HKASLD Bi-Monthly Scientific Meeting Journal Review Dr. Mak Wing - - PowerPoint PPT Presentation

HKASLD Bi-Monthly Scientific Meeting – Journal Review

Resident Specialist, Department of Medicine and Therapeutics Prince of Wales Hospital

• Dr. Mak Wing Yan, Joyce

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. Gane EJ et al. New Zealand

• 7/8 (88%) ↑ HBV DNA (<20,000

IU/ml)

• None HBV clinical flare
• None required Rx

Clin Gastroentrol Hepatol 2017. Wang C et al. Hong Kong

• 3/327 (0.91%) had HBV

reactivation

• One in icteric phase, one in liver

failure Ann Intern Med 2017. SJ Bersoff-Matcha et al. USA – FDA

• 29 reports of HBV reactivation
• Two death
• One liver transplantation

J Viral Hepat 2018. Tamori A et al. Japan

• HBsAg Pos with HBV DNA < 2000

IU/ml: 3/22 (12%) ↑ HBV DNA ; no clinical flare

• Resolved HBV infection: 1/765

(0.1%) had HBV reactivation

FDA issued boxed warning on HBV reactivation in patients receiving DAA treatment

Study Design

• Phase 3b multicenter, open-label, non-randomized trial
• To evaluate the efficacy and safety of ledipasvir-sofosbuvir for the treatment
• f 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

• nset 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%) – àmay 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