Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study.

BACKGROUND: Eradication of hepatitis C virus (HCV) infection via interferon-based treatment lowers hepatocellular carcinoma risk; some research suggests this effect extends to interferon-free treatment. AIMS: The objective of this retrospective cohort study was to examine the association of direct-acting antiviral (DAA) exposure with risk of incident liver cancer in real-world data. METHODS: From United States administrative claims data through March 31, 2017, we identified 30 183 adult HCV patients exposed to DAAs. For comparison, we identified contemporary adult HCV patients without evidence of HCV treatment (N = 137 502), and historical HCV patients treated with interferon prior to the introduction of DAAs (N = 12 948). Included patients had at least 12 months of prior enrolment and no evidence of prior liver cancer at baseline. Hazard ratios (HRs) estimating risk of incident liver cancer associated with DAA treatment were calculated using Cox proportional hazards methods. RESULTS: Relative to untreated HCV patients, DAA-treated patients were older, more likely to be male, and more likely to have cirrhosis at baseline. After adjustment, DAA treatment was associated with a significantly reduced risk of liver cancer relative to no treatment (adjusted HR = 0.84, 95% CI: 0.73-0.96), and relative to interferon-based treatment in the pre-DAA era (HR = 0.69, 95% CI: 0.59-0.81). CONCLUSIONS: In this large, population-based study, DAA-based treatment was associated with a reduced risk of incident liver cancer relative to both no HCV treatment and to interferon-based treatment in the pre-DAA era. As additional follow-up time of DAA-treated patients accrues, we anticipate that the long-term benefits of DAA treatment will become more apparent.

Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir-containing regimens.

Treatment with the direct-acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of ≥95% in hepatitis C virus (HCV) genotypes (GT) 1-6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV-mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo.

Augmentation of hepatitis C virus-specific immunity and sustained virologic response.

Treatment for chronic hepatitis C virus (HCV) infection has rapidly evolved into interferon-free directly acting antiviral regimens (DAA) that result in high sustained virologic response. DAAs primarily work by suppressing HCV replication and rely less on the immune system than interferon-based therapies. However, it is unclear whether the immune system recovers with suppression of HCV replication and contributes to HCV clearance with DAA therapy. We previously demonstrated HCV clearance is associated with increased HCV-specific immunity in CHCV-GT-1-infected patients during treatment with sofosbuvir (SOF)+ribavirin (RBV). Here, we aimed to analyse changes in HCV-specific immunological responses associated with viral clearance with combination DAA therapy of SOF+ledipasvir (LDV) for 12 weeks in CHCV-GT1 (N=14) patients who relapsed without augmentation of HCV-specific immunity during treatment with SOF+RBV. Phenotypic and functional changes within the T-cell compartment of PBMCs pre- and post-treatment were analysed. Retreatment of relapsers with LDV/SOF resulted in all patients attaining SVR12 . Suppression of HCV was associated with a decline in T-cell exhaustion markers (CD57; Tim3; PD1) along with augmented of HCV-specific T-cell IFN-gamma responses post-treatment. Addition of LDV to SOF was associated with augmentation of HCV-specific immunity and SVR in patients who previously failed SOF+RBV therapy without increased immunity. These findings demonstrate a novel effect of DAA in inducing host immune responses to aid HCV clearance and achieve SVR.

Effect of HIV on liver fibrosis among HCV-infected African Americans.

Degree of liver fibrosis largely determines treatment urgency for hepatitis C virus (HCV). This retrospective study examined fibrosis stages and predictive factors in African Americans with HCV monoinfection and human immunodeficiency virus (HIV)/HCV coinfection. Nearly 50% of patients had early-stage fibrosis in the study, despite the long duration of infection in many patients. HIV was associated with the early fibrosis group. These results indicate that a large proportion of patients with HCV infection, including those with HIV, could possibly await more-effective and better-tolerated treatment.