Maureen Whitsett, David M.Feldman, Calvin Q.Pan

Division of Gastroenterology and Hepatology, Department of Medicine, NYU Langone Health, New York University School of Medicine, New York, NY, USA

Keywords:

ABSTRACT

1.Introduction

Co-infection with hepatitis C virus (HCV) and hepatitis B virus(HBV)represents a significant challenge to health care providers,as patients with co-infection and HBV viremia tend to develop liver fibrosis and hepatocellular carcinoma at higher rates than those with mono-infection.1Co-infection of HCV and HBV, which share routes of transmission, can be observed in high-risk patient populations, organ transplant recipients, as well as those living in endemic areas.2In 2016, the global prevalence of chronic HBV infection was estimated to be nearly 4%.3Over 71 million people,or 1%of the global population,are estimated to have HCV infection.4In addition, among 350 million carriers of HBV in the world, it is estimated that approximately 3.5-7 million patients are coinfected with HCV.5

Guidelines for the treatment of HCV and HBV offer similar parameters for when to offer treatment;6however,recommendations on the management of co-infected patients vary among different societies.The American Association for the Study of Liver Disease(AASLD)and European Association for the Study of the Liver(EASL)recommend treatment initiation for all patients with HCV infection,regardless of the presence or absence of cirrhosis.Both organizations offer treatment regimen suggestions for direct-acting antiviral (DAA) therapy with or without ribavirin or interferon.7,8The recommendation to initiate treatment of HBV depends upon the viremia levels,elevation of alanine aminotransferase(ALT),as well as the presence of fibrosis.Treatment of HBV is also indicated in special patient populations, such as patients who have active HBV infection and are undergoing chemotherapy or pregnant mothers with high levels of HBV deoxyribonucleic acid (DNA) during late pregnancy.9,10Patients with chronic HBV who are not receiving treatment require monitoring at regular intervals.11,12Hepatitis B reactivation is defined as an abrupt increase in the HBV and is welldocumented in patients with previously undetected HBV DNA due to inactive or resolved HBV infection.13

While HBV reactivation was a known phenomenon with interferon-based therapy for patients with HBV and HCV coinfection,14-17the surge of numbers of HBV reactivation cases in coinfected patients had not been reported until after Food and Drug Administration(FDA)approval of DAA treatment in HCV patients.18In a recent report from FDA,among 29 patients who received DAA therapy and presented with HBV reactivation,one patient required a liver transplant and one patient died from acute liver failure.The post-marketing DAA safety report prompted the FDA to release a black box warning which required that physicians screen for coinfection of HBV in all patients who will begin DAA therapy.In addition,close monitoring of co-infected patients for reactivation is mandated by society guidelines.19The current review will provide the updates on the data relevant to the risk assessment of HBV reactivation in HCV patients on DAA therapy.We also summarize the recommendations of the society guidelines and discuss the appropriate management strategies in different patient profiles.

2.Patients’ profile from case reports and case series

Prior to the release of a black box warning for hepatitis B reactivation by the FDA on DAA therapy, there were five case reports and an observational study by Wang et al.which describe HBV reactivation in DAA treated HCV patients with HBV coinfection.20-26These case reports and clinical observations indicated that reactivation can be transient and without clinical symptoms.However, it usually causes a hepatitis flare.HBV reactivation may occur regardless of HCV genotype and type of DAA regimens, regardless of baseline HBV DNA levels and even in patients with undetectable levels pre-treatment, and can occur anywhere from 4 to 48 weeks after initiation of therapy.27-29Two case reports have detailed reactivation in 3 patients since the FDA released its black box warning.7,30The patients’ profiles and their baseline risk for HBV reactivation are presented in Table 17,20-25,30.

In addition to case reports, two observational case series have been published recently.Wang et al.26conducted an observational study in China in 2016 and observed that the severity of HBV reactivation was associated with HBsAg status.Among ten HBsAgpositive patients who underwent DAA therapy,3/10(30%)of them presented with HBV reactivation after initiating DAA treatment.The outcomes of these patients were the following: one had an asymptomatic reactivation, one developed clinically apparent jaundice, and one developed “hepatic failure”.None of the 124 HBsAg negative patients (0%) who were considered having occult HBV infection had HBV reactivation during or post DAA treatment.26All patients developed HBsAg positivity with DAA therapy although it is unclear when the HBsAg seroreversion (HBV serological reactivation) occurred.In 2017, Bersoff-Matcha et al.19reported 29 cases of HBV reactivation in an FDA review of the safety of DAAs.Ten of the patients do not have any laboratory data(prior to starting DAA therapy).Nine patients had detectable HBV DNA prior to starting therapy, 7 patients were positive for HBsAg with undetectable HBV DNA, and 3 patients had no detectable HBV DNA and negative HBsAg.Mean age for individuals as 60.7 years,13 were men, 16 were women.16 patients had genotype 1, 2 with other genotypes, and 11 with unclear genotypes.Time to reactivation ranged from 14 days to 196 days.There were 2 deaths and one patient required liver transplantation.19These studies demonstrate that patients who are HBsAg negative can indeed develop HBV reaction, albeit the frequency of reactivation is quite low.

3.Risk analyses of HBV reactivation in cohort studies

The risk of HBV reactivation in HCV infected patients was also analyzed in several retrospective and prospective cohort studies.31,32Using the electronically retrieved cohort of HCV infected veterans (ERCHIVES) database, Butt et al.33examined 34 632 patients who received DAA therapy for HCV.HBV reactivation was defined variably in this cohort of patients.In this group,the rate of HBV reactivation was 2.4%(P ＜0.001,lower than the 17.7%rate observed in the peg-interferon/ribavirin arm).Of the larger treatment group, 33.9% of patients were HBcAb+ (9343/27 550),11.1%of patients were HBsAg+(3322/29 886),and 4.4%of patients were HBeAg+ (84/1898).

Table 1 Overview of clinical characteristics and risk factors in HCV patient cases with HBV reactivation after initiating DAA treatment.

Liu et al.5performed a prospective,phase 3b,multicenter,openlabel study which entailed treatment of HBV/HCV co-infected patients with sofosbuvir and ledipasvir for 12 weeks.There were 111 total patients.Only 5 patients experienced an increased HBV DNA and ALT elevation ＞2 times the upper limit of normal(ULN)during treatment.Only one of these patients developed symptomatic acute hepatitis with HBV reactivation.There were 70 patients with HBV DNA levels of 20 IU/mL prior to starting treatment; 53% of these patients experienced an increase in HBV DNA of at least 1 log10 during the 12 weeks of treatment.Serper et al.34examined the rate of significant ALT flares, HBV reactivation, and hepatic decompensation in patients with positive HBcAb who received DAA therapy within the Veterans Affairs healthcare system.In total,during treatment,14% of patients developed ALT elevation greater than or equal to 2 times the ULN, 3% of patients developed elevations 4 times the ULN,20 patients had ALT elevations exceeding 300 IU/mL, and 2 patients had ALT elevations exceeding 1000 IU/mL.

Tamori et al.'s study aimed to compare the rate of HBV reactivation in those with “resolved HBV infection” (N = 765), defined as HBcAb+, and those with co-infection (N = 25), defined as HBsAg+.HBV reactivation was defined as either new HBV viremia＞20 IU/mL or an increase in the viral load greater than 2 log copies/mL.Following EASL recommendation for HBV/HCV co-infection and DAA therapy, three patients in the HBsAg+ group with HBV DNA ＞2000 IU/mL before treatment were started on entecavir prior to DAA therapy.Throughout treatment and afterwards their viral loads remained undetectable 12 weeks after completion of DAA therapy.Three patients in the same group with HBV DNA ＜2000 IU/mL experienced HBV reactivation during DAA therapy.Only one patient of 765 in the resolved HBV infection group experienced HBV reactivation, which was an appearance of HBV viral DNA of 21 IU/mL.This study seems to support that very rarely patients with HBcAb will reactivate when treated with DAA therapy.35

4.Current recommendations from guidelines

Current major guidelines strongly recommend screening for HBV infection for any patient with HCV before initiation and during DAA therapy regardless of past HBV status,HCV genotype and class of DAAs used.HBV reactivation can be prevented with pre-DAAtreatment screening and prophylactic treatment when necessary.The FDA guidelines recommend periodic monitoring for reactivation in patients with prior HBV exposure (or HBcAb+,HBsAg-)in addition to those with chronic infection (HBsAg+, HBcAb-).19Both EASL and AASLD make suggestions regarding appropriate candidates for HBV therapy with DAA treatment.The AASLD recommends treatment of any patient who would normally meet criteria for HBV therapy (for HBeAg-negative patients with HBV DNA ＞2000 IU/mL) as well as any patient with coinfection and cirrhosis.For patients who are HBcAb+ but HBsAg- (thus patients who would not qualify for nucleo(t)side treatment),ALT should be assessed at the start and completion of treatment as well as at varying intervals post-treatment.HBV DNA and HBsAg should be tested if ALT increases or fails to normalize after treatment.Treatment options for co-infected patients include entecavir or tenofovir(TDF or TAF).Additionally, any patient with risk factors for HBV acquisition receiving DAA therapy should receive HBV vaccination.11EASL recommendations vary in the suggestion that those with HBsAg+ should receive nucleo(t)side prophylaxis for 12 weeks post-treatment with DAA.12Neither organization recommends testing for HBV DNA at the initiation of DAA treatment routinely to identify patients with occult HBV infection.The summary of the aforementioned guidelines is presented in Table 2.

5.Discussions

There are numerous postulated mechanisms for HBV reactivation during treatment, many of which are based upon clinical observations.HCV infection tends to predominate in many coinfected patients, which suggests that HBV viral replication is somehow suppressed by active HCV infection.One possible mechanism is that HCV viremia induces expression of certain interferons which suppress HBV;36clinically, this seems to be supported by the fact that patients who have received interferon-based therapies experience HBV reactivation once therapy has completed.As DAA therapy typically leads to a rapid reduction in HCV levels within weeks,37HBV reactivation has been observed much earlier in those treated with DAA compared to interferon-based regimens.38The risk of reactivation of HBV in immunocompromised patients has been well-described, as lymphocyte depletion and poor antibody production permits unchecked HBV replication as well as protein expression.Fatality rates are reported as high as 10%in certain cancer patient populations.5The risk of reactivation with serious clinical consequences in patients undergoing DAA therapy is still unclear, though present studies suggest it is lower in those without HBsAg expression when compared to those with chronic HBV.39,40A recent meta-analysis by Mücke et al.38noted that within the available literature, no cases of HBV-related hepatitis were reported in patients with HBV reactivation with resolved infection(anti-HBc+ but HBsAg-).

As more data are required to evaluate the underlying mechanisms of HBV reactivation in this setting,it remains unclear which patients should receive prophylaxis with DAA therapy (beyond those eligible for HBV treatment) as well as if HBV DNA should be checked at least once in all patients.It is recommended that prior to initiating therapy with DAA patients undergo testing for the presence of HBsAg as well as anti-HBc.Additionally, it is important to understand that a baseline HBV DNA level should be obtained as this would allow for detection of reactivation based upon the increase in HBV DNA by greater than 1 log copies/mL.5Patients with cirrhosis, irrespective of the presence of HBsAg, should undergo treatment for HBV concurrently.Additionally, those who meetcriteria for treatment under current AASLD guidelines should also receive therapy.It is reasonable to check both HBV DNA and HBsAg when ALT levels increase during treatment or after treatment and if ALT levels do not return to normal with HCV eradication.Finally,Serper et al.'s suggestions are reasonable in terms of testing for the presence of HBsAg once sustained virologic response has been achieved in order to detect any subclinical seroconversion which arose with HCV eradication.34

Table 2 Current recommendations from guidelines on the screening and pre-emptive treatment of HBV in patients with HCV prior to DAA therapy.

Fig.1.Algorithm of managing patients with risk of hepatitis B reactivation from DAAs for hepatitis C.Abbreviations: DAA, direct-acting antiviral; ALT, alanine aminotransferase;DNA,deoxyribonucleic acid;HBV,hepatitis B virus;HBcAb,hepatitis B core antibody;HBeAg,hepatitis B e antigen;HBsAb,hepatitis B surface antibody;HBsAg,hepatitis B surface antigen; ULN, upper limit of normal; TDF/TAF, tenofovir.

In conclusions, rare cases of HBV reactivation occur in the context of HCV DAA therapy.Published data indicated that the reactivations were predominantly in HBsAg-positive patients, but they can rarely occur in patients who are HBsAg negative with HBcAb positivity.The severity of the flares has been highlighted by the FDA report, which presented 29 cases of HBV reactivation between 2013 and 2016 including 8 cases of fulminant hepatitis/liver failure, 2 deaths, and 1 required transplant.All major guidelines recommend that all patients initiating DAA therapy should undergo HBV testing prior to treatment.We proposed the clinical management algorithm of patients with risk of hepatitis B reactivation from DAAs for hepatitis C and presented it in Fig.1.The pre-emptive antiviral therapy for HBV should be considered in HBsAg-positive patients with high levels of viremia not already on HBV treatment.If HBV DNA is less than guideline criteria for HBV treatment,one should consider pre-emptive HBV antiviral therapy versus HBV DNA monitoring during DAA therapy.For patients who are HBsAg negative but HBcAb positive,there is insufficient evidence for firm guidelines on recommending pre-emptive HBV therapy.Therefore,close monitoring of serum ALT levels during/post-treatment(peak incidence of HBV reactivation at week 8-12 on-treatment,cases as late as 5 months post-treatment reported)is highly recommended.

Authors’ contributions

C.Q.Pan provided concepts, outlines, and performed literature research.M.Whitsett also performed literature research.C.Q.Pan and M.Whitsett wrote the manuscript with assistance from D.M.Feldman.C.Q.Pan provided critical reviews and communicated with the journal.

Conflict of interest

C.Q.Pan has received research grants from Gilead and Merck.He also serves as a consultant or advisor for Gilead, and speakers’bureau for Gilead, Abbvie, and Intercept.Other authors have no conflicts of interest to disclosed.

Acknowledgements

The manuscript was prepared by authors without other assistance.We would like to thank Ms.Dan Wang for editorial works.