Background: Directly acting antivirals (DAA) are replacing interferon-based hepatitis C therapy. On interferon-based treatment, HCV RNA plasma levels were early predictors of treatment response and mainstays for response-guided therapy. However, the clinical utility of HCV RNA levels to guide duration of DAA therapy has not yet been determined. The aim of this study was to determine the ability of on-treatment plasma HCV RNA levels to predict treatment outcome in HCV mono-infected and HIV/HCV co-infected patients treated with ledipasvir and sofosbuvir.
Methods: In two NIAID clinical trials, SYNERGY A (HCV mono-infected, n=17) and ERADICATE (HIV/HCV co-infected, ARV naïve n=13, on cART n=37), subjects were treated with a fixed dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 weeks. In both trials, patients were treatment-naïve, non-cirrhotics, and infected with HCV genotype 1. Serial measurements of plasma HCV RNA were performed by the Roche COBAS TaqMan HCV test v1.0 and the Abbott real-time PCR assay. The positive predictive value and negative predictive value at week 4 and end of treatment (EOT) for both assays were calculated.
Results: By the Abbott assay on SYNERGY, 11/17 patients had detectable (6/17 quantifiable) HCV RNA at week 4 and 5/17 patients had detectable but unquantifiable HCV RNA at EOT (Figure 1a). All patients with undetectable HCV RNA at week 4 and EOT achieved SVR12, and none with detectable HCV RNA relapsed (PPV 100 and NPV 0). By the Roche assay (Figure 1b), all patients had undetectable HCV RNA at EOT and achieved SVR 12 (PPV 100).
On ERADICATE, 32/50 patients had detectable (9/50 quantifiable) HCV RNA by the Abbott assay at week 4 (Figure 1a), 31 of whom achieved SVR4 (PPV 100 and NPV 3.1). At EOT, 7/49 patients had detectable but unquantifiable HCV RNA by the Abbott assay, all of whom achieved SVR4 (PPV 100 and NPV 0). By the Roche assay (Figure 1b), all 50 patients were undetectable at EOT and 1 relapsed (PPV 98).
Conclusions: Contrary to past experience with interferon-containing treatments, the presence of detectable HCV RNA levels at EOT is not predictive of relapse in these studies. The low negative predictive values at week 4 underscore the importance of continued therapy for patients who fail to achieve undetectable levels of HCV RNA early on during treatment because their chances of achieving SVR are still high.