Hepatitis B virus reactivation in transplant patients treated for hepatitis C recurrence: Prophylaxis makes the difference

Hepatitis C virus (HCV) is known to cause suppression of hepatitis B virus (HBV) replication in patients with HBV/HCV coinfection.[1]Chu C.M. Yeh C.T. Liaw Y.F. Low-level viremia and intracellular expression of hepatitis B surface antigen (HBsAg) in HBsAg carriers with concurrent hepatitis C virus infection.J Clin Microbiol. 1998; 36: 2084-2086Crossref PubMed Google Scholar Loss of HBV suppression following interferon (IFN)-based HCV treatment is a well-known phenomenon[2]Potthoff A. Berg T. Wedemeyer H. Late hepatitis B virus relapse in patients co-infected with hepatitis B virus and hepatitis C virus after antiviral treatment with pegylated interferon-a2b and ribavirin.Scand J Gastroenterol. 2009; 44: 1487-1490https://doi.org/10.3109/00365520903329585Crossref PubMed Scopus (47) Google Scholar and HBV reactivation in patients treated for HCV with direct-acting antivirals (DAAs) has recently attracted clinical attention. Indeed, some of the identified cases had serious outcomes, resulting in liver transplantation or death.3Ende A.R. Kim N.H. Yeh M.M. Harper J. Landis C.S. Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report.J Med Case Rep. 2015; 9: 164https://doi.org/10.1186/s13256-015-0630-8Crossref PubMed Scopus (83) Google Scholar, 4Bersoff-Matcha S.J. Cao K. Jason M. Ajao A. Jones S.C. Meyer T. et al.Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. food and drug administration adverse event reporting system.Ann Intern Med. 2017; 166 (Epub 2017 Apr 7325): 792-798https://doi.org/10.7326/M7317-0377Crossref PubMed Scopus (0) Google Scholar Subsequent series of HBV/HCV-coinfected patients treated with DAAs have shown that viral reactivation was relatively common in hepatitis B surface antigen (HBsAg)-positive patients, and a meta-analysis identified a similar incidence but an earlier viral reactivation and a higher incidence of hepatitis due to reactivation compared to IFN treatments.5Sulkowski M.S. Chuang W.L. Kao J.H. Yang J.C. Gao B. Brainard D.M. et al.No evidence of reactivation of hepatitis B virus among patients treated with ledipasvir-sofosbuvir for hepatitis C virus infection.Clin Infect Dis. 2016; 63 (Epub 2016 Aug 1202): 1202-1204PubMed Google Scholar, 6Wang C. Ji D. Chen J. Shao Q. Li B. Liu J. et al.Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents.Clin Gastroenterol Hepatol. 2017; 15 (Epub 2016 Jul 1015): 132-136https://doi.org/10.1016/j.cgh.2016.1006.1023Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 7Mucke V.T. Mucke M.M. Peiffer K.H. Weiler N. Welzel T.M. Sarrazin C. et al.No evidence of hepatitis B virus reactivation in patients with resolved infection treated with direct-acting antivirals for hepatitis C in a large real-world cohort.Aliment Pharmacol Ther. 2017; 46 (Epub 12017 Jun 14119): 432-439https://doi.org/10.1111/apt.14177Crossref PubMed Scopus (38) Google Scholar, 8Belperio P.S. Shahoumian T.A. Mole L.A. Backus L.I. Evaluation of hepatitis B reactivation among 62,920 veterans treated with oral hepatitis C antivirals.Hepatology. 2017; 66 (Epub 22017 May 29118): 27-36https://doi.org/10.1002/hep.29135Crossref PubMed Scopus (97) Google Scholar, 9Chen G. Wang C. Chen J. Ji D. Wang Y. Wu V. et al.Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: a systematic review and meta-analysis.Hepatology. 2017; 66 (Epub 22017 May 29127): 13-26https://doi.org/10.1002/hep.29109Crossref PubMed Scopus (112) Google Scholar Liver transplantation (LT) offers a unique model to assess the risk of HBV reactivation associated with DAAs in recipients with HBV markers prior to LT or in recipients of liver donors with HBV markers, given the immunosuppressed state that favours replication, particularly when no HBV prophylaxis is given. The multicentre prospective cohort CUPILT (ANRS C023 “Compassionate use of Protease Inhibitors in viral C Liver Transplantation”; ClinicalTrials.gov number NCT01944527) enrolled 699 liver recipients between October 2013 and December 2015.[10]Houssel-Debry P. Coilly A. Fougerou-Leurent C. Jezequel C. Duvoux C. De Ledinghen V. et al.12 weeks of a ribavirin-free sofosbuvir and nonstructural protein 5A inhibitor regimen is enough to treat recurrence of hepatitis C after liver transplantation.Hepatology. 2018; 68: 1277-1287PubMed Google Scholar Of them, 241 patients with positive pre-transplant HBV markers treated with second generation DAAs for HCV recurrence[10]Houssel-Debry P. Coilly A. Fougerou-Leurent C. Jezequel C. Duvoux C. De Ledinghen V. et al.12 weeks of a ribavirin-free sofosbuvir and nonstructural protein 5A inhibitor regimen is enough to treat recurrence of hepatitis C after liver transplantation.Hepatology. 2018; 68: 1277-1287PubMed Google Scholar were included in the present study: at LT, 18 (7.4%) were HBsAg-positive and 223 (92.6%) were HBV core antibody (HBcAb)-positive. The most frequently used DAA combinations were sofosbuvir + NS5A inhibitors (daclatasvir, ledipasvir) ± ribavirin in 87.1% of patients for 12 or 24 weeks, with a rate of sustained virological response at week 12 (SVR12) of 93.4%. HBV DNA and alanine aminotransferase (ALT) levels were obtained at baseline, end of treatment (EOT), and 12 weeks after DAA discontinuation (FU-W12) from medical records or from retrospective testing of available stored plasma samples, using the Abbott RealTime HBV assay. To determine the number of HBV reactivation cases in this population, we included and discussed here all patients with detectable HBV DNA at 1 or more points during HCV treatment follow-up. HBV virological reactivation was defined as a significant increase in HBV DNA levels (>1 log10 IU/ml increase) or levels changing from undetectable (<10 IU/ml) to detectable (>10 IU/ml) after the start of DAAs.[11]Hoofnagle J.H. Reactivation of hepatitis B.Hepatology. 2009; 49: S156-165https://doi.org/10.1002/hep.22945Crossref PubMed Scopus (475) Google Scholar A total of 60 (24.9%) recipients ought to have received HBV prophylaxis, according to international guidelines[12]Terrault N.A. Lok A.S.F. McMahon B.J. Chang K.M. Hwang J.P. Jonas M.M. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1809) Google Scholar: i.e. HBsAg-positive recipients, recipients of HBcAb-positive donors, and HBcAb-positive human immunodeficiency virus (HIV)-infected patients. However, prophylaxis was recorded in only 48 of these cases (Fig. 1). HBV prophylaxis included hepatitis B immune globulin (HBIG) monotherapy in 6 (12.5%) cases, HBIG + nucleos(t)ide inhibitors in 13 (27.1%), and nucleos(t)ide inhibitors without HBIG in 29 (60.4%). Between transplantation and DAA introduction, the HBV status was reassessed in 193 patients (80.0%), with a mean delay of 21.4 ± 28.5 months (0.0–161.7) before HCV treatment baseline, and 4 (2.1%) were HBsAg-positive. Overall, 5 (2.1%) had detectable HBV DNA at 1 to 3 time points of DAA treatment follow-up (Fig. 1 and Table 1). Three of these patients were HBsAg-negative and HBcAb-positive at LT with no initial indication of HBV prophylaxis. Patient 0321-048-1 was prospectively determined to be HBV DNA-positive during DAA therapy, while at DAA introduction a positive HBsAg and a high viral load were demonstrated by the present retrospective study. The liver donor was HBcAb-negative. This de novo post-LT-infection was treated with entecavir with an HBV virological response, but a second LT was required due to decompensated cirrhosis. Patient 0327-041-1 had an occult HBV infection with a negative HBsAg, a low-level viremia throughout follow-up without any HBV treatment, and multiple mutations within the S gene (sG112K, sS114P, sT126N, sT127A/T, sY134H, sS136Y, and sS143A). The third patient (0304-009-1) experienced transient very low-level HBV viremia at EOT with further undetectable results and no increase in ALT levels, and was the only 1 of these 3 HBcAb-positive recipients to exhibit an HBV reactivation as defined. Two patients were HBsAg-positive at LT. Patient 0327-021-1 was HBsAg-positive at LT, but HBsAg-negative at DAA baseline, and was no longer receiving HBV prophylaxis. This patient was cirrhotic before starting DAAs, and experienced SVR12. He presented a virological reactivation, as defined, with a low-level viremia detected at FU-W12 and an ALT increase between EOT and FU-W12, and died at FU-W38 from bacterial infection. Patient 0902-013-1 was HBsAg-positive at LT and received tenofovir + HBIG prophylaxis. However, he experienced HBV recurrence with a positive HBsAg before starting DAAs, and a low-level HBV viremia at baseline: HBV treatment adherence was questionable. He exhibited an increased viral load at EOT and developed an oedematous-ascitic decompensation with raised ALT after DAA discontinuation: this patient exhibited the only HBV reactivation with clinical hepatitis in this retrospective study.Table 1Patients with detectable HBV DNA during HCV treatment follow-up.No.HBV status at LTHIV statusLiver donorHBcAb statusHBV treatmentPre-DAAsBaseline fibrosis score*Metavir score.DAAHBV status at baselineHBV DNA (log IU/ml)ALT (IU/ml)Clinical eventRegimenSVRBaselineEOTFU W12Post-treatmentBaselineEOTFU W120321-048-1HBcAb+NegNegNoneF424-wks SOF + LDVYesHBsAg+6.645.071.72381613None0327-041-1HBcAb+NegNegNoneF0-F212-wks SOF + DCVYesHBcAb+2.492.091.3261013None0304-009-1HBcAb+NegNegNoneF424-wks SOF + DCVYesHBcAb+Und. <11.52n.a.Und. <1 (W48)721516None0327-021-1HBsAg+NegNegNoneF412-wks SOF + DCVn.a.HBcAb+Und. <1Und. <12.17n.a.371630Death at FU-W380902-013-1HBsAg+NegNegTDF + HBIGF424-wks SOF + DCVYesHBsAg+1.493.46Und. <119n.a.142AscitesDCV, daclatasvir; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCV, hepatitis C virus; n.a., not available; RBV, ribavirin; SOF, sofosbuvir; TDF, tenofovir disoproxil fumarate.* Metavir score. Open table in a new tab DCV, daclatasvir; HBIG, hepatitis B immune globulin; HBV, hepatitis B virus; HCV, hepatitis C virus; n.a., not available; RBV, ribavirin; SOF, sofosbuvir; TDF, tenofovir disoproxil fumarate. The rate of HBV DNA detection was also analysed according to HBV prophylaxis status. Our retrospective study included 193 patients with no HBV prophylaxis: 181 HBcAb-positive recipients with no indication of HBV prophylaxis and 13 patients with an initial indication, but with no prophylaxis recorded before the start of DAA therapy (Fig. 1). Of these 193 patients, 4 had detectable DNA during DAA treatment follow-up, but only 2/4 experienced virological reactivation after starting DAAs. Meanwhile, 48 patients received HBV prophylaxis, and 1/48, with poor prophylaxis adherence, experienced a clinical HBV reactivation. Thus, among 241 HBV/HCV-coinfected liver transplant recipients treated with DAAs for HCV recurrence, 5 (2.1%) had detectable HBV replication during treatment follow-up, and 3 (1.2%) fulfilled the criteria of virological reactivation, which was clinically significant in a single patient whereas another patient died during the follow-up, from a liver-unrelated cause. The definition of viral reactivation, a >1 log10 IU/ml viral load increase or levels changing from undetectable to detectable after DAA baseline, was quite stringent compared to definitions used in other published studies on this topic: indeed, the consequences of an even minimal replication could be amplified by the immunosuppressive treatment administered after transplantation. Despite this strict definition, only 1.2% experienced viral reactivation, which is quite reassuring. In the liver transplant setting, some specific populations are at high risk of HBV recurrence, such as HBsAg-positive recipients or patients with HBV reactivation; i.e., HBcAb-positive/HIV-positive recipients or recipients of a liver from an HBcAb-positive donor, and HBV prophylaxis is warranted in these cases.[12]Terrault N.A. Lok A.S.F. McMahon B.J. Chang K.M. Hwang J.P. Jonas M.M. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1809) Google Scholar In our cohort study, 25% of the patients (60/241) met these conditions, but 12/60 were not provided HBV prophylaxis at DAA start and at least 1 additional patient exhibited poor adherence. Among these 13 patients, 2 viral reactivations with clinical consequences were identified. We hypothesize that the absence of prophylaxis or poor adherence was primarily responsible for the HBV reactivation. Although transplantation is a fertile ground for reactivation due to the immunosuppressive therapy, our results are consistent with previous reports: reactivation during DAA treatment occurs mainly in HBsAg-positive patients, with rates ranging from 2 to 55%. Meanwhile, 75% of the patients (181/241) were patients with resolved HBV infection at the time of LT (HBsAg-negative/HBcAb-positive), without HIV infection or a liver from an HBcAg-positive donor, who did not require long-term HBV prophylaxis. An increased reactivation risk could have been expected for this specific population. In our cohort, 3 (1.7%) of these patients had detectable HBV DNA during DAA treatment follow-up, but only 1 HBV reactivation fulfilled the definition of HBV reactivation without any clinical consequences. Our study has some limitations, including the observational design of the CUPILT cohort, the absence of a control transplant population with HBV mono-infection, and the lack of routine serological HBV testing at the start of DAAs in 20% of patients. However, in this transplant setting HBV status at the time of LT is relevant to assess the risk of HBV reactivation. In conclusion, our study highlights the need to assess HBV markers at HCV treatment baseline, as recommended by recent guidelines,[13]EASL Recommendations on Treatment of Hepatitis C 2016. J Hepatol 2017;66a:153-194. https://doi.org/10.1016/j.jhep.2016.1009.1001. Epub 2016 Sep 1022.Google Scholar and as stressed by Bersoff-Matcha et al. who showed that not of all the cases submitted to the FAERS had an HBsAg test result reported.[4]Bersoff-Matcha S.J. Cao K. Jason M. Ajao A. Jones S.C. Meyer T. et al.Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. food and drug administration adverse event reporting system.Ann Intern Med. 2017; 166 (Epub 2017 Apr 7325): 792-798https://doi.org/10.7326/M7317-0377Crossref PubMed Scopus (0) Google Scholar According to current guidelines, all patients starting therapy with HCV DAAs must be assessed before treatment initiation for HBsAg, HBsAb, and HBcAb status, and patients at risk of HBV reactivation (both HBsAg and anti-HBc-positive patients) should have their HBV DNA levels monitored at baseline, during DAA therapy and for several weeks after stopping treatment. This monitoring during DAA follow-up is crucial to a timely implementation of HBV prophylaxis, if required. However, our study is very reassuring and allows us to conclude that if a risk exists, it is extremely rare. We have identified a single reactivation event exclusively attributable to DAAs and furthermore without clinical impact. Our retrospective study also identified an occult HBV infection which did not lead to reactivation, suggesting that factors other than detectable HBV DNA at baseline may influence HBV reactivation upon treatment with DAAs. Additional studies may be necessary to determine the risk factors for HBV reactivation, but our study confirms that its occurrence is very rare among HBsAg-negative anti-HBc-positive patients, including in the liver transplant setting. Our results reaffirm that, beyond the risk of HBV reactivation, this subgroup of patients should undergo clinical monitoring for liver events as recommended by the liver transplant guidelines. However, a specific monitoring during DAA treatment seems dispensable. Thus, HBV reactivation in the setting of LT is potentially preventable. Regardless of HBV-HCV coinfection and LT, proper screening of HBV status is necessary and essential. It is important to recognize that our study has shown that guidelines on prophylaxis and monitoring in transplant patients were not rigorously followed in “real life”, but that this ultimately had little clinical impact. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the Supplementary data to this article: Download .pdf (.56 MB) Help with pdf files Supplementary Data