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Long-Term TDF-Inclusive ART and Progressive Rates of HBsAg Loss in HIV-HBV Coinfection—Lessons for Functional HBV Cure?

Audsley, Jennifer PhDa,b; Avihingsanon, Anchalee MD, PhDc; Littlejohn, Margaret PhDd; Bowden, Scott PhDd; Matthews, Gail V. MD, PhDe,f; Fairley, Christopher K. MD, PhDg,h; Lewin, Sharon R. MD, PhDa,b; Sasadeusz, Joe MD, PhDb,i

Author Information

aThe Peter Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia;

bDepartment of Infectious Diseases, The Alfred Hospital and Monash University, Melbourne, Australia;

cHIV-NAT, Thai Red Cross AIDS Research Centre and Tuberculosis Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;

dVictorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, at the Doherty Institute, Melbourne, Australia;

eThe Kirby Institute, Sydney, Australia;

fDepartment of Infectious Diseases, St Vincent's Hospital, Sydney, Australia;

gMelbourne Sexual Health Centre, Alfred Health, Melbourne, Australia;

hCentral Clinical School, Faculty of Medicine, Monash University, Melbourne, Australia; and

iVictorian Infectious Disease Service, Royal Melbourne Hospital, at the Doherty Institute, Melbourne, Australia.

Correspondence to: Jennifer Audsley, Peter Doherty Institute for Infection and Immunity, University of Melbourne, 792 Elizabeth Street, Melbourne, Victoria 3010, Australia (e-mail: [email protected]).

Supported by Gilead Sciences.

Presented in part as a poster at the 10th IAS Conference on HIV Science; July 21–24, 2019; Mexico City, Mexico.

S.R.L. receives research support from National Health and Medical Research Council of Australia (NHMRC), National Institutes of Health (NIH), American Foundation for AIDS Research (amfAR), Gilead Sciences, Merck, and ViiV. She has participated in advisory boards to Merck, Gilead, ViiV, Bionore, Abivax, Calimmune, InniVirVax, and Scientific Advisory Board of the Agence National de Recherche du SIDA. J.S. has received research funding from Gilead Sciences and the NHMRC. A.A. has participated in speaker's bureau sponsored by Jensen-Cilag. G.V.M. has received research funding from Gilead Sciences and Abbvie. SRL is an NHMRC practitioner fellow and GVM is an NHMRC Career Development Fellow. The remaining authors have no funding or conflicts of interest to disclose.

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 15, 2020 - Volume 84 - Issue 5 - p 527-533
doi: 10.1097/QAI.0000000000002386
  • Free

Abstract

INTRODUCTION

Almost 37 million people worldwide are infected with HIV and about 7.4% are coinfected with hepatitis B virus (HBV).1 The prevalence of chronic HBV (CHB) infection in people with HIV varies geographically, with CHB prevalence estimates in HIV-infected individuals in Australia and in Asia of 6%–9%.2,3 HBV infection in Asia-Pacific is usually acquired at or soon after birth and well before HIV acquisition compared to Western countries, where rates of new HBV infection are highest in young adults around the time of HIV acquisition.4

HIV infection has a significant impact on the natural history of CHB infection, with increased levels of HBV DNA, accelerated progression of liver disease, and increased liver-associated mortality.5–7 Although mortality has decreased with widespread introduction of effective antiretroviral therapy (ART), morbidity and mortality remain significantly higher in those with HIV-HBV coinfection compared to HIV monoinfection, indicating an unmet need for effective HBV eradication strategies.8

Tenofovir disoproxil fumarate (TDF) is very effective in suppressing both HIV and HBV replication in HIV-HBV coinfection and is active against both wild-type HBV and HBV strains that contain lamivudine (LMV)-resistance polymerase gene mutations.9–11 However, around 10% of HIV-HBV coinfected individuals on TDF-inclusive regimens have persistently detectable HBV DNA or viral rebound after initial control of HBV DNA.12

Currently, the loss of hepatitis B surface antigen (HBsAg), with or without acquisition of anti-HBs, is the best possible outcome of HBV infection and is considered a functional cure.13 Loss of HBsAg is associated with a reduction in the risk of hepatocellular carcinoma, and this risk reduction is greater than that achieved with HBV suppression by long-term nucleos(t)ide analogue treatment.14,15 We and others have shown previously that, after the initiation of HBV-active antiretroviral treatment of HIV-HBV coinfection, rates of HBsAg loss and seroconversion approach 19% in the first 2 years of treatment,16,17 a significantly higher rate than seen after the initiation of nucleos(t)ide reverse-transcriptase inhibitor (NRTI) in HBV monoinfection, which was reported at 2% over 96 weeks.18 It remains unclear whether the increased rate of HBsAg loss in the first 2 years of treatment setting of HIV-HBV coinfection continues at the same rate or whether it plateaus over time. In a large prospective cohort of HIV-HBV coinfected individuals on TDF containing HBV-active ART, we now report the results from 5-year follow-up.

Participants and Methods

Study Participants

Ninety-two HIV/HBV coinfected individuals were enrolled from sites in Australia (The Alfred Hospital, and Melbourne Sexual Health Clinic, Melbourne; St Vincent's Hospital, Sydney) and Thailand (HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok) during July 2008–November 2009. Written informed consent was obtained from all participants, and the study approved by the relevant human research ethics committees in Australia and Thailand. Eligibility criteria and follow-up for the first 2 years has been previously described.19 Known HDV-positive status was not an exclusion.

Data Collection

Clinical and laboratory data were collected at study entry and follow-up visits. Laboratory measurements included alanine aminotransferase (ALT), aspartate aminotransferase (AST), hemoglobin, white blood cell count, platelets, HBeAg, HBe antibody (anti-HBe), HBsAg, hepatitis B surface antibody (anti-HBs), hepatitis C virus (HCV) antibody, HIV RNA, current CD4 count, and nadir CD4 count. HDV antibody status, if available, was not collected. Data on alcohol intake and compliance with ART were also collected. Participants were followed at 6-monthly intervals for the first 2 years of follow-up and annually thereafter.

HBV DNA Quantification

HBV DNA quantification was performed at each site as previously described.19 For analysis of data up to and including year 2, HBV DNA was classified as detectable (≥20 IU/mL) or undetectable (<20 IU/mL). After that, HBV DNA was classified as detectable (≥15 IU/mL) or undetectable (<15 IU/mL) due to the use of assays with a lower limit of detection (LLOD).

HIV RNA Quantification

HIV RNA quantification was performed at each site previously described.19 For analysis of data up to and including year 2, HIV RNA was classified as detectable (≥50 copies/mL) or undetectable (<50 copies/mL). After that HIV RNA was classified as detectable (≥20 copies/mL) or undetectable (<20 copies/mL) due to the use of assays with an LLOD.

Quantitative HBs Antigen

HBsAg quantification was measured by chemiluminescent microparticle immunoassay at the Victorian Infectious Diseases Reference Laboratory as previously described20 using the Roche Elecsys HBsAg assay on a Cobas e411 instrument (Roche Diagnostics, Mannheim, Germany). The LLOD for HBsAg was 0.05 IU/mL.

Statistical Analysis

Potential attrition bias was assessed by comparing study entry variables of the group who were active in the study at year 5 with those who were lost to follow-up (LTFU). The χ2 test was used for categorical variables, whereas continuous variables were compared using the Mann–Whitney test. A Kaplan–Meier curve was constructed to examine HBsAg loss over time on TDF. Laboratory variables at years 2 and 5 were compared using the Wilcoxon signed rank test (continuous variables) or the McNemar test (categorical variables). Associations between study entry characteristics and HBsAg loss were examined at the univariate level using the Mann–Whitney test for continuous variables and the χ2 test for categorical variables. In all analyses, P < 0.05 was considered significant. Analyses were completed using IBM SPSS Statistics software (Version 24.0.0.0; IBM, Armonk, NY).

RESULTS

Study Participants and Clinical Features

At year 5, the cohort retained 84.8% (n = 79) of the 92 individuals at study entry, with 10 LTFU and 3 deaths (see Table S1, Supplemental Digital Content, https://links.lww.com/QAI/B470). There were 2 liver-related deaths (one hepatocellular carcinoma and one end-stage liver disease) and one suicide. Seven participants missed their year 5 visit, leaving available data at the year 5 visit for 78.3% of the study entry cohort. By year 5, the median duration on TDF was 6.8 years (minimum-maximum 4.8–12.8). Cohort demographics at study entry and year 5 are shown in Table 1.

T1
TABLE 1.:
Cohort Demographics—At Study Entry and Year 5

HBV Serology Changes

By year 5 of follow-up from study entry, 11 participants had lost HBsAg from the time they started TDF—12.0% (95% confidence interval 6.8 to 20.2) of the total study entry cohort (n = 92) or 15.3% (95% confidence interval: 8.8 to 25.3) of those with data available to year 5 (n = 72). HBsAg loss was observed between starting TDF and the study entry visit (n = 3), at the year 2 follow-up visit (n = 3), the year 3 follow-up visit (n = 4), and the year 5 follow-up visit (n = 1). Given most participants (n= 85) had commenced TDF before study entry (median duration on TDF at study entry 1.9 years), we also examined HBsAg loss by duration on TDF (Figs. 1A, B). Median duration on TDF before HBsAg loss was 48 months (min 13, max 88). Cumulative rates of HBsAg loss are shown in Figure 1B. HBsAg loss continued out to 7.3 years at which time the cumulative rate of HBsAg loss was 15.3% and after which it appeared to plateau. Acquisition of anti-HBs (HBsAg seroconversion) was also observed in 4 participants, simultaneously with HBsAg loss (2 at year 2, one at year 3, and one at year 5 follow-up visits). An additional 2 participants gained anti-HBs but did not lose HBsAg.

F1
FIGURE 1.:
A, Duration (months) on tenofovir (TDF) to HBsAg loss. Please note time is duration on TDF, not duration of follow-up. B, Kaplan–Meier survival curve, duration on tenofovir (TDF) to HBsAg loss. Numbers below the graph represent HBsAg-positive participants on TDF at each time point. Please note time is duration on TDF, not duration of follow-up.

Study entry characteristics of those with HBsAg seroloss/seroconversion were compared with the rest of the cohort and we observed that study entry median quantitative HBsAg (qHBsAg) was significantly lower in the seroloss/seroconversion group: 4 IU/mL (25th−75th percentile 4–831) compared with 1622 IU/mL (25th−75th percentile 297–7207), P = 0.001. All participants who lost HBsAg were HBeAg-negative, and all but one were HBeAb-positive. However, HBeAg status at study entry was not significantly different between those with HBsAg seroloss/conversion and those who remained HBsAg-positive. Study entry qHBsAg level remained significantly associated with HBsAg seroloss when the 3 participants with HBsAg loss at study entry were excluded from the analysis (P = 0.03). No other factor examined was significantly associated with HBsAg loss; this included country of recruitment (Thailand or Australia) to check for the impact of childhood or adult acquisition of HBV (P = 0.34). We specifically assessed available immune factors for association with HBsAg loss, comparing those with HBsAg seroloss/seroconversion with the rest of the cohort. This included total CD4 and CD8 count, percentage CD4 and CD8, and CD4:CD8 ratio at both study entry and preTDF sample date. None of them were associated with HBsAg loss. There were also no associations with change in any CD4 or CD8 parameters (%, total count and ratio) between the preTDF or study entry visits, nor between study entry and m24 (data not shown).

We further examined immune restoration for the full cohort. Total CD4 cell count increased by a median 245 cells/mm3 between preTDF sample date and 5 years of follow-up, with a simultaneous decrease in median total CD8 cell count of 70 cells/mm3 (Fig. 2). As time between preTDF sample and study entry varied (median 2.7 years, IQR 1.2–5.2 years), we then focused on immune restoration during on-study follow-up for the full cohort. We compared CD4 and CD8 cell counts at study entry and year 2; and at year 2 with year 5. The median CD4 cell counts at study entry and year 2 were significantly different (P = 0.04); however, there was no significant difference between year 2 and year 5 (P =0.59). There were no significant differences at those time points in CD8 cell count.

F2
FIGURE 2.:
Change in total CD4 and CD8 cells counts over time, from the time of the preTDF sample to month 60, by study visit.

The cohort was 12.1% HBeAg-positive at study entry. This decreased to 10.5% at year 2 and then increased to 14.5% by year 5. None of those changes were significantly different. HBe serology changes at year 5 were observed in 9 participants, including HBeAg loss/seroconversion (n = 2, 2.8% of the Year 5 cohort), reacquisition of HBeAg (n = 4, 5.6% of the Year 5 cohort), and loss or gain of anti-HBe (n = 3). Multiple changes in anti-HBe serology at study entry/year 2/year 5 were observed in 2 participants. One participant (always anti-HBe-negative) gained HBeAg by year 2, which was subsequently lost by year 5; and the other (always HBeAg-negative) gained anti-HBe by year 2, which was subsequently lost by year 5.

Viral Suppression at Year 5

At study entry, 90.2% of the cohort had undetectable HBV DNA; by year 2, this was 91.8% and this increased to 98.5% by year 5. Median (25th–75th percentile) log10 HBV DNA was 1.18 (1.18–1.30) IU/mL and this was not significantly different from month 24 (Table 2). There was one individual with detectable HBV DNA at year 5, with a viral load too low (31 IU/mL) for sequencing, detectable HIV RNA (33,957 copies/mL), and reported adherence to ART but no HIV mutations associated with ARV resistance (protease inhibitor or nucleoside reverse transcriptase inhibitor) on genotypic testing. This suggested suboptimal ART adherence.

T2
TABLE 2.:
Difference in Laboratory Parameters Between Study Entry and Year 5; and Year 2 and Year 5 of Study (Wilcoxon Signed Rank Test)

At study entry, 94.4% of the cohort had undetectable HIV RNA; this decreased to 87.7% by year 2, but increased to 91.4% by year 5. Median (25th–75th percentile) log10 HIV RNA was 1.30 (1.30–1.30) copies/mL and this was significantly different from year 2 (P <0.01), Table 2. Of the 6 detectable HIV RNA results at year 5, half were viral blips <300 copies/mL and another was a single high-level result (3.6 log10 copies/mL) immediately preceded and followed by undetectable results. Two were related to adherence—one participant who also had detectable HBV DNA (albeit 3 logs lower) and the other with HIV RNA 4.9 log10 copies/mL and undetectable HBV DNA.

Laboratory Changes

We compared laboratory results at study entry and year 5, and then to determine whether changes were confined to the initial phase of the study, we also compared outcomes at year 2 and year 5. There was significantly lower HIV RNA, ALT, AST, ALP, and LDH at year 5 compared to study entry (Wilcoxon signed rank test, Table 2). Significant changes continued throughout follow-up, with significantly lower HIV RNA, ALT, AST, ALP, GGT, and LDH at year 5 compared to year 2 (Wilcoxon signed rank test, Table 2).

Potential Attrition Bias

Although this study is an observational surveillance cohort and not statistically powered to a specific outcome, study entry characteristics of those LTFU by year 5 was compared to those who remained in active follow-up to investigate potential attrition bias. Two variables—log10 HBV DNA (higher in LTFU group) and HBeAg status (greater proportion HBeAg positive in LTFU group)—were statistically significantly different between the 2 groups (see Table S2, Supplemental Digital Content, https://links.lww.com/QAI/B470). There was no statistically significant difference between both groups in the proportion that were HBV DNA-positive.

DISCUSSION

The aim of this study was to examine the long-term impact of TDF-inclusive ART in the setting of HIV-HBV coinfection. We found that HBsAg loss continued over time but plateaued, detectable HBV DNA was rare by 5 years of follow-up, and liver enzyme levels continued to improve.

An important finding of this study was that loss of HBsAg continued throughout 5 years of follow-up. Cumulative HBsAg loss in the total cohort was 12%, rising to 15% in per protocol analysis. These rates are higher than HBsAg loss in HBeAg-positive monoinfected individuals, which was 9% after 5 years of TDF therapy.21 They are also in accordance with previously reported HBsAg loss of up to 23% in HIV-infected individuals, depending on duration of follow-up and exposure to ART.16,17,22–29 Some studies report that most HBsAg loss occurs in the first 12–36 months of ART.16,17,22 Our data in HIV-HBV coinfection suggest a plateau in HBsAg loss, as has been reported in an ART-experienced French coinfection cohort; however, their decline was observed after year 3 of receiving TDF, whereas in our cohort, it appeared to occur after year 6 of TDF.22

Reasons underlying the higher initial rates of HBsAg loss in the setting of HIV are unclear but may relate to immune reconstitution, resulting in enhanced immunological control with the commencement of ART. In our study, country of recruitment was not significantly associated with HBsAg loss; so, age at HBV acquisition does not seem to be a factor in HBsAg loss. A study of HIV monoinfection in the United States showed that after commencing ART, the slope of plotted CD4+ cell counts increased significantly from the previous year for the first 4 years of treatment and then plateaued.30 Recent 10-year data from a European cohort showed that the most rapid improvement in CD4 count was approximately 3 months after commencement of ART followed by a gradual increase for up to 5 years.31 Our data showed that for the total cohort, CD4 increase was significantly different from study entry to year 2, but this was not significant between year 2 and year 5. Taken together, these data suggest that the pattern of HBsAg loss temporarily parallels immune reconstitution and further supports the hypothesis that this may be the mechanism driving enhanced HBsAg loss.

Data on 7 years of treatment with TDF in HBV monoinfection have been published, in which cumulative HBsAg loss was observed in 4.9% of the total cohort.32 It seems that the rate of HBsAg loss in coinfection is higher on initial commencement of ART, particularly HBV-active ART such as TDF, but falls within a few years to levels similar to that observed in long-term treatment in HBV monoinfection.

The only significant association that we found with HBsAg loss was lower quantitative HBsAg. This has been observed previously17,27,33 and is unsurprising, given decreasing levels of HBsAg predict complete HBsAg loss.

On more intensive evaluation of available immune function factors, we did not observe an association between CD4 or CD8 change and HBsAg loss; however, these are surrogate markers of immune restoration and we did not examine T-cell subsets. Differences in the proportion and composition of CD4 and CD8 subsets play a major role in immune restoration.34–36 There was a median increase of 245 total CD4 cells/mm3 and decrease of 70 total CD8 cells/mm3 for the cohort from preTDF to 5 years of follow-up, which is indicative of immune restoration. Rates of change for these parameters declined over follow-up, which parallels the plateau observed in HBsAg loss. Although a hypothesis of immune restoration driving HBsAg loss is possible, this was not supported by the limited immune factors available in this study. It may require more sophisticated immunological studies to elucidate the role of HIV-related immune restoration in HBsAg loss, or alternatively there may be other mechanism involved.

Recent efforts in HBV therapy have turned toward a functional cure of HBV with HBsAg loss as the primary endpoint. These data may offer important insights into mechanisms and potential targets for functional cure in the wider HBV population.

Surprisingly, we did not observe an overall decrease in HBeAg positive status, which would have been expected at higher levels than HBsAg loss, whereas in our cohort, there was a slight nonsignificant increase from year 2 to year 5 follow-up. After the initiation of anti-HBV therapy in CHB monoinfection, rates of HBeAg seroconversion can occur in up to 12%–20% of individuals after interferon therapy and 7%–29% after NRTI.37 In NRTI-treated HIV-HBV coinfection, observed rates of HBeAg seroconversion are higher at 15%–57%.17,22,24,26–29,37–41 The reason for the lack of HBeAg loss in our cohort is unclear. One reason could be that the cohort contained very few HBeAg-positive individuals, which is not surprising, given almost 71% of the cohort had received more than 1 year of LMV-inclusive ART at study entry. We also observed 4 individuals who regained HBeAg at year 5; this has been described previously.17,22 Furthermore, fluctuating results may also be due to HBeAg levels close to assay LLOD.

Suppression of HBV DNA as measured by very sensitive assays continued to increase so that it was almost universal by 5 years on a per protocol analysis. Persistent HBV was therefore extremely rare, in contrast to our and other findings of around 10% persistently detectable HBV DNA/viral rebound after initial control in HIV-HBV coinfection over shorter follow-up. This demonstrates that if one waits long enough, full viral suppression is eventually achieved. Accordingly, there is no reason to consider intensification strategies in the setting of low-level residual HBV viremia. These findings are similar to other published long-term studies in HIV-HBV coinfection.22,26,29 Our current figures at 5 years of follow-up are comparable to that observed in HBV monoinfection and it may be that longer duration of TDF is required to maintain similar levels of HBV suppression that can be achieved with shorter TDF duration in HBV monoinfection. This may be related to known higher baseline levels of HBV in HIV coinfection.6,42

Improvement in several liver-related laboratory parameters was observed with long duration of TDF, supporting the continuing benefits of TDF on liver-related disease in HIV-HBV coinfection; however, this was not observed in all participants and there were 2 liver-related deaths.

LTFU and deaths in long-term observational cohorts are expected, and our rates are similar to those observed in HIV-HBV coinfection long-term follow-up.22 We do not believe that this cohort has been unduly affected by attrition bias because only HBV DNA (higher in the LTFU group) and HBeAg status (greater proportion HBeAg positive in the LTFU group) were significantly different between the 2 groups. HBeAg-positive status is well known as a surrogate marker for HBV viral load in HIV-HBV coinfection; so, it is not surprising that both these factors were significant. Those in the LTFU group potentially may have been more likely to nonadherent, as indicated by the higher study entry HBV DNA. Losing these individuals could have biased the HBV DNA suppression results at 5 years of follow-up.

This study did have some limitations. The cohort included participants who were on TDF before study entry, and 3 participants lost HBsAg between their preTDF samples and study entry; so, the median duration on TDF may be overestimated. Study visits changed from 6-monthly to annual after the first 2 years of follow-up; so, this may also have overestimated median time to HBsAg loss or seroconversion. The cohort contained a mix of HBV genotypes but due to the numbers with HBsAg seroloss, we could not analyze by genotype. HBsAg loss and HBsAg seroconversion were combined as one outcome due to the small number of seroconversions, and this did not allow separate analysis of seroconversion alone. We were also not able to examine T-cell subsets to more intensively investigate potential immunological mechanisms that may have underlined the increased rates of HBsAg loss.

In summary, we found that there was high and ongoing loss of HBsAg over 5 years of follow-up in HIV-HBV coinfected individuals on TDF-containing ART, and detectable HBV was rare. There was continued improvement in multiple liver-related parameters and no evidence of HBV resistance to TDF. HBsAg loss was 15% over 5 years and although the pattern of HBsAg loss temporarily parallels immune reconstitution, we could not identify predictive immune markers. More sophisticated immunological investigations may be required for full elucidation. Overall, the high rates of HBsAg loss offer important potential insights into HBV cure strategies, which are the major focus of current HBV research. Finally, the beneficial impact of TDF on HBV serology, liver biochemistry, and HBV suppression is ongoing with long-term use in HIV-HBV coinfection.

ACKNOWLEDGMENTS

The authors sincerely thank the participants in this study who have been involved for many years. They also thank the clinical research nursing staff at all sites.

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Keywords:

HIV; HBV; HBsAg seroloss; long-term ART; tenofovir

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