Ledipasvir/Sofosbuvir for Patients Coinfected With Chronic Hepatitis C and Hepatitis B in Taiwan: Follow-up at 108 Weeks Posttreatment

Abstract

Background For patients coinfected with hepatitis C virus (HCV) and hepatitis B virus (HBV), HCV treatment with direct-acting antivirals can lead to HBV reactivation. We evaluated HBV reactivation during ledipasvir/sofosbuvir treatment and 108-week follow-up. Methods In Taiwan, 111 patients with HCV genotype 1 or 2 and HBV received ledipasvir/sofosbuvir (90mg/400mg) once-daily for 12 weeks. HBV virologic reactivation was defined as postbaseline increase in HBV DNA from either <lower limit of quantification (LLOQ, 20 IU/mL) to ≥LLOQ or ≥LLOQ to >1 log10 IU/mL. HBV clinical reactivation was HBV virologic reactivation with alanine aminotransferase (ALT) >2x upper limit of normal (ULN). Factors associated with development of HBV virologic or clinical reactivation were evaluated with logistic regression analysis. Results All patients (100%, 111/111) maintained HCV suppression through 108 weeks after treatment. HBV virologic reactivation occurred in 73% of patients (81/111). Clinical reactivation occurred in 9% (10/111). The majority of HBV virologic reactivations (86%, 70/81) occurred by follow-up week 12 while clinical reactivation was generally more delayed. Eight (7%, 8/111) initiated HBV therapy. In regression analyses, baseline HBV DNA and HBsAg levels were associated with HBV virologic reactivation and baseline ALT, HBV DNA, and HBsAg levels were associated with HBV clinical reactivation. Conclusion Among HCV/HBV coinfected patients treated with direct-acting antivirals for HCV, HBV virologic reactivation occurred in a majority of patients during treatment and follow-up. In most patients, HBV virologic reactivation was asymptomatic; only a small proportion initiated HBV treatment. Notably, clinical reactivation may still occur >3 months after end of therapy.

A Phase 2 open label study of ledipasvir/sofosbuvir for 12 weeks in subjects with hepatitis B virus infection

“…In this single‐center Phase 2 pilot study, CHB infected patients either with the low replicative state (inactive carriers) or virally suppressed on anti‐HBV NA therapy showed a statistically significant decline in qHBsAg levels during the 12 weeks of therapy with combination LDV/SOF taken once daily. The mean HBsAg decline (Table 2) at Week 12 therapy with combination LDV/SOF (mean log 10 IU/ml decline in the low replicative state group of 0.39 and NA‐therapy suppressed group of 0.40) was similar to those seen in a prior HBV‐HCV study whereby subjects were treated for HCV using 12 weeks of combination LDV/SOF and had a mean decline of 0.47 log 10 IU/ml 7 . Interestingly, the observed HBsAg levels gradual return to pretreatment baseline by 12 weeks posttreatment supports the hypothesis of a direct antiviral effect of LDV/SOF, albeit transient, as opposed to the unrelated natural decay of HBsAg.…”

“…The mean HBsAg decline (Table 2) at Week 12 therapy with combination LDV/SOF (mean log 10 IU/ ml decline in the low replicative state group of 0.39 and NA-therapy suppressed group of 0.40) was similar to those seen in a prior HBV-HCV study whereby subjects were treated for HCV using 12 weeks of combination LDV/SOF and had a mean decline of 0.47 log 10 IU/ml. 7 Interestingly, the observed HBsAg levels gradual return to pretreatment baseline by 12 weeks posttreatment supports the hypothesis of a direct antiviral effect of LDV/SOF, albeit transient, as opposed to the unrelated natural decay of HBsAg.…”

“…7 Overall, 37 of 111 (33%) subjects studied in this cohort had an HBsAg decline of ≥0.5 log 10 IU/ ml at 12 weeks on LDV/SOF. 7 Moreover, in a separate study, Loggi et al 8 also found a similar case of an HBV-HCV coinfected patient that was treated with anti-HCV DAAs and observed an HBV DNA increase of more than 2 log but with simultaneous HBsAg decline, and subsequent HBsAg loss. Adult participants were eligible to enroll if they had CHB, either in an inactive carrier state not requiring anti-HBV medication or were virally suppressed on only one NA.…”

Immunopathogenesis of Acute Flare of Chronic Hepatitis B: With Emphasis on the Role of Cytokines and Chemokines

“…After DAA was widely used for treating chronic hepatitis C for its efficacy, convenience and safety, HBV reactivation has been documented to be an important issue in co-infected patients [36][37][38][39][40][41][42]51,52]. Chen conducted a systemic review and meta-analysis to investigate and compare the rate of HBVr in CHC patients treated with interferon (IFN)-based therapy and in co-infected patients treated with DAA therapy [39].…”

“…Direct-acting antiviral agents (DAAs) have become the new standard for the treatment of patients with HCV infection [38,51,52]. However, during the treatment of HCV, HBV may reactivate in patients with HBV and HCV co-infection [36][37][38][39][40][41][42][43].…”