Real-World Effectiveness of DAA Therapies in Human Immunodeficiency Virus/Hepatitis C Virus Coinfection: 996 Veterans Can't Be Wrong.

The advent of direct acting antivirals (DAAs) has revolutionized treatment for hepatitis C virus (HCV), particularly among patients coinfected with human immunodeficiency virus (HIV). The similar rates of sustained virologic response (SVR) among HIV/HCV coinfected and HCV monoinfected patients in clinical studies have prompted the Food and Drug Administration to remove HIV/ HCV coinfection as a population with unmet medical need [1]. However, the complex comorbidities of HIV/HCV coinfected patients, coupled with concerns for drug interactions with HIV antiretrovirals (ARV), have raised concerns that the high rates of SVR observed in clinical trial populations could not be achieved in real-world HIV/HCV populations. The report by Bhattacharya et al, provides an affirmative answer. The authors present results of one of the largest observational HIV/HCV cohorts to date [2]. This report of US veterans with HIV genotype 1 HCV coinfection prescribed 12 weeks of ledipasvir/sofosbuvir (LDV/ SOF) ± ribavirin (RBV) or ombitasvir/ paritaprevir/ritonavir+dasabuvir(OPrD) ± RBV is remarkable not only for overall size (n = 996) and longitudinal follow up (n = 905, 90.9%) but also for substantial percentages of patients with traditionally negative predictors of treatment success: black race (n = 667, 67%), diagnosis of cirrhosis (n = 225, 23%), and previous treatment experience (n = 160, 16%). In addition, a broad range of HIV regimens were represented: integrase strand transfer inhibitors (ISTI, 37%), nonnucleoside reverse transcriptase inhibitors (NNRTI, 30%), and protease inhibitors (PI, 29%), many of which were excluded in the registration trials. In the intent-to-treat analysis, the authors report an overall SVR rate of 90.9% (823/905), which is similar to reported rates (88–92%) among all HCVinfected veterans [3]. In a multivariate analysis that included race, cirrhosis, genotype-1 subtype, prior HCV treatment, proton pump inhibitor (PPI) prescription, CD4 count, and ARV regimen, cirrhosis was the only significant negative predictor of SVR (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31–0.87, P = .01). In addition to reinforcing that HCV is highly curable in the HIV-infected patient, the authors attempted to address other outstanding questions of efficacy including [1]: the report of lower SVR in persons of black race in the ION-4 registration trial—particularly those on efavirenz [2], the safety of concomitant dosing of LDV/SOF with tenofovir disoproxil fumarate (TDF) and a pharmacologic booster (ritonavir or cobicistat) —which was not addressed in the ION-4 trial, and [3] the report of lower SVR in patients receiving LDV/ SOF and concomitant PPI. In ION-4, HIV/HCV coinfected persons of black race experienced lower rates of SVR12 than nonblacks (90% [95% CI, 83 to 95] vs. 99% [95% CI, 97 to 100], P < .001), with a nonsignificant trend toward virologic relapse among blacks on efavirenz [4]. Follow-up candidate gene and genome wide association studies failed to identify pharmacogenomic markers of treatment failure, but both were underpowered due to the overall high SVR in the study [5]. In the study by Bhattacharya, black veterans had similar SVR to nonblacks (90.5% [546/603] vs 91.7% [277/302]). Subgroup analyses did not observe a difference in SVR with and without efavirenz in black veterans prescribed LDV/SOF ± RBV (92.1% vs 91%, P = .72). Although these data provide some reassurance to the use of efavirenz and LDV/SOF in black patients, the inclusion of veterans who received RBV in addition to LDV/SOF could be confounding due to impact of RBV on relapse, particularly among the cirrhotic populations. If nothing else, the mystery around this finding in the ION-4 provides a good reason to discuss switching the patient off of an efavirenz-based regimen prior to starting LDV/SOF, which benefits the patient on multiple fronts. E D I T O R I A L C O M M E N T A R Y