Management of patients coinfected with HCV and HIV: a close look at the role for direct-acting antivirals

Abstract

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.

Figure 1

Mechanisms of fibrosis progression in coinfected patients. The mechanism of more advanced fibrosis progression reported in coinfected patients is multifactorial. There are HIV-related, HCV-related, and host-related factors that can lead to fibrosis. The damage to the liver tissue can occur by steatosis, necroinflammation, or stellate cell activation or a combination of any of these mechanisms. Ultimately, ongoing damage via these mechanisms results in fibrosis, which can progress to cirrhosis if the etiology is not identified and managed.

Figure 2

Phase 2 SVR-12 interim analysis: telaprevir in addition to PEG-IFN and RBV in coinfected patients. Study 110 was a randomized phase 2 trial assessing the efficacy and safety of telaprevir in combination with pegylated interferon alfa-2a and ribavirin (T/PR) compared with pegylated interferon alfa-2a and ribavirin alone (PR). All patients enrolled completed 48 weeks of therapy. Those in the study arms received telaprevir at 750 mg every 8 hours or 1125 mg every 8 hours (if on efavirenz [EFV]) for 12 weeks and PR for 48 weeks. Those in the control arm received placebo for 12 weeks and PR for 48 weeks. Part A of the study included patients not on ART. Part B of the study included patients on either EFV in combination with tenofovir (TDF) and emtricitabine (FTC) or atazanavir boosted with ritonavir (ATV/r) in combination with TDF and either FTC or lamivudine (3TC). This SVR-12 interim analysis reports that 74% of patients in the treatment study arm (T/PR) maintained an undetectable HCV RNA (Roche COBAS TaqMan v2.0; lower limit of detection, <10 IU/mL) as compared with 45% of those in the standard of care arm (PR).

Figure 3

Phase 2 SVR-12 interim analysis: boceprevir in addition to PEG-IFN and RBV in coinfected patients. The P05411 study was a randomized phase 2 trial assessing the efficacy and safety of boceprevir in combination with PEG-IFN alfa-2b and RBV (Peg2b/RBV+BOC) compared with PEG-IFN alfa-2a and RBV alone (Peg2b/RBV). All patients enrolled completed 48 weeks of therapy, starting with a 4-week lead-in phase of Peg2b/RBV. Following the lead-in phase, those in the study arm received boceprevir at 800 mg every 8 hours and Peg2b/RBV for an additional 44 weeks. Those in the control arm received placebo and Peg2b/RBV for an additional 44 weeks. This SVR-12 interim analysis reports that 61% of patients in the study treatment arm maintained an undetectable HCV RNA (Roche TaqMan v2.0; lower limit of detection, 9.3 IU/mL) as compared with 27% of those on the standard of care Peg2b/RBV.

Figure 4

A framework for the management of HCV in HIV-coinfected patients.