Faculty Bibliography

Patients with cirrhosis who are infected with hepatitis C virus (HCV) are the most in need of antiviral treatment. Virologic cure improves fibrosis and quality of life while reducing liver-related morbidity and mortality. In mid-2011, the addition of direct-acting antiviral agents (DAAs)-the protease inhibitors boceprevir (Victrelis, Merck) and telaprevir (Incivek, Vertex)-to pegylated interferon alpha-2a/b and ribavirin revolutionized the treatment of HCV infection by increasing cure rates across all fibrosis scores in patients with genotype 1 HCV infection. However, patients with advanced fibrosis or cirrhosis are the most difficult to treat, and the addition of DAAs increases treatment side effects as well as potency. Five phase III DAA trials have been published to date, but they contain limited data on patients with cirrhosis. This review will examine the available data and will describe the evolution of HCV therapy in patients with cirrhosis from the standard-of-care therapy of the past decade into the new era of DAAs.

Hepatoportal sclerosis (HPS) is one of several entities known to cause noncirrhotic portal hypertension. To date, its etiology is unknown. There have been increasing reports of HPS occurring in patients with human immunodeficiency virus (HIV), and the US Food and Drug Administration (FDA) recently issued an advisory regarding the development of noncirrhotic portal hypertension in association with didanosine (ddI) use. We report on a patient with HIV who had taken ddI for 4 years and who developed portal hypertension. Histopathological review of paired liver biopsies showed an initial drug hepatotoxicity, microvascular liver injury, and the presence of HPS. Despite cessation of ddI, the latter biopsy showed resolution of the drug-induced injury, but it also showed progression of the HPS. The patient's portal hypertension also progressed suggestive of an unremitting vascular injury. This case demonstrates the development of HPS resulting from a drug-induced microvascular injury. The paired biopsies demonstrate that the initial vascular injury may disappear but that the portal hypertension and HPS progress.

Hepatitis C (HCV) treatment is on the cusp of change with the approval of the first direct-acting antivirals: telaprevir and boceprevir. Drug-drug interactions with HIV antiretrovirals, increased toxicity, and rapid selection of HCV-resistant mutants are among the treatment complexities expected in this difficult-to-treat population. Until the current standard of care changes, focus should be on strategies to optimize management of HIV/HCV-coinfected patients with currently available options. This article reviews the latest predictive factors of response to HCV treatment with the current standard of care in HIV-coinfected patients, and new treatment options.

The year 2011 marks the dawn of the new era of direct-acting antivirals for hepatitis C. For the first time since 1998, the U.S. Food and Drug Administration approved two new antiviral drugs for the treatment of chronic hepatitis C virus genotype 1. Dual therapy with pegylated interferon and ribavirin is no longer the standard of care for genotype 1. The new treatment paradigm includes one direct-acting antiviral, a protease inhibitor, in combination with pegylated interferon and ribavirin. This combination nearly doubles the chances of response to treatment, but at the cost of increased toxicity. Many agents with different mechanisms of action and improved safety profiles are in clinical development. The holy grail of HCV treatment is an all oral, interferon-free treatment. The ideal regimen will be potent, well tolerated, with minimal drug-drug interactions and once daily. This article covers new concepts of treatment of hepatitis C with DAAs and gives an overview of the recent highlights in direct-acting antiviral development.

Background: SVR in hepatitis C virus (HCV)-infected patients is associated with improvements in liver histology and reduced risk of hepatocellular carcinoma and liver-related mortality. Data regarding long-term durability of SVR and incidence of liver-related morbidity/ mortality following peginterferon-based treatment are limited. This prospective long-term follow-up study of a large diverse cohort of patients assessed the durability of SVR and the incidence of significant clinical events in patients achieving an SVR following interferon-based treatment. Methods: HCV-infected patients recruited from 10 trials of interferon- based therapies +/- ribavirin were assessed for significant liverrelated clinical events. In HCV RNA serum-negative patients (<50IU/mL at the final week 24 follow-up assessment), the durability of undetectable serum HCV RNA was assessed. The efficacy population consisted of (a) all patients previously treated with conventional/pegylated interferon +/- ribavirin and (b) the subset of naive patients previously treated with peginterferon alfa-2a (40 kD) +/- ribavirin, all with undetectable HCV RNA at the last visit of the original study. Results: Among 1,724 patients evaluable for safety, 25 significant clinical events were detected in 21 (1.2%) patients: ascites (n = 5), encephalopathy (n = 4), hepatic malignancy (n = 1) and death (n = 15; 3 hepatic related). Of the 21 patients, 8 had significant hepatic-related clinical events, of whom 4 had baseline cirrhosis. No liver transplantations were reported. In the efficacy population, 99% (1331/1343) of patients previously treated with peginterferon alfa-2a +/- ribavirin continued to have undetectable HCV RNA after mean follow-up 3.9 years. Less than 1% (12/1343) of patients in the peginterferon alfa-2a +/- ribavirin group became HCV RNA detectable after a mean of 1.8 years. Conclusion: SVR achieved with peginterferon alfa-2a +/- ribavirin should be considered a cure for HCV and is associated with a low incidence of significant clinical events

BACKGROUND & AIMS: Few studies evaluated the efficacy of HCV re-treatment and the predictors of response in HIV/HCV co-infected patients. The role of insulin resistance as a predictor of response in this population is unknown. The aim of this study is to evaluate the safety and efficacy of pegylated interferon-alpha-2a and ribavirin in re-treatment of HIV/HCV co-infected patients, predictors of sustained virological response, including insulin resistance, and the relationship between insulin resistance and liver histology. METHODS: This prospective, multi-centered study included HIV/HCV co-infected patients with prior interferon-based treatment failure. Patients received pegylated interferon-alpha-2a and ribavirin for 48 weeks. Serum HCV RNA was measured 24 weeks post treatment to assess sustained virological response. Insulin resistance was defined as HOMA-IR >2. Correlations between baseline insulin resistance and steatosis, and/or cirrhosis were determined. RESULTS: Sustained virological response was achieved in 14/96 (15%) patients. 35% of patients with HOMA-IR < 2 (6/17) achieved sustained virological response vs 14% (5/36) of those with HOMA-IR between 2-4, and 7% (3/41) of those with HOMA-IR > 4 (p = 0.01). In multivariable analysis, insulin resistance and log HCV RNA were negatively associated with sustained virological response [AOR 0.17; 95% CI 0.05-0.64, p = 0.009, and AOR 0.36; 95% CI 0.14-0.93, p = 0.04, respectively]. Steatosis and cirrhosis correlated with insulin resistance (p = 0.02 and 0.03, respectively) but neither independently predicted sustained virological response. Discontinuations due to severe adverse events occurred in 8% of cases, and 2 patients died of unrelated causes. CONCLUSIONS: In HIV/HCV co-infected patients undergoing re-treatment, sustained virological response rate is low; those patients without insulin resistance are significantly more likely to achieve sustained virological response