Hepatitis C and HIV co-infection: closing the gaps.

Abstract

Hepatitis C virus (HCV) infection causes substantial morbidity and mortality, but patients with human immunodeficiency virus (HIV) co-infection are 3 times more likely to develop cirrhosis or liver decompensation than those infected with hepatitis C alone.1 Unlike the treatment of HIV, for which the goal is viral suppression, treatment of hepatitis C is finite in duration, and the goal is to achieve a sustained virologic response (SVR), which is a lack of detectable HCV RNA at least 12 weeks after completion of treatment. Clinically, SVR is considered to represent eradication of hepatitis C infection, although reinfection is possible. Achieving SVR is associated with a significant decrease in subsequent decompensation of liver function, liver cancer, and all-cause mortality in persons with HIV co-infection.2 However, treatment of hepatitis C in patients with HIV co-infection has been limited by the reluctance of many HIV clinicians to use interferon alfa and the hesitation of many hepatologists to treat persons with HIV. Twostudies in this issueof JAMA suggest solutions to this clinical conundrum. In theTURQUOISE-I trial, Sulkowski and colleagues3 studied theoral combinationofparitaprevir (aprotease inhibitor) pharmacokinetically enhanced by ritonavir (also used in regimens to treatHIV), plus ombitasvir (anNS5A inhibitor), and dasabuvir (a nonnucleoside NS5B polymerase inhibitor) (collectively referred to as 3D) and ribavirin for 12 or 24weeks inpatientswithHIVandHCVco-infection.Thesepatients either had not received prior HCV treatment (treatment naive) or did not achieve SVR with previous pegylated interferon alfa (pegIFN) plus ribavirin and had compensated cirrhosis ormilder liver fibrosis. In all patients, HIVwas virologically suppressed because of the concern about development of HIV resistance given receipt of ritonavir monotherapy. The authors reported SVR in 29 of 31 patients (94%) who received 12 weeks of 3D-plus-ribavirin therapy and 29 of 32 patients (91%) who received 24 weeks of therapy. In another report in this issue of JAMA, Osinusi and colleagues4 studied a more narrowly defined group of patients with HIV and HCV co-infection without prior HCV treatment and also without cirrhosis. These patients received the combination of ledipasvir (an NS5A inhibitor) plus sofosbuvir (a nucleotide NS5B polymerase inhibitor) for 12 weeks. Some patients were not receiving antiretroviral treatment for their HIV (unlike ritonavir, ledipasvir plus sofosbuvir does not have anti-HIV activity). Forty-nine of 50 patients (98%) achieved SVR. No patients discontinued study drugs because of adverse events in either study.However, 10%of patients receiving the 3D-plus-ribavirin regimen had to reduce their doses of ribavirinbecauseofanemia,underscoring theneed for closemonitoring of hemoglobin levels for patients treated with these agents. Twopatients in the studyby Sulkowski et al3 and 1 patient in the study by Osinusi et al4 experienced virologic failure. The 2 patients who had virologic failure while receiving 3Dplus ribavirin bothhad cirrhosis andhadpreviouslynot responded to pegIFN plus ribavirin. Patientswith these clinical characteristicswere excluded fromthe trial of sofosbuvir plus ledipasvir. Of note, bothpatients hadvariants associatedwith resistance to all 3 classes of direct antiviral agents (DAAs) contained in 3D plus ribavirin. The clinical significance of these variants for re-treatment of HCV remains unknown. These2 studies leavemanyquestionsunanswered,butdetails in each reinforce the transformative nature of new treatment regimens of all-oral DAAs. One key observation is that DAA-containing regimens result in equivalent SVR rates inpatients co-infected with HIV/HCV compared with HCVmonoinfectedpatients. In the eraof pegIFNplus ribavirin, the SVR rate forpatients co-infectedwithHIVandgenotype 1HCV was27%comparedwith41%inanHCVmonoinfectionstudy.5,6 In contrast, studies that include a DAA have closed this gap. This is reflected in current practice guidelines. The Guidelines for the Use of Antiviral Agents in HIV-1 Infected Adults and Adolescents7 refers readers to the HCV guidance for HCV antiviral therapy recommendations.TheHCVguidance states, “HIV/HCV-co-infected persons should be treated and retreated the same as persons without HIV infection, after recognizing and managing interactions with antiretroviral medications.”8 The Food andDrug Administration–approved product label for the combination of ledipasvir plus sofosbuvir (Harvoni) used the data from a clinical trial among patients with HIV/HCV co-infection (PHOTON-1) to support an indication for the combination of sofosbuvir plus ribavirin in patients infected with genotype 1 who were interferon ineligible, including those with HCVmonoinfection. Because the data generated from trials involving HCVmonoinfection and HIV/HCVco-infectionarebeingtreatedas interchangeable from a clinical and regulatory standpoint, it is time to integrate patientswithHIV/HCVco-infection into trialswithpatientswith HCV monoinfection once appropriate antiretroviral drug interaction studies are complete. Another important observation fromthese 2 reports is the closureof thegap inSVRratesbetweenblackpatientsandwhite patientswithHCV infection. Blackpatients aredisproportionRelated articles pages 1223 and 1232 Opinion