All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa–ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) at week 12 after the end of therapy. Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea. Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.)

Abnormal levels of liver enzymes are common among persons infected with human immunodeficiency virus (HIV), and may be caused by multiple factors, including medication toxicity and coinfection with hepatitis C virus (HCV) or hepatitis B virus (HBV).^1-3 Coinfection with HCV and HIV is common, occurring in 50% to 80% of individuals who acquired HIV through parenteral exposures. Chronic HBV infection occurs in 10% to 15% of persons infected with HIV.^2,4

Hepatologists are frequently asked to evaluate human immunodeficiency virus (HIV)-infected patients with abnormal liver enzymes and to assess the causal role of medications, such as antiretroviral drugs. Recently, the use of HIV-1 specific non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine (NVP) and efavirenz (EFV), has been associated with severe hepatic injury. We prospectively studied the incidence of severe hepatotoxicity (grade 3 or 4 change in alanine or aspartate transaminase levels) among 568 patients receiving NNRTI-containing antiretroviral therapy, including 312 and 256 patients prescribed EFV and NVP, respectively. Hepatitis C virus (HCV) and hepatitis B virus (HBV) were detected in 43% and 7.7% of patients, respectively. Severe hepatotoxicity was observed in 15.6% of patients prescribed NVP and 8.0% of those prescribed EFV, but only 32% of NVP and 50% of EFV-associated episodes were detected during the first 12-weeks of therapy. The risk was significantly greater among persons with chronic viral hepatitis (69% of cases) and those prescribed concurrent protease inhibitors (PIs) (82% of cases). Nonetheless, 84% of patients with chronic HCV or HBV did not experience severe hepatotoxicity. Severe hepatotoxicity occurs throughout the course of NNRTI therapy and is more common among patients prescribed nevirapine, those coinfected with HCV or HBV, and those coadministered protease inhibitors.

Due to shared routes of transmission, an estimated 15% to 30% of human immunodeficiency virus (HIV)-infected persons are coinfected with hepatitis C virus (HCV) in the United States and Europe.^1,2 Human immunodeficiency virus infection appears to increase the persistence of the hepatitis C virus, the level of HCV RNA, and, in most studies, progression of HCV-related liver disease.^3-9 However, there are conflicting reports regarding the effect of HCV on the natural history of HIV disease. Prior to the availability of highly active antiretroviral therapy (HAART), increased rates of progression of HIV disease were detected in some studies^5,10,11 but not others.^12-17 Recently, Greub et al¹⁸ reported that, in a study involving HIV-infected patients in Switzerland, among patients receiving HAART, HCV-coinfected patients had decreased survival rates, increased risk of progression to acquired immunodeficiency syndrome (AIDS), and impaired CD4 cell recovery.

Research from JAMA — Ombitasvir, Paritaprevir Co-dosed With Ritonavir, Dasabuvir, and Ribavirin for Hepatitis C in Patients Co-infected With HIV-1 — A Randomized Trial