A sprint to increase response to HCV treatment: expectancies but caution

J Hepatol. 2011 Nov;55(5):1154-8. Epub 2011 Jul 1

Asselah T.

Source

Service d'Hépatologie, Hôpital Beaujon, Clichy, France. tarik.asselah@bjn.aphp.fr

Abstract

BACKGROUND:

Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies.

METHODS:

We conducted a double-blind study in which previouslyuntreated adults with HCV genotype 1 infection were randomly assigned to one of the three groups. In all the three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately.

RESULTS:

A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (p < 0.001), and in 213 of the 311 patients (68%) in group 3 (p < 0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (p = 0.04), and in 29 of the 55 patients (53%) in group 3 (p = 0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively.

CONCLUSIONS:

The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared to standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir.

BACKGROUND:

In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.

METHODS:

To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of the three groups. In all the three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.

RESULTS:

A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, p < 0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log(10)IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41-46% of boceprevir-treated patients and 21% of controls.

CONCLUSIONS:

The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared to peginterferon-ribavirin alone.

Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Comment on

N Engl J Med. 2011 Mar 31;364(13):1195-206.

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Side-effects of pegylated interferon plus ribavirin therapy with or without protease inhibitor direct acting antiviral agents during treatment of chronic hepatitis C virus infection

Orv Hetil. 2011 Dec 11;152(50):1997-2009

[Article in Hungarian]

Hunyady B, Kovács B, Battyáni Z.

Source

Kaposi Mór Oktató Kórház Belgyógyászati Osztály Kaposvár Pécsi Tudományegyetem, Klinikai Központ I. Belgyógyászati Klinika Pécs Ifjúság u. 13. 7624.

Abstract

Hepatitis C virus (HCV) infection affects 2-3% of the population, approximately 170 million people worldwide, causing chronic HCV-related hepatitis with subsequent liver cirrhosis, hepatic failure, hepatocellular cancer, and liver-related mortality in a large number of patients. The gold standard therapy, pegylated interferon alpha in combination with ribavirin can eradicate hepatitis C virus infection in approx. 40% of treatment-naïve patients infected with HCV genotype G1, and only 15-20% of patients with previous treatment. Success rate is substantially improved with the development and registration of two direct acting anti-hepatitis C virus protease inhibitors (boceprevir and telaprevir) in the second decade of 21st century: combined with the standard therapy, almost three quarter of previously untreated, and more than half of previously unsuccessfully treated patients can achieve sustained viral response with protease inhibitor based triple therapies. A major barrier to successful treatment is the association of peginterferon/ribavirin therapy with frequent and sometimes serious adverse effects. In clinical trials, approximately 10-15% of treated patients discontinue peginterferon and ribavirin due to adverse events; however, in routine clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The side effects of peginterferon/ribavirin therapy affect virtually all organ systems, and addition of protease inhibitor can amplify these side effects (particularly anemia), and/or may lead to new ones (i.e., dysgeusia with boceprevir or skin rush with telaprevir). There is considerable regional and global variability in the nature and prevalence of these adverse effects as well as in the best strategies to ameliorate their impact on hepatitis C virus treatment. This article summarizes the side effects of dual and triple therapies and their management based on the labels of the drugs, on a comprehensive literature review, as well as on the recently published opinion of an international panel of experts - with the provision of providing help for the physicians treating hepatitis C virus infection to achieve the best possible success with the highest possible safety for the patients. Orv. Hetil., 2011, 152, 1997-2009.

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Formulary management of the protease inhibitors boceprevir and telaprevir for chronic hepatitis C virus

J Manag Care Pharm. 2011 Nov;17(9):685-94

Tungol A, Rademacher K, Schafer JA.

Source

Prime Therapeutics LLC, 1305 Corporate Center Dr., Eagan, MN 55121. USA. jschafer@primetherapeutics.com.

Abstract

Background: Hepatitis C virus (HCV) is the most common chronic bloodborne illness in the United States. The incidence of acute hepatitis C in the United States peaked near 50,000 cases in the late 1980s but has stabilized since 2003 to less than 5,000 cases annually. The combination of pegylated interferon (peginterferon) and ribavirin has been the standard recommended treatment for HCV. Protease inhibitors telaprevir and boceprevir were approved by the FDA in May 2011 for the treatment of hepatitis C genotype 1 in combination with peginterferon and ribavirin. Objective: To review the phase 3 trials for telaprevir and boceprevir and provide managed care considerations. Methods: A MEDLINE review was performed for articles published and available through September 15, 2011, using keywords "boceprevir" or "telaprevir" with an emphasis on phase 3 trials. The literature search was limited to articles in English, clinical trials, randomized controlled trials, and research conducted in humans. Additional information was obtained from the FDA website. Results: Three phase 3 trials are available for telaprevir, which provided data that were the basis for FDA approval. Boceprevir demonstrated efficacy and safety in 2 pivotal phase 3 trials. Both agents demonstrated statistically significantly higher rates of virologic response compared with the standard of care involving peginterferons and ribavirin. Telaprevir and boceprevir also demonstrated efficacy in the treatment of patients who had previously failed dual therapy for hepatitis C. Safety concerns for both agents include anemia, drug interactions, skin rashes, and gastrointestinal adverse events. Conclusions: Decision makers have many factors to consider in developing a strategy around hepatitis C. Increased drug costs, patient management, adherence, comparative safety and efficacy, and appropriate utilization management controls are important issues. Payers may consider developing clinical programs to encourage adherence and appropriate use and leverage an appropriate channel to ensure cost-effective therapy.

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Clinical relevance of detectable but not quantifiable hepatitis C virus RNA during boceprevir or telaprevir treatment

Hepatology. 2011 Nov 16. doi: 10.1002/hep.24791. [Epub ahead of print]

Harrington PR, Zeng W, Naeger LK.

Source

Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993. Patrick.Harrington@fda.hhs.gov.

Abstract

Boceprevir- and telaprevir-based treatments for chronic hepatitis C virus (HCV) infection use specific response-guided therapy (RGT) guidelines. Eligibility for shortened treatment duration is based on achieving Undetectable HCV RNA early during treatment. It is unclear whether a detected HCV RNA level that is below the assay lower limit of quantitation (Detectable/BLOQ) is comparable to an Undetectable HCV RNA level, particularly regarding RGT decision making. We analyzed data from boceprevir and telaprevir clinical trials to obtain a comprehensive understanding of the frequency and clinical relevance of Detectable/BLOQ HCV RNA measurements. In Phase 3 trials P05216 (boceprevir), C216 (telaprevir) and 108 (telaprevir), Detectable/BLOQ levels were reported for approximately 10-20% of all on-treatment HCV RNA measurements. In P05216 and C216, subjects with Detectable/BLOQ HCV RNA, on average, had a reduced sustained virologic response (SVR) rate compared to subjects with Undetectable HCV RNA at the same on-treatment timepoint. At key RGT timepoints (Week 8 for boceprevir, Week 4 for telaprevir), subjects with Detectable/BLOQ HCV RNA had an approximately 20% lower SVR rate compared to subjects with Undetectable HCV RNA, and this difference widened for later on-treatment timepoints. A similar trend was observed for Study 108, but the differences in SVR rates were more modest, which may be explained by a higher frequency of reported Detectable/BLOQ results. Analyses of Phase 2 boceprevir and telaprevir trials indicated subjects with Detectable/BLOQ HCV RNA at RGT timepoints benefited from extended treatment duration. CONCLUSIONS: During boceprevir- and telaprevir-based treatment, subjects with Detectable/BLOQ HCV RNA had a reduced virologic response compared to subjects with Undetectable HCV RNA. Eligibility for shortened treatment duration should be based on patients achieving Undetectable HCV RNA at RGT decision timepoints. (HEPATOLOGY 2011.).

Copyright © 2011 American Association for the Study of Liver Diseases.

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HCV Infection May Predict Coronary Artery Disease

By: HEIDI SPLETE, Internal Medicine News Digital Network

NATIONAL HARBOR, MD. – Coronary artery disease was significantly more prevalent in patients with hepatitis C virus infection, compared with control subjects, based on a retrospective review. The findings were presented at the annual meeting of the American College of Gastroenterology.

"An association of coronary artery disease [CAD] with hepatitis C has been suggested, but definitive data are still lacking," said Dr. Sanjaya Satapathy, who conducted the study while at Long Island Jewish Medical Center in New Hyde Park, N.Y.

To estimate the prevalence of CAD in hepatitis C patients, Dr. Satapathy and his colleagues reviewed data from 934 individuals with hepatitis C infection who were seen at a single center between May 2002 and December 2008. Of these patients, 63 had undergone coronary angiography. The investigators compared their data with data from 63 matched controls without hepatitis C.

Overall severity of CAD according to the combined Reardon severity score was significantly greater in the hepatitis C virus (HCV) group than in the controls (6.3 vs. 2.6, respectively), suggesting that being HCV-positive increases the severity of, or risk for, CAD, Dr. Satapathy said.

The researchers defined CAD in two different ways for their analysis. CAD defined as stenosis greater than 50% was found in 44 of the HCV cases (70%) compared with 30 controls (48%). CAD defined as stenosis greater than 75% was found in 42 patients with hepatitis C (67%) compared with 29 controls (46%).

In addition, the prevalence of multivessel coronary artery disease was significantly higher in the HCV patients compared with the controls (57% vs. 16%, respectively). The prevalence of single-vessel involvement was greater in the control group.

"HCV seropositive status is a strong predictor for CAD," Dr. Satapathy said. However, "HCV patients are more likely to remain undertreated with antiplatelet and lipid-lowering agents," he noted.

The study was limited by the retrospective design and small sample size, said Dr. Satapathy. However, the findings suggest that CAD is significantly more common and severe in HCV-positive patients, and this should be considered by clinicians treating these patients, he said.

Dr. Satapathy said he had no financial conflicts to disclose.

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Hepatitis C doesn't affect cognitive function of women, but some evidence HIV does

Michael Carter

Published: 08 December 2011

Infection with hepatitis C does not affect the cognitive performance of women with or at risk of HIV, according to data from the Women’s Interagency HIV Study (WIHS) published in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

“We were unable to show a significant association between the presence of HCV [hepatitis C virus]…and performance on our cognitive battery nor that there is an interaction between HIV and HCV in their effect on cognitive function,” write the authors.

However, their was some evidence that infection with HIV had an impact on cognition.

A number of earlier studies have suggested that hepatitis C-infected individuals have an increased risk of neurocognitive impairments. Moreover, replicating virus has been found in the brains of patients with the infection. It has also been suggested that co-infection with HIV and hepatitis C could have a worse impact on cognitive function than either virus alone.

Women have been unrepresented in research exploring the impact of hepatitis C on cognition. Therefore, investigators from the WIHS designed a study involving 1338. Just under a fifth (18%) had detectable hepatitis C virus and 67% were infected with HIV.

“To our knowledge this cohort for our study is over twice as large as any previously reported study of the effects of HCV and HIV on cognition,” note the investigators.

The patients were divided into six groups:

• Negative for both HIV and hepatitis C RNA (392 individuals).

• HIV-negative/hepatitis C RNA-positive (42 individuals).

• HIV-positive/hepatitis C RNA-negative (480 individuals).

• AIDS/hepatitis C RNA-negative (241 individuals).

• AIDS/hepatitis C RNA-positive (88 individuals)

The patients had a battery of four tests to assess their cognitive function. The results were controlled for age, ethnicity, depression, liver disease status and current or past drug and alcohol abuse, all of which have been shown to affect cognitive function.

There were significant differences between the patients according to their hepatitis C and/or HIV-infection status.

Individuals infected with hepatitis C were a significant nine years older than women who did not have hepatitis C (p < 0.001). Rates of injecting drug use were also significantly higher among the women with hepatitis C (85% vs. 12%), and hepatitis C-infected women were also significantly more likely to report recent use of cocaine (p < 0.001).

As expected, liver function was significantly poorer in those infected with hepatitis C, and the women with an AIDS diagnosis had lower CD4 cell counts than other individuals (p = 0.001).

After controlling for potential confounders, the investigators failed to find any association between hepatitis C viraemia and cognitive performance.

In their first set of analysis, they established a significant connection between poorer liver function and poorer cognitive function (p < 0.001). However, this relationship disappeared after controlling for factors such as age, ethnicity, depression and general mental health.

Nevertheless, infection with HIV was associated with impaired speed of information processing and perceptual motor ability (p < 0.001).

The investigators do not regard their findings as definitive: “The question of whether HCV has a direct effect on cognition will require future studies with a complete neuropsychological batter, a large control group and a large group of HCV-mono-infected subjects.” They also believe that such studies would need “a cohort that includes both men and women.”

Reference

Crystal H et al. Effects of hepatitis C and HIV on cognition in women: data from the Women’s Interagency HIV Study. J Acquir Immune Defic Syndr, online edition, doi: 10.1097/QAI.0b013e318240566b, 2011 (click herefor the free abstract).

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