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Background. We and others have shown that primary hepatitis C (HCV) infection in men infected with human immunodeficiency virus (HIV) causes early-onset liver fibrosis; however, little is known about the long-term natural history of the liver disease in these HIV-infected men. Methods. We followed a cohort of HIV-infected men with primary HCV infection in New York City. Results. Four men who were not cured after their primary HCV infection developed decompensated cirrhosis within 17 months to 6 years after primary HCV infection. Three died within 8 years of primary HCV infection, and 1 survived after liver transplant done 2 years after primary HCV infection. Three of the 4 men had AIDS at the time of primary HCV infection, and the most rapid progression occurred in the 2 men with the lowest CD4 counts at the time of HCV infection. Liver histopathology was most consistent with HCV-induced damage even though some had exposures to other potential hepatotoxins. Conclusions. Primary HCV infection resulted in decompensated cirrhosis and death within 2-8 years in 4 HIV-infected men. The rapid onset of fibrosis due to primary HCV infection in HIV-infected men cannot therefore be considered benign. The rate of continued progression to liver failure may be proportional to the degree of underlying immunocompromise caused by HIV infection. More research is needed to better define the mechanisms behind accelerated liver damage.

Monotherapy is an ineffective way to treat hepatitis C and it leads to rapid development of resistance. An increasing number of drugs are currently being developed for the treatment of hepatitis C. This allows combination strategies that can overcome the development of resistance and improve sustained virologic response rates. This article focuses on the 2 main strategies in development: quadruple combination therapies, including pegylated-interferon and triple/quadruple pegylated-interferon free combination therapies. If the first combinations are leading to extremely high sustained virologic responses, the second ones offer hope that the era of pegylated-interferon will end soon.

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.

BACKGROUND: Before the introduction of combination antiretroviral therapy (cART), patients infected with the human immunodeficiency virus (HIV) rarely died of liver disease. In resource-rich countries, cART dramatically increased longevity. As patients survived longer, hepatitis C virus (HCV) infection became a leading cause of death; however, because patients with AIDS continue to have 5-fold greater mortality than non-AIDS patients, it is unclear whether HCV infection increases mortality in them. METHODS: In this investigation, which is part of the Longitudinal Studies of the Ocular Complications of AIDS, plasma banked at enrollment from 2025 patients with AIDS as defined by the Centers for Disease Control and Prevention were tested for HCV RNA and antibodies. RESULTS: Three hundred thirty-seven patients had HCV RNA (chronic infection), 91 had HCV antibodies and no HCV RNA (cleared infection), and 1597 had no HCV markers. Median CD4(+) T-cell counts/microL were 200 (chronic), 193 (cleared), and 175 (no markers). There were 558 deaths. At a median follow-up of 6.1 years, patients with chronic HCV had a 50% increased risk of mortality compared with patients with no HCV markers (relative risk [RR], 1.5; 95% confidence interval [CI], 1.2-1.9; P = .001) in an adjusted model that included known risk factors. Mortality was not increased in patients with cleared infection (RR, 0.9; 95% CI, .6-1.5; P = .82). In patients with chronic HCV, 20.4% of deaths were liver related compared with 3.8% in patients without HCV. CONCLUSIONS: Chronic HCV infection is independently associated with a 50% increase in mortality among patients with a diagnosis of AIDS, despite competing risks. Effective HCV treatment may benefit HIV/HCV-coinfected patients with AIDS.

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.