https://orcid.org/0000-0003-3357-2438
Abstract
In the Swiss HIV Cohort Study, 61 of 222 (27%) HIV–suppressed persons with chronic hepatitis B virus (HBV) infection had HBV replication after 2 years on tenofovir, of whom 77% were suppressed thereafter. Self-reported adherence to therapy and HBV viral load at tenofovir initiation were predictors of persistent replication.
Worldwide, approximately 8% of persons with human immunodeficiency virus (HIV, PWH) have chronic hepatitis B virus (HBV) coinfection [1]. Despite optimal treatment with tenofovir-containing antiretroviral therapy (ART), some individuals experience incomplete HBV suppression. In a systematic review that included 550 individuals with HIV/HBV coinfection on tenofovir, only 79% achieved HBV suppression at 2 years [2]. Ongoing viral replication during antiviral therapy contributes to the progression of liver disease and is associated with a higher risk of developing hepatocellular carcinoma [3–5].
Previous studies have generally included small numbers of individuals from heterogeneous populations over short follow-up periods [4, 6, 7]. We aimed to describe the determinants of persistent HBV replication despite HIV suppression on tenofovir-containing ART in the Swiss HIV Cohort Study (SHCS).
METHODS
We considered all SHCS [8] participants with chronic HBV infection, defined as the presence of 2 reactive hepatitis B surface antigen (HBsAg) test results >6 months apart, and at least 4 years of tenofovir-containing ART before October 2019. Participants with an HIV RNA ≥200 copies/mL at the time point of HBV virological outcome assessment were considered to have suboptimal ART adherence and excluded from these analyses. Further exclusion criteria were no HBV DNA or HBsAg available at tenofovir start and missing HBV DNA measurements on tenofovir. The SHCS is a longitudinal, observational, cohort study initiated in 1988 that includes >80% of PLWH on ART in Switzerland [8]. Clinical and laboratory data were collected prospectively every 6 months. Self-reported treatment adherence was assessed using standardized questionnaires, with good adherence being defined as having missed zero or 1 dose of ART during the preceding 4 weeks [9]. Our main outcomes were HBV suppression at 2 years and at the latest follow-up visit. HBV suppression was defined as HBV DNA <20 IU/mL, low-level viremia as HBV DNA 20–2000 IU/mL, and high-level viremia as HBV DNA >2000 IU/mL [4]. “Persistent viremia” was defined as an HBV viral load ≥20 IU/mL both after 2 years and at the latest follow-up. The local ethics committees of the participating centers approved the SHCS, and written informed consent was obtained from all participants.
Demographic and clinical characteristics at tenofovir start were described using either absolute numbers and proportions or medians and interquartile ranges (IQRs). We determined the proportion of participants with HBV replication (HBV DNA >20 IU/mL) after 2 years and persistent replication at the time of the latest available follow-up and explored related risk factors using multivariable logistic regression adjusted for sex, age, ethnicity, Centers for Disease Control and Prevention stage 3, prior HBV active ART (lamivudine or emtricitabine), hepatitis D virus (HDV) coinfection, CD4 cell count, as well as HBV DNA levels (per log10 IU/mL) at tenofovir start and treatment self-reported adherence at 2 years [6]. Statistical analyses were performed using Stata version 16.0.
RESULTS
Study Population
Of 272 PWH with chronic hepatitis B, we excluded 21 with replicating HIV and 29 with missing HBV DNA measurements at 2 years (Supplementary Figure). Among the remaining 222 individuals, median age was 41 years (IQR, 36–47), 43 (19%) were women, 47 (21%) of sub-Saharan African origin, and 162 (73%) had a previous AIDS-defining condition (Supplementary Table). At tenofovir start, 130 of 222 participants (59%) had been previously treated with lamivudine- or emtricitabine-containing ART, 3 of 222 (1%) with non-HBV active ART, and 89 of 222 (40%) were ART-naive. From the 133 ART-experienced individuals at the time of tenofovir initiation, 95 (71%) had an HIV viral load ≤200 copies/mL. Of 221 participants with available measurements, 103 (47%) had a CD4 count >350 cells/µL at tenofovir start. At tenofovir start, 34 of 221 (15%) had a suppressed HBV viral load, 58 of 221 (26%) had low-level hepatitis B viremia, and 129 of 221 (59%) had high-level hepatitis B viremia. HDV coinfection was documented in 30 of 218 (14%), of whom 67% were replicating at tenofovir start.
HBV Replication at 2 Years
Hepatitis B viremia was present in 61 of 222 (27%) participants at 2 years, including 6 of 61 (10%) with high-level viremia (Figure 1A). The proportion of individuals who reported good adherence was higher in individuals with a suppressed HBV viral load (144 of 147, 98%) than in those with ongoing HBV replication (56 of 61, 92%, P = .03). In multivariable analyses, persistent hepatitis B viremia at 2 years was associated with high HBV DNA levels at tenofovir start (odds ratio [OR], 1.38; 95% confidence interval [CI]: 1.20–1.57), whereas it was less likely in individuals with a CD4 count >350/µL at tenofovir start (OR, 0.41; 95% CI: .19–.90), in those with hepatitis D coinfection (OR, 0.07; 95% CI: .01–.59), and in individuals with good self-reported adherence at 2 years (OR, 0.04; 95% CI: .01–.33; Figure 1B).
A, Distribution and course of HBV DNA levels at tenofovir start, after 2 years of therapy, and at latest follow-up. B, Forest plot of possible risk factors for HBV replication (HBV DNA >20 IU/mL) at 2 years (multivariable analysis). Good adherence was defined as having missed zero or 1 and poor adherence was defined as having missed 2 or more doses of ART during the preceding 4 weeks. Abbreviations: ART, antiretroviral therapy; CDC, Centers for Disease Control and Prevention; CI, confidence interval; HBV, hepatitis B virus; OR, odds ratio.
Long-Term HBV Replication
Participants on tenofovir-containing ART were followed for a median of 8.4 years (IQR, 5.2–10.9). At the latest follow-up visit, 32 of 205 (16%) participants had HBV replication (Figure 1A). Among 61 individuals with HBV replication at 2 years, 14 (23%) had persistent viremia: 11 (79%) were men, 3 (21%) of sub-Saharan African origin, 8 (57%) had a previous AIDS-defining condition, 7 (50%) had been previously treated with a lamivudine- or emtricitabine-containing ART regimen, and 12 (86%) had high-level hepatitis B viremia at tenofovir start. We identified 18 of 161 (11%) individuals with HBV suppression at 2 years who experienced incident HBV replication at the latest follow-up visit.
DISCUSSION
In this nationwide cohort of HIV-suppressed PWH with HBV coinfection, 27% of participants had HBV replication after 2 years of tenofovir-containing ART. After prolonged therapy, only 23% of those with replication at 2 years had persistent viremia. Self-reported adherence to ART and a high HBV viral load at tenofovir initiation were important predictors of replication at 2 years.
Although some cohorts of PWH/HBV with long-term follow-up and comparable proportions of pretreated individuals showed similar HBV suppression rates, our results contrast with those from recent studies. HBV suppression rates after 5 years of tenofovir were 96% in an observational study in Taiwan and 99% in Australia [10, 11]. Differences in the natural history of HBV infection and HBV genotypes across settings, as well as the variations in the definition of HBV suppression, could be potential explanations for the different observations [12]. In addition, in the study by Audsley et al, individuals who had previously been treated with tenofovir were also included in the analysis, which may be a reason for the high rates of undetectable hepatitis B viremia at baseline (90% compared with 15% in our cohort) [10].
In our study, participants with suboptimal self-reported treatment adherence were 25 times more likely to have ongoing HBV replication at 2 years, despite HIV suppression. These results support the assumption that the adherence level in PLWH and HBV coinfection may have to be higher in order to reach HBV suppression than HIV suppression [4, 6, 13]. As shown in other studies, individuals with HDV coinfection were significantly less likely to have ongoing hepatitis B replication after 2 years, whereas individuals with high HBV DNA levels at tenofovir start were more likely to have persistent HBV replication [14]. Even in the presence of HIV, HDV appears to be dominant over HBV and to exert an inhibitory effect on HBV replication [14].
Three-quarters of participants with replicating HBV after 2 years of tenofovir therapy achieved HBV suppression after prolonged therapy. Thus, replication after 2 years of tenofovir does not necessarily imply treatment failure; the duration to achieve HBV suppression may be longer, as it has been shown in previous studies [2, 4]. However, the majority of individuals who achieved HBV suppression in our study had reached this outcome after 3 years of tenofovir therapy [4, 11].
We identified a few participants with suppressed hepatitis B viral load at 2 years but with replication at a later time point on tenofovir therapy, underlining the importance of long-term follow-up of individuals with HIV/HBV coinfection. First, because ongoing viral replication during antiviral therapy has a negative impact on serological and clinical outcomes [3–5]. Second, because the mechanisms for the reemergence of HBV replication are still unclear, and as shown in our study, HIV suppression does not seem to be a good proxy for HBV suppression.
Our study is one of the largest to have examined long-term data on HBV replication during continuous tenofovir therapy among persons with suppressed HIV RNA. However, during the observation period, most participants received tenofovir disoproxil fumarate (TDF) and not tenofovir alafenamide (TAF). Although previous studies showed a comparable efficacy of TDF and TAF in viral suppression in HBV monoinfection, it remains to be determined if results from TDF treatment outcomes are fully applicable to TAF [15]. As we did not systematically measure tenofovir diphosphate levels from dried blood spots, we had to rely on self-reports of treatment adherence with a risk of overestimating it.
CONCLUSIONS
Although HBV replication is frequent after 2 years of tenofovir in HIV/HBV coinfection, most individuals eventually achieve viral suppression. Clinical and virological long-term monitoring of these individuals is important as virological rebound rarely occurs. In order to minimize the negative impact of persistent HBV replication on clinical outcomes, it will be crucial to understand why a minority of individuals do not reach suppression, including by conducting genome-wide HBV sequencing analyses and immunological studies.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Acknowledgments. We thank the participants, the physicians and study nurses for excellent patient care, and the data and coordination center for continuous support.
Members of the Swiss HIV Cohort Study (SHCS). Abela I, Aebi-Popp K, Anagnostopoulos A, Battegay M, Bernasconi E, Braun DL, Bucher HC, Calmy A, Cavassini M, Ciuffi A, Dollenmaier G, Egger M, Elzi L, Fehr J, Fellay J, Furrer H, Fux CA, Günthard HF (president of the SHCS), Hachfeld A, Haerry D (deputy of the “Positive Council”), Hasse B, Hirsch HH, Hoffmann M, Hösli I, Huber M, Kahlert CR (chair of the Mother & Child Substudy), Kaiser L, Keiser O, Klimkait T, Kouyos RD, Kovari H, Kusejko K (head of the Data Center), Martinetti G, Martinez de Tejada B, Marzolini C, Metzner KJ, Müller N, Nemeth J, Nicca D, Paioni P, Pantaleo G, Perreau M, Rauch A (chair of the Scientific Board), Schmid P, Speck R, Stöckle M (chair of the Clinical and Laboratory Committee), Tarr P, Trkola A, Wandeler G, and Yerly S.
Disclaimer. Data are gathered by 5 Swiss university hospitals, 2 Cantonal hospitals, 15 affiliated hospitals, and 36 private physicians (listed at http://www.shcs.ch/180-health-care-providers).
Financial support. This study has been financed within the framework of the SHCS, supported by the Swiss National Science Foundation (SNF; grant 177499 to H. F. G. and E. B.). G. W. was supported by a professorship from the SNF (PP00P3_176944). C. B. was supported by the European treatment network for HIV, hepatitis and global infectious diseases (NEAT ID Grant).
References
Author notes
Potential conflicts of interest. E. H. reports support for attending meetings and/or travel from Gilead Sciences and ViiV Healthcare (paid to institution). B. S. reports a grant from Institutional Grant Inselspital Bern, support for attending meetings and/or travel from Gilead Sciences and ViiV Healthcare (paid to institution), and participation on a data and safety monitoring board (DSMB) or advisory board for Gilead Sciences (paid to institution). H. F. G. reports grants from National Institute of Health (NIH) and the Yvonne Jacob Foundation; an unrestricted research grant from Gilead Sciences (paid to institution); and participation on a DSMB or advisory board for Merck, Gilead Sciences, Janssen, ViiV Healthcare, GSK, and Novartis (paid to author). M. S. reports participation on a DSMB or advisory board for Gilead Sciences, ViiV Healthcare, Moderna, MSD, and Pfizer. E. B. reports grants or contracts from Merck Sharp and Dohme (paid to institution); support for attending meetings and/or travel from AbbVie, Gilead Sciences, Merck Sharp and Dohme, Pfizer AG, and ViiV Healthcare (paid to institution); and participation on a DSMB or advisory board for Gilead Sciences, Merck Sharp and Dohme, Pfizer AG, ViiV Healthcare, Ely Lilly, and Astra Zeneca (Paid to institution). P. S. has received consulting/advisory board membership fees from Gilead Sciences. A. C. reports grants from Gilead Sciences, ViiV Healthcare, MSD (unrestricted educational grant; Groupe LIPO et métabolisme; grant to institution), and MSD (research grant). A. R. reports serving on advisory boards for Gilead Sciences and MSD (paid to institution), travel grants from Gilead Sciences and Pfizer, and research support by an investigator-initiated trial grant from Gilead Sciences (all renumeration went to institution). G. W. reports grants or contracts from Gilead Sciences and Roche Diagnostics (paid to institution); payment or honoraria for lectures, presentations, speakers and bureaus, manuscript writing, or educational events from Gilead Sciences and MSD (paid to institution). All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
