those with a short lead-in (21% vs. 10%, respectively). Another 14% discontinued treatment early because of an adverse event; discontinuations occurred more often among patients with a long lead-in (40% vs. 11%).

Protease inhibitors are known to inhibit the metabolism of calcineurin inhibitors, which was reflected in the study by the need to reduce the median daily doses of cyclosporine (from 200 mg to 50 mg) and tacrolimus (from 1.0 mg to 0.06 mg) after protease inhibitor therapy began.

Many patients (49%) required blood transfusions during triple therapy. During the first 16 weeks of therapy, these patients used a median of 2.5 units. The majority of patients (86%) used growth factors, including granulocyte-colony stimulating factor in 44% and erythropoietin in 79%. Medication dose reductions were most frequent for ribavirin (in 78%). A total of 7% were hospitalized for anemia, Dr. Burton said.

Renal insufficiency, defined as an increase in creatinine of greater than 0.5 mg/dL from baseline, developed in 32%. Of two rejection episodes in the study, one involved a patient coming off a protease inhibitor.

Dr. Burton suggested that future studies should focus on identifying predictors for nonresponse to avoid unnecessary treatment and associated toxicities such as complications of anemia and adverse events related to significant protease inhibitor–calcineurin inhibitor interactions, such as worsening renal function and graft rejection when transitioning off a protease inhibitor.

Dr. Burton disclosed that he is an investigator in a clinical trial sponsored by Vertex Pharmaceuticals, which makes telaprevir.☐

BOSTON  – Liver transplant recipients with hepatitis C virus infection who underwent triple-drug therapy achieved a high extended rapid virologic response rate but often contended with treatment complications in a retrospective multicenter cohort study.

The extended rapid virologic response (eRVR) rate seen in 57% of patients was "encouraging, given a very difficult-to-cure population," Dr. James R. Burton, Jr., said at the annual meeting of the American Association for the Study of Liver Diseases. He noted, however, that it’s not clear if the encouraging eRVR rate will predict sustained virologic response (SVR) as it does in non-liver transplant patients.

The use of peginteferon plus ribavirin in liver transplant recipients with hepatitis C virus infection has an SVR of only 30%. While triple therapy with peginterferon, ribavirin, and a protease inhibitor (boceprevir or telaprevir) has significantly improved rates of SVR in patients infected with genotype 1 hepatitis C virus, its safety and efficacy in liver transplant recipients is unknown, said Dr. Burton, medical director of liver transplantation at the University of Colorado Hospital, Aurora.

With 101 patients, the five-center study is the largest involving triple therapy in liver transplant recipients with hepatitis C virus infection.

Telaprevir was the protease inhibitor used most often in patients (90% vs. 10% with boceprevir). Nearly all patients (96%) had a lead-in treatment phase with peginterferon plus ribavirin. A minority of patients (14%) had an extended lead-in phase of at least 90 days (median of 189 days) and were excluded from efficacy, but not safety, analyses. The other patients had a lead-in lasting a median of 29 days. The patients with a long lead-in phase had a median of 398 total treatment days, compared with a median of 154 days for those with a shorter lead-in time.

The efficacy study population involved genotype 1–infected patients (54% genotype 1a, 39% 1b, and 7% mixed) from five medical centers. Most patients were men (76%); they had a median age of 58 years and a median duration of 54 months from their liver transplant to starting a protease inhibitor. An unfavorable IL28B genotype was found in 69% of 45 patients tested. In the 60% of patients who had undergone previous antiviral therapy, 29% had a partial response. On liver biopsy, another 47% of patients had either bridging fibrosis or cirrhosis.

The immunosuppressive agents used by the patients included cyclosporine (66%) and tacrolimus (23%). A small percentage did not receive a calcineurin inhibitor or rapamycin. Another 27% were taking corticosteroids, and 72% were taking mycophenolate mofetil or mycophenolic acid.

On treatment, the percentage of patients who had an HCV RNA level less than the limit of detection increased from 55% at 4 weeks to 63% at 8 weeks. At 12 weeks the percentage was 71%. An eRVR, defined as negative HCV RNA tests at 4 and 12 weeks, occurred in 57%. An eRVR occurred significantly more often among patients who had at least a 1 log drop in HCV RNA levels during the lead-in phase than did those with less than a 1 log drop (76% vs. 35%).

Overall, 12% of patients experienced virologic breakthrough, and treatment was stopped. This occurred more often among those with a long lead-in vs. those with a short lead-in (21% vs. 10%, respectively). Another 14% discontinued treatment early because of an adverse event; discontinuations occurred more often among patients with a long lead-in (40% vs. 11%).

Protease inhibitors are known to inhibit the metabolism of calcineurin inhibitors, which was reflected in the study by the need to reduce the median daily doses of cyclosporine (from 200 mg to 50 mg) and tacrolimus (from 1.0 mg to 0.06 mg) after protease inhibitor therapy began.

Many patients (49%) required blood transfusions during triple therapy. During the first 16 weeks of therapy, these patients used a median of 2.5 units. The majority of patients (86%) used growth factors, including granulocyte-colony stimulating factor in 44% and erythropoietin in 79%. Medication dose reductions were most frequent for ribavirin (in 78%). A total of 7% were hospitalized for anemia, Dr. Burton said.

Renal insufficiency, defined as an increase in creatinine of greater than 0.5 mg/dL from baseline, developed in 32%. Of two rejection episodes in the study, one involved a patient coming off a protease inhibitor.

Dr. Burton suggested that future studies should focus on identifying predictors for nonresponse to avoid unnecessary treatment and associated toxicities such as complications of anemia and adverse events related to significant protease inhibitor–calcineurin inhibitor interactions, such as worsening renal function and graft rejection when transitioning off a protease inhibitor.

Dr. Burton disclosed that he is an investigator in a clinical trial sponsored by Vertex Pharmaceuticals, which makes telaprevir.☐

BOSTON – Poor interferon: It was once the favored (and virtually only) effective therapy for hepatitis C viral infections, and now clinicians can’t wait to get rid of it.

Several investigational interferon-free oral regimens were the focus of studies presented at the annual meeting of the American Association for the Study of Liver Diseases.

The regimens combine various flavors of direct-acting antivirals (DAAs), with or without interferon’s faithful sidekick ribavirin, in dizzying combinations with varying degrees of efficacy.

Triple Therapy With Only New Agents

A triple DAA regimen that has been under study consists of daclatasvir, an investigational viral NS5Areplication complex inhibitor; asunaprevir, an investigational NS3 protease inhibitor; and BMS-791325, a nonnucleoside NS5B polymerase inhibitor (all three were from Bristol-Myers Squibb). This cocktail yielded high sustained virologic response (SVR) rates after both 12 and 24 weeks of treatment in previously untreated noncirrhotic patients with hepatitis C virus (HCV) genotype 1 chronic infections.

"SVR₄ [SVR at 4 weeks post therapy] was achieved in all treatment-naïve genotype patients with post-treatment data available, including harder-to-treat patients with genotype 1a infection, high viral load, non-cirrhotic IL28b genotype," said Dr. Gregory T. Everson, professor of medicine and director of the section of hepatology at the University of Colorado in Denver.

In pilot studies, a dual regimen of daclatasvir and asunaprevir for 24 weeks was effective in prior null responders with genotype 1b but not 1a infections, prompting the investigators to see whether a triple whammy could improve efficacy in genotype 1a infections, remain tolerable, and ideally, be effective when given for only 12 weeks.

The ongoing open-label study compares daclatasvir 60 mg daily, asunaprevir 200 mg twice daily, and BMS-791325 75 mg twice daily for 12 or 24 weeks; a second part of the study looking at the combination with a 150-mg-higher dose of the latter agent does not have mature data as yet.

In a modified intention-to-treat analysis at 4 weeks of treatment, all 16 patients in a 24-week treatment cohort had HCV RNA levels below the lower limit of quantification (LLOQ). A the primary end point of 12 weeks, 15 (94%) had maintained viral suppression. At week 4 post treatment, 15 of the 16 patients still had viral RNA below the quantifiable level, for an SVR₄ rate of 94%. One patient in this cohort withdrew from the trial at week 9 and is therefore considered a treatment failure.

In a second cohort of 16 patients treated for 12 weeks, rates of below-target or undetectable HCV RNA were 100% at treatment week 4, and 88% at week 12. Two patients who had withdrawn from the trial before the protocol-defined last treatment and therefore were not included in the 12-week analysis also had RNA levels below the LLOQ on subsequent visits, Dr. Everson said. The SVR₄ and SVR₁₂ rates were each 94% in this cohort.

The regimen was generally tolerated. No patients dropped out of the study due to adverse drug-related events, and no cases of viral breakthrough or post-treatment relapse have been reported to date, Dr. Everson said.

Ribavirin Optional

In another study, Dr. Mark S. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore, and his colleagues reported on a combination of daclatasvir and Gilead’s HCV polymerase inhibitor sofosbuvir with or without ribavirin, in patients with HCV genotypes 1, 2, and 3.

They looked at the combination of the two DAAs with or without ribavirin for 24 weeks of treatment in treatment-naïve patients with genotypes 1a or 1b, 2, and 3, and in two separate arms for 12 weeks in patients infected with genotypes 1a or 1b.

In the open-label trial, patients were randomly assigned to one of eight treatment groups. A total of 44 patients infected with genotypes 2 or 3 were assigned to receive daclatasvir 60 mg and sofosbuvir 400 mg daily, with one group also receiving ribavirin. In addition, 44 patients with genotypes 1a or 1b were assigned to daclatasvir and sofosbuvir at the same doses, with or without ribavirin, and in a separate randomization, 82 patients with genotype 1a or 1b were assigned to receive 12 weeks of the two DAAs with or without ribavirin.

The authors found that the combinations achieved SVRs in more than 93% of the entire patient sample. Among 44 patients with genotypes 2 or 3, 93% had an SVR₂₄ rate of 93%, with 1 patient having a confirmed relapse.

Among 126 patients with genotype 1, 96% of those who had reached 12 weeks post treatment had an SVR₁₂, including 3 who did not have an SVR₄. The SVR₂₄ rate in this group was 98%. One patient in this group was reinfected with a new HCV strain.

"Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin," Dr. Sulkowski said.

He noted that the combination was generally well tolerated, with low hemoglobin – often a concern with DAAs – occurring only among those patients who received ribavirin.

Sofosbuvir Stands Alone (Almost)

Another relatively simple regimen that was well tolerated and achieved sustained virologic response in some patients was a combination of sofosbuvir and weight-based or low-dose ribavirin. This combination was associated with a significant number of relapses, however.

Dr. Anu Osinusi, a clinical investigator at the National Institute of Allergy and Infectious Diseases, sought to determine whether a less complex and more tolerable regimen could be effective in an urban population with untreated HCV infection.

They enrolled 60 patients with HCV genotype 1. The majority of the patients were African Americans. In part 1 of the trial, the patients had stage 0 to 2 fibrosis. Part 2 of the trial included patients with all stages, including those with Child-Pugh Class A disease. Patients in part 1 received sofosbuvir 400 mg plus ribavirin 1,000-1,200 mg (10 patients). In part 2, 25 patients each were randomized either to the regimen above or to the same dose of sofosbuvir with low-dose ribavirin (600 mg).

In an interim intention-to-treat analysis, there was one dropout in part 1, and the remaining nine patients all had HCV RNA less than the LLOQ at weeks 4 and 12, at end of treatment, and maintained them out to SVR₁₂.

In the second, randomized phase, 1 patient dropped out at week 3 of treatment in the full-dose ribavirin group; the remaining 24 patients all had RNA undetectable or below target at weeks 4, 12, and end of treatment, but by post-treatment week 4, 6 patients had relapse, yielding an SVR₄ of 72%.

In the low-dose ribavirin arm, 3 patients dropped out by week 8. The remaining 22 patients, while on treatment, all had viral suppression at week 4, but 4 weeks after the end of therapy, 8 patients had relapsed, leaving an SVR₄ of 56% (64% in a modified intention-to-treat analysis). "Ongoing analysis is currently focused on identifying the biologic correlates of HCV clearance, as well as identifying the mechanisms of relapse," Dr. Osinusi said.

The relapses were independent of baseline factors such as HCV RNA level, IL28B genotype, weight, race, degree of fibrosis, and ribavirin dose.

Both regimens were well tolerated, and both produced significant improvement of inflammation with treatment.

Dr. Everson’s study was supported by Bristol-Myers Squibb. He has received research support from the company. Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Osinusi’s study was funded by the National Institutes of Health. She reported having no relevant financial disclosures.

BOSTON – Poor interferon: It was once the favored (and virtually only) effective therapy for hepatitis C viral infections, and now clinicians can’t wait to get rid of it.

Several investigational interferon-free oral regimens were the focus of studies presented at the annual meeting of the American Association for the Study of Liver Diseases.

The regimens combine various flavors of direct-acting antivirals (DAAs), with or without interferon’s faithful sidekick ribavirin, in dizzying combinations with varying degrees of efficacy.

Triple Therapy With Only New Agents

A triple DAA regimen that has been under study consists of daclatasvir, an investigational viral NS5Areplication complex inhibitor; asunaprevir, an investigational NS3 protease inhibitor; and BMS-791325, a nonnucleoside NS5B polymerase inhibitor (all three were from Bristol-Myers Squibb). This cocktail yielded high sustained virologic response (SVR) rates after both 12 and 24 weeks of treatment in previously untreated noncirrhotic patients with hepatitis C virus (HCV) genotype 1 chronic infections.

"SVR₄ [SVR at 4 weeks post therapy] was achieved in all treatment-naïve genotype patients with post-treatment data available, including harder-to-treat patients with genotype 1a infection, high viral load, non-cirrhotic IL28b genotype," said Dr. Gregory T. Everson, professor of medicine and director of the section of hepatology at the University of Colorado in Denver.

In pilot studies, a dual regimen of daclatasvir and asunaprevir for 24 weeks was effective in prior null responders with genotype 1b but not 1a infections, prompting the investigators to see whether a triple whammy could improve efficacy in genotype 1a infections, remain tolerable, and ideally, be effective when given for only 12 weeks.

The ongoing open-label study compares daclatasvir 60 mg daily, asunaprevir 200 mg twice daily, and BMS-791325 75 mg twice daily for 12 or 24 weeks; a second part of the study looking at the combination with a 150-mg-higher dose of the latter agent does not have mature data as yet.

In a modified intention-to-treat analysis at 4 weeks of treatment, all 16 patients in a 24-week treatment cohort had HCV RNA levels below the lower limit of quantification (LLOQ). A the primary end point of 12 weeks, 15 (94%) had maintained viral suppression. At week 4 post treatment, 15 of the 16 patients still had viral RNA below the quantifiable level, for an SVR₄ rate of 94%. One patient in this cohort withdrew from the trial at week 9 and is therefore considered a treatment failure.

In a second cohort of 16 patients treated for 12 weeks, rates of below-target or undetectable HCV RNA were 100% at treatment week 4, and 88% at week 12. Two patients who had withdrawn from the trial before the protocol-defined last treatment and therefore were not included in the 12-week analysis also had RNA levels below the LLOQ on subsequent visits, Dr. Everson said. The SVR₄ and SVR₁₂ rates were each 94% in this cohort.

The regimen was generally tolerated. No patients dropped out of the study due to adverse drug-related events, and no cases of viral breakthrough or post-treatment relapse have been reported to date, Dr. Everson said.

Ribavirin Optional

In another study, Dr. Mark S. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore, and his colleagues reported on a combination of daclatasvir and Gilead’s HCV polymerase inhibitor sofosbuvir with or without ribavirin, in patients with HCV genotypes 1, 2, and 3.

They looked at the combination of the two DAAs with or without ribavirin for 24 weeks of treatment in treatment-naïve patients with genotypes 1a or 1b, 2, and 3, and in two separate arms for 12 weeks in patients infected with genotypes 1a or 1b.

In the open-label trial, patients were randomly assigned to one of eight treatment groups. A total of 44 patients infected with genotypes 2 or 3 were assigned to receive daclatasvir 60 mg and sofosbuvir 400 mg daily, with one group also receiving ribavirin. In addition, 44 patients with genotypes 1a or 1b were assigned to daclatasvir and sofosbuvir at the same doses, with or without ribavirin, and in a separate randomization, 82 patients with genotype 1a or 1b were assigned to receive 12 weeks of the two DAAs with or without ribavirin.

The authors found that the combinations achieved SVRs in more than 93% of the entire patient sample. Among 44 patients with genotypes 2 or 3, 93% had an SVR₂₄ rate of 93%, with 1 patient having a confirmed relapse.

Among 126 patients with genotype 1, 96% of those who had reached 12 weeks post treatment had an SVR₁₂, including 3 who did not have an SVR₄. The SVR₂₄ rate in this group was 98%. One patient in this group was reinfected with a new HCV strain.

"Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin," Dr. Sulkowski said.

He noted that the combination was generally well tolerated, with low hemoglobin – often a concern with DAAs – occurring only among those patients who received ribavirin.

Sofosbuvir Stands Alone (Almost)

Another relatively simple regimen that was well tolerated and achieved sustained virologic response in some patients was a combination of sofosbuvir and weight-based or low-dose ribavirin. This combination was associated with a significant number of relapses, however.

Dr. Anu Osinusi, a clinical investigator at the National Institute of Allergy and Infectious Diseases, sought to determine whether a less complex and more tolerable regimen could be effective in an urban population with untreated HCV infection.

They enrolled 60 patients with HCV genotype 1. The majority of the patients were African Americans. In part 1 of the trial, the patients had stage 0 to 2 fibrosis. Part 2 of the trial included patients with all stages, including those with Child-Pugh Class A disease. Patients in part 1 received sofosbuvir 400 mg plus ribavirin 1,000-1,200 mg (10 patients). In part 2, 25 patients each were randomized either to the regimen above or to the same dose of sofosbuvir with low-dose ribavirin (600 mg).

In an interim intention-to-treat analysis, there was one dropout in part 1, and the remaining nine patients all had HCV RNA less than the LLOQ at weeks 4 and 12, at end of treatment, and maintained them out to SVR₁₂.

In the second, randomized phase, 1 patient dropped out at week 3 of treatment in the full-dose ribavirin group; the remaining 24 patients all had RNA undetectable or below target at weeks 4, 12, and end of treatment, but by post-treatment week 4, 6 patients had relapse, yielding an SVR₄ of 72%.

In the low-dose ribavirin arm, 3 patients dropped out by week 8. The remaining 22 patients, while on treatment, all had viral suppression at week 4, but 4 weeks after the end of therapy, 8 patients had relapsed, leaving an SVR₄ of 56% (64% in a modified intention-to-treat analysis). "Ongoing analysis is currently focused on identifying the biologic correlates of HCV clearance, as well as identifying the mechanisms of relapse," Dr. Osinusi said.

The relapses were independent of baseline factors such as HCV RNA level, IL28B genotype, weight, race, degree of fibrosis, and ribavirin dose.

Both regimens were well tolerated, and both produced significant improvement of inflammation with treatment.

Dr. Everson’s study was supported by Bristol-Myers Squibb. He has received research support from the company. Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Osinusi’s study was funded by the National Institutes of Health. She reported having no relevant financial disclosures.

BOSTON – Poor interferon: It was once the favored (and virtually only) effective therapy for hepatitis C viral infections, and now clinicians can’t wait to get rid of it.

Several investigational interferon-free oral regimens were the focus of studies presented at the annual meeting of the American Association for the Study of Liver Diseases.

The regimens combine various flavors of direct-acting antivirals (DAAs), with or without interferon’s faithful sidekick ribavirin, in dizzying combinations with varying degrees of efficacy.

Triple Therapy With Only New Agents

A triple DAA regimen that has been under study consists of daclatasvir, an investigational viral NS5Areplication complex inhibitor; asunaprevir, an investigational NS3 protease inhibitor; and BMS-791325, a nonnucleoside NS5B polymerase inhibitor (all three were from Bristol-Myers Squibb). This cocktail yielded high sustained virologic response (SVR) rates after both 12 and 24 weeks of treatment in previously untreated noncirrhotic patients with hepatitis C virus (HCV) genotype 1 chronic infections.

"SVR₄ [SVR at 4 weeks post therapy] was achieved in all treatment-naïve genotype patients with post-treatment data available, including harder-to-treat patients with genotype 1a infection, high viral load, non-cirrhotic IL28b genotype," said Dr. Gregory T. Everson, professor of medicine and director of the section of hepatology at the University of Colorado in Denver.

In pilot studies, a dual regimen of daclatasvir and asunaprevir for 24 weeks was effective in prior null responders with genotype 1b but not 1a infections, prompting the investigators to see whether a triple whammy could improve efficacy in genotype 1a infections, remain tolerable, and ideally, be effective when given for only 12 weeks.

The ongoing open-label study compares daclatasvir 60 mg daily, asunaprevir 200 mg twice daily, and BMS-791325 75 mg twice daily for 12 or 24 weeks; a second part of the study looking at the combination with a 150-mg-higher dose of the latter agent does not have mature data as yet.

In a modified intention-to-treat analysis at 4 weeks of treatment, all 16 patients in a 24-week treatment cohort had HCV RNA levels below the lower limit of quantification (LLOQ). A the primary end point of 12 weeks, 15 (94%) had maintained viral suppression. At week 4 post treatment, 15 of the 16 patients still had viral RNA below the quantifiable level, for an SVR₄ rate of 94%. One patient in this cohort withdrew from the trial at week 9 and is therefore considered a treatment failure.

In a second cohort of 16 patients treated for 12 weeks, rates of below-target or undetectable HCV RNA were 100% at treatment week 4, and 88% at week 12. Two patients who had withdrawn from the trial before the protocol-defined last treatment and therefore were not included in the 12-week analysis also had RNA levels below the LLOQ on subsequent visits, Dr. Everson said. The SVR₄ and SVR₁₂ rates were each 94% in this cohort.

The regimen was generally tolerated. No patients dropped out of the study due to adverse drug-related events, and no cases of viral breakthrough or post-treatment relapse have been reported to date, Dr. Everson said.

Ribavirin Optional

In another study, Dr. Mark S. Sulkowski, medical director of the viral hepatitis center at Johns Hopkins University, Baltimore, and his colleagues reported on a combination of daclatasvir and Gilead’s HCV polymerase inhibitor sofosbuvir with or without ribavirin, in patients with HCV genotypes 1, 2, and 3.

They looked at the combination of the two DAAs with or without ribavirin for 24 weeks of treatment in treatment-naïve patients with genotypes 1a or 1b, 2, and 3, and in two separate arms for 12 weeks in patients infected with genotypes 1a or 1b.

In the open-label trial, patients were randomly assigned to one of eight treatment groups. A total of 44 patients infected with genotypes 2 or 3 were assigned to receive daclatasvir 60 mg and sofosbuvir 400 mg daily, with one group also receiving ribavirin. In addition, 44 patients with genotypes 1a or 1b were assigned to daclatasvir and sofosbuvir at the same doses, with or without ribavirin, and in a separate randomization, 82 patients with genotype 1a or 1b were assigned to receive 12 weeks of the two DAAs with or without ribavirin.

The authors found that the combinations achieved SVRs in more than 93% of the entire patient sample. Among 44 patients with genotypes 2 or 3, 93% had an SVR₂₄ rate of 93%, with 1 patient having a confirmed relapse.

Among 126 patients with genotype 1, 96% of those who had reached 12 weeks post treatment had an SVR₁₂, including 3 who did not have an SVR₄. The SVR₂₄ rate in this group was 98%. One patient in this group was reinfected with a new HCV strain.

"Virologic response did not vary according to IL28B genotype, viral subtype, or the administration of ribavirin," Dr. Sulkowski said.

He noted that the combination was generally well tolerated, with low hemoglobin – often a concern with DAAs – occurring only among those patients who received ribavirin.

Sofosbuvir Stands Alone (Almost)

Another relatively simple regimen that was well tolerated and achieved sustained virologic response in some patients was a combination of sofosbuvir and weight-based or low-dose ribavirin. This combination was associated with a significant number of relapses, however.

Dr. Anu Osinusi, a clinical investigator at the National Institute of Allergy and Infectious Diseases, sought to determine whether a less complex and more tolerable regimen could be effective in an urban population with untreated HCV infection.

They enrolled 60 patients with HCV genotype 1. The majority of the patients were African Americans. In part 1 of the trial, the patients had stage 0 to 2 fibrosis. Part 2 of the trial included patients with all stages, including those with Child-Pugh Class A disease. Patients in part 1 received sofosbuvir 400 mg plus ribavirin 1,000-1,200 mg (10 patients). In part 2, 25 patients each were randomized either to the regimen above or to the same dose of sofosbuvir with low-dose ribavirin (600 mg).

In an interim intention-to-treat analysis, there was one dropout in part 1, and the remaining nine patients all had HCV RNA less than the LLOQ at weeks 4 and 12, at end of treatment, and maintained them out to SVR₁₂.

In the second, randomized phase, 1 patient dropped out at week 3 of treatment in the full-dose ribavirin group; the remaining 24 patients all had RNA undetectable or below target at weeks 4, 12, and end of treatment, but by post-treatment week 4, 6 patients had relapse, yielding an SVR₄ of 72%.

In the low-dose ribavirin arm, 3 patients dropped out by week 8. The remaining 22 patients, while on treatment, all had viral suppression at week 4, but 4 weeks after the end of therapy, 8 patients had relapsed, leaving an SVR₄ of 56% (64% in a modified intention-to-treat analysis). "Ongoing analysis is currently focused on identifying the biologic correlates of HCV clearance, as well as identifying the mechanisms of relapse," Dr. Osinusi said.

The relapses were independent of baseline factors such as HCV RNA level, IL28B genotype, weight, race, degree of fibrosis, and ribavirin dose.

Both regimens were well tolerated, and both produced significant improvement of inflammation with treatment.

Dr. Everson’s study was supported by Bristol-Myers Squibb. He has received research support from the company. Dr. Sulkowski’s study was supported by Vertex Pharmaceuticals. He is a consultant to the company and has received grant and research support from it. Dr. Osinusi’s study was funded by the National Institutes of Health. She reported having no relevant financial disclosures.