HKASLD Bi-Monthly Scientific Meeting – Journal Review Dr. Mak Wing Yan, Joyce Resident Specialist, Department of Medicine and Therapeutics Prince of Wales Hospital
HBV-HCV Co-infection • Faster progression of fibrosis, greater risk of cirrhosis, liver decompensation and HCC • Global prevalence unknown • U.S. studies reported 1.4-5.8% HCV-infected patients are HBsAg +ve • 12-14% of HBV Asian patients are positive for anti-HCV
Interaction between HBV and HCV • Dominant HCV infection à Suppressing replication of HBV to low level • Cure of HCV infection à Favorable environment for HBV replication • Reactivation of HBV infection has been reported with Peg-INF and RBV treatment for HCV • Previous audit in QEH on HCV treatment in 2014 (n=143) – 7 patients (4.9%) had HBV-HCV co-infection – 6 patients (85.7%) achieved SVR – NONE had HBV reactivation during course of combination therapy
HBV reactivation after DAA • No prospective study so far • Cases of HBV reactivation during treatment with DAA have been reported
Case report Place Outcomes Antivir Ther 2016. New Zealand • 7/8 (88%) ↑ HBV DNA (<20,000 Gane EJ et al. IU/ml) • None HBV clinical flare • None required Rx Clin Gastroentrol Hepatol 2017. Hong Kong • 3/327 (0.91%) had HBV Wang C et al. reactivation FDA issued boxed warning on HBV • One in icteric phase, one in liver failure reactivation in patients receiving DAA Ann Intern Med 2017. USA – FDA treatment • 29 reports of HBV reactivation SJ Bersoff-Matcha et al. • Two death • One liver transplantation J Viral Hepat 2018. Japan • HBsAg Pos with HBV DNA < 2000 Tamori A et al. IU/ml: 3/22 (12%) ↑ HBV DNA ; no clinical flare • Resolved HBV infection: 1/765 (0.1%) had HBV reactivation
Study Design • Phase 3b multicenter, open-label, non-randomized trial • To evaluate the efficacy and safety of ledipasvir-sofosbuvir for the treatment of HCV genotype 1 or 2 in Taiwanese patients coinfected with HBV
Patients • 111 patients at 14 centers in Taiwan from Jan through July 2016 • 20 years of age or older • With chronic infection with HCV genotype 1 or 2 and HBV (HBsAg or HBV DNA positivity for at least 6 months) • Excluded – Patients receiving HBV treatment within 6 months before baseline – Patients with clinical evidence of hepatic decompensation or HCC • All patients received a fixed-dose combination tablet of ledipasvir-sofosbuvir (90 and 400mg) for 12 weeks
Study assessments • HCV RNA (lower limit of quantification LLOQ of 15 IU/ml) • HBV DNA (LLOQ of 20 IU/ml) • HBV serology (HBsAg, Anti-HBs, HBeAg, Anti-Hbe) • IL28B genotyping • NS5A and NS5B resistance-associated substitutions (RASs) were evaluated using deep-sequencing at a 15% cutoff
Study assessments • HCV RNA, HBV DNA and HBsAg levels were tested – At screening, baseline – Weeks 1,2, 4, 8, and 12 – Post-treatment week 4 – Every 12 weeks thereafter up to post-treatment week 108 • HBV serology – At screening, baseline – Week 12 – Every 12 weeks up to post-treatment week 108
Primary endpoint • Rate of sustained virologic response (defined as an HCV RNA level below the LLOQ at 12 weeks after the end of treatment)
Secondary endpoint • Change in plasma HBV DNA from baseline while on treatment and during post-treatment follow-up • Proportion of patients who required HBV therapy • Prevalence of existing RASs at baseline and emergence of RASs on virologic failure
Statistical analysis • The Clopper-Pearson method was used to calculate point estimates and 2- sided 95% exact confidence intervals for rates of SVR • Exploratory logistic regression analysis was performed to identify factors that were independently associated with an increased risk of HBV reactivation, defined as – a concomitant change in HBV DNA from baseline <LLOQ to ≧ LLOQ, or – An increase >1 log 10 IU/ml from baseline ≧ LLOQ – And ALT > 2x ULN
RESULTS
Baseline Demographics
Efficacy
HBV Reactivation • 77% had HBV DNA still quantifiable at post-treatment week 48 • 2 had concomitant ALT elevation >2xULN at post- treatment week 48 • One started ETV at post- treatment week 53 following onset of malaise, anorexia and jaundice
HBV Reactivation • 3 started anti-viral for HBV • 14/39 (36%) had persistent HBV DNA > 1 log at post- treatment week 48 • None had concomitant ALT elevation
Factors associated with HBV reactivation ALT>2x ULN at baseline was the only factor associated with clinical HBV reactivation
Virologic resistance testing • Genotype 1: – 13% had NS5A RASs at baseline • Genotype 2: – 81% had NS5A RASs at baseline • All patients with or without baseline RASs achieved SVR
Safety • No patient discontinued treatment due to adverse events • Serious adverse events: – Optic neuritis – Duodenal ulcer – Post-procedural colonic bleeding – Torn meniscus
Discussion – Major findings in this study • 12 weeks of fixed-dose combination of ledipasvir-sofosbuvir is a highly effective treatment for HCV genotype 1 or 2 infection in patients coinfected with HBV • Consistent with results from phase 3 trials in the HCV genotype1 mono- infected population • Traditional risk factors for lower rates of SVR, including cirrhosis and HBV coinfection, have little effect on the antiviral efficacy of SOF-LDV
High efficacy of SOF/LDV in Genotype 2 infection • Ledipasvir – Low potency against genotype 2a and 2b replicons in vitro • Sofosbuvir – Pangenotypic NS5B inhibitor – Fully active against genotype 2a and 2b replicons in vitro • Minor synergistic interaction of sofosbuvir and ledipasvir • 100% sustained virologic response rate not unexpected
HBV reactivation during DAA • 1st study to prospectively assess risk of HBV reactivation in HBV-HCV coinfected patients receiving treatment for HCV infection • Variety of events: – ‘Silent’ reactivation: isolated increases in HBV DNA – Clinically significant reactivation: elevation in HBV DNA and ALT – Liver failure • Two fatal cases reported in literature - both in patients who met the criteria for initiation of HBV treatment • Majority were asymptomatic increases of HBV DNA and/or ALT in the absence of concomitant liver injury
HBV Reactivation – what we know from this study ? • Consistent with the results in this study – 63% showed an increase in HBV DNA – 5% had a concomitant increase in ALT – None had liver injury or a fatal outcome • Few cases of late ALT elevation after post-treatment week 12 – Long term safety monitoring is warranted in HBsAg-positive HBV-HCV coinfected patients treated with DAAs
Mechanism of HBV Reactivation • Exact mechanism unknown • Rapid HCV suppression with DAA à Reduced activation of interferon cascade à enhanced HBV replication • Degree of reactivation related to degree of immune control before treatment – Those with detectable HBV DNA are at higher risk
Limitations • Small sample population – Limited detection of rare events • All sites were in Taiwan and all patients were of Asian race – Limited generalizability – IL28B CC genotype predominant (77%) – High proportion of patients with genotype 1b HCV (57%) – à may have contributed to the high rates of SVR observed
Conclusion • Treatment with ledipasvir-sofosbuvir for 12 weeks was highly effective for the treatment of genotype 1 and 2 HCV-infected patients with HBV coinfection • Increases in HBV DNA were observed in most patients but not associated with ALT flares or clinical complications • HCV-infected patients should be evaluated for HBV infection before HCV treatment with DAAs • Those who are HBsAg-positive should be monitored during and after treatment for HBV reactivation
Proposed algorithm for managing HBV- HCV co-infection receiving DAA treatment
EASL AASLD
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