Individuals with HIV–hepatitis B virus (HBV) coinfection have higher HBV DNA levels, more rapid liver disease progression, and considerably higher liver disease-related mortality than those with HBV monoinfection [1–3]. Although greater immune deficiency is associated with increased HBV-related disease progression , high rates of HBV-related disease events continue to be seen following the introduction of HAART .
Nucleos(t)ide analogues with dual HBV and HIV activity such as lamivudine (3TC), emtricitabine (FTC), and tenofovir (TDF) are common agents within antiretroviral therapy (ART) regimens. These drugs provide potent HBV DNA suppression [4–7], but drug resistance in HBV develops in around 20% per year with 3TC monotherapy (and presumably FTC) . Rates of TDF HBV resistance are considerably lower , and an early report  suggests greater beneficial impact halting HBV-related liver disease progression.
The Strategies for Management of AntiRetroviral Therapy (SMART) was a randomized controlled trial, which examined a strategy of episodic ART among HIV-infected persons with baseline CD4 cell counts of more than 350 cells/μl and demonstrated that CD4 cell-guided episodic interruption was associated with higher rates of opportunistic diseases, non-AIDS clinical morbidity, and all-cause mortality as compared with continuous ART .
Although recruitment of HBV-coinfected patients with active hepatitis in SMART study was not recommended the inclusion of some HBV-coinfected participants and frequent use of anti-HBV-active ART within the SMART study provided an ideal opportunity to examine aspects of HIV–HBV immunopathogenesis, in particular, the impact of ART interruption on markers of HIV and HBV disease activity.
Participants and methods
The design and data collection methods of the SMART trial have previously been reported . Briefly, the SMART study was a randomized clinical trial that compared two distinct strategies of using ART in a large cohort of participants over 13 years of age with confirmed HIV-1 infection and CD4 cell counts of more than 350 cells/μl at the time of screening. In the drug conservation strategy arm, participants interrupted or deferred ART until the CD4 cell count dropped below 250 cells/μl. ART was resumed or initiated until the CD4 cell count reached above 350 cells/μl and then suspended again. Cycles of ART were guided by CD4 cell count levels or the presence of HIV-related symptoms or if the CD4 cell percentage dropped below 15%. In the viral suppression strategy arm, participants continued ART with the goal of maximal viral suppression in accordance with HIV treatment guidelines. The choice of antiretroviral agents and combinations was based on clinician/patient preference and was continued without interruption. The primary outcome was the development of a new or recurrent opportunistic disease or death from any cause.
The protocol allowed for participants with chronic HBV infection to use monotherapy with specific antihepatitis drugs (e.g. adefovir) while not receiving ART. The protocol had no exclusion criteria based on alanine aminotransferase (ALT) level but recommended that patients requiring continued ART for management of chronic HBV infection should not be enrolled.
During screening, patients' medical charts were reviewed for documentation of HBV and hepatitis C virus (HCV) status. If there was no laboratory evidence of a positive hepatitis B surface antibody (HBsAb) or two positive hepatitis B surface antigen (HBsAg) results obtained at least 6 months apart, HBsAb and HBsAg tests were performed. If there was no evidence of a prior positive anti-HCV antibody result or a negative result from within the previous year, anti-HCV antibody tests were performed. In the absence of plasma HCV RNA results, chronic HCV infection was defined based on the presence of hepatitis C antibody and denoted as ‘HCV-positive’. Chronic HBV infection was defined as the persistence of HBsAg over a minimum of 6 months and denoted as ‘HBV-positive’.
Stored baseline and follow-up plasma samples of HBV-positive participants were analyzed for levels of HBV DNA using the branched DNA assay (VERSANT HBV DNA 3.0; Bayer Diagnostics, Leverkusen, Germany) with a lower level of detection of 357 IU/ml.
Data collection and follow-up
Prior to randomization, the following information was collected: ART history, nadir CD4 cell count and highest HIV RNA level, prior three laboratory results for CD4 cell count and percentage, and plasma HIV RNA. Participants were seen at 1 month and every 2 months during year 1 and every 4 months in year 2 onward, with clinical assessment, CD4 cell count and HIV-RNA measurement, and storage of plasma samples. Retrospective collection of available ALT level data was undertaken following SMART study completion.
Participants were divided into three mutually exclusive groups: HBV-positive, HCV-positive, and non-HBV/HCV. Participants who were both HBV-positive and HCV-positive (six drug conservation and eight virological suppression) were included in the HBV-positive group. Baseline characteristics were compared between drug conservation and virological suppression HBV-positive, HCV-positive, and non-HBV/HCV participants using Pearson's χ2 test for binomial proportions for categorical variables and nonparametric rank tests for continuous variables (Wilcoxon test for treatment group comparisons and Kruskal–Wallis for comparisons across hepatitis groups). The impact of hepatitis status on time to ART reinitiation in the drug conservation arm was evaluated by Kaplan–Meier analysis. Factors associated with ART initiation were further examined in Cox proportional hazard models adjusting for age, sex, prior AIDS, baseline and nadir CD4 cell count, and baseline and highest plasma HIV RNA test. Median CD4+ slope from baseline to 4 months of follow-up was compared by hepatitis subgroups in the drug conservation arm using the Kruskal–Wallis test.
The proportion of participants with more than 1 log increase in plasma HBV DNA at follow-up visits was compared by Fisher's exact test for drug conservation and virological suppression hepatitis subgroups including HBV-positive participants on HBV-active ART (3TC, FTC, or TDF) at baseline. Pearson correlation coefficients were used to determine the correlation between change in plasma HBV DNA and change in CD4 cell count, and change in plasma HIV RNA.
Predictors for change in log10 HBV DNA over time were assessed by linear regression, using an outcome of area under the curve of the log10 HBV DNA values from baseline to month 12. This analysis included 54 drug conservation and 46 virological suppression participants with HBV DNA results available at baseline and at least one follow-up visit. All plasma HBV DNA results available in the first 12 months and prior to 11 January 2006 were included in the analyses.
Time-to-event analyses were censored at the earliest of the date of death, the lost to follow-up date, or 11 January 2006, the date that ART-experienced drug conservation participants were advised to reinitiate ART following the recommendations of an independent Safety Data Monitoring Board. All P values are two-sided. Analyses were performed using SAS (version 9.1; SAS Institute Inc., Cary, North Carolina, USA).
There were 5472 participants enrolled in the SMART study from January 2002 to January 2006 (2752 in the virological suppression arm and 2720 in the drug conservation arm). Prevalence of HBV and HCV were 2.3% (n = 62) and 14.0% (n = 385), respectively, in the virological suppression arm, and 2.6% (n = 72) and 15.1% (n = 411), respectively, in the drug conservation arm. The HBV prevalence includes 14 participants (0.3%) with HBV–HCV coinfection. Baseline characteristics by hepatitis status are shown in Table 1. Demographic and clinical characteristics were similar across the hepatitis groups in both arms, apart from HIV transmission category; the proportion with injecting drug use-acquired HIV infection was much higher among HCV-positive participants. Overall, 84% of participants were on ART at entry, including 74% on HBV-active ART. Among HBV-positive participants in the drug conservation arm, 67% were on HBV-active ART, including 25% on TDF-containing regimens.
Despite high rates of HBV-active therapy, 54% of HBV-positive participants had detectable HBV DNA at baseline, and among these participants, the median log10 HBV DNA level was 7.4 and 8.1 IU/ml in the virological suppression and drug conservation arms, respectively. In the drug conservation arm, baseline median log10 HBV DNA (interquartile range) was 2.55 (2.55–2.55), 3.27 (2.55–8.19), and 8.08 (3.77–8.60) in the TDF-containing, 3TC (without TDF)-containing, and no HBV-active ART groups, respectively. In the drug conservation arm, the proportion with detectable HBV DNA (>2.55 log10 IU/ml) at baseline was 23.5, 51.9, and 81.0% in the TDF-containing, 3TC (no TDF)-containing, and no HBV-active ART groups, respectively (P = 0.002).
Plasma hepatitis B virus DNA rebound
Among HBV-positive participants in the drug conservation (n = 54) and virological suppression (n = 46) arms, HBV DNA rebound of more than 1 log from baseline was seen in 31–33% and 3–4%, respectively, at early time points (months 1–4) (P = 0.021, 0.004, and 0.003 for months 1, 2, and 4 comparisons, respectively). ART reinitiations among HBV-positive participants in the drug conservation arm reduced this proportion over subsequent time points, although the proportion with more than 1 log rebound at 12 months remained higher in the drug conservation vs. virological suppression arms (19 vs. 7%, respectively; P = 0.14). Among HBV-positive participants on HBV-active ART at baseline in the drug conservation arm (n = 44), the proportion with more than 1 log rebound was higher among those receiving TDF-containing regimens (with or without 3TC/FTC) (n = 17) as compared with those receiving 3TC only-containing regimens (n = 27) over the initial 4 months (60–89 vs. 0–20%; P = 0.044, 0.015, and 0.002 for months 1, 2, and 4 comparisons, respectively). The three HBV-positive participants in the virological suppression arm with HBV DNA rebound of more than 1 log at 12 months were either on no ART at baseline (n = 2) or on a 3TC-containing (non-TDF) ART regimen (n = 1).
Among HBV-positive participants with a baseline HBV DNA of less than 1000 IU/ml in the drug conservation (n = 24) and virological suppression (n = 22) arms, HBV DNA rebound of more than 1 log from baseline was seen in 42–60 and 0–8%, respectively, at early time points (months 1–4) (P = 0.04, 0.002, and 0.007 for months 1, 2, and 4 comparisons, respectively).
HBV DNA rebounds of more than 3 log from baseline were documented in 13 HBV-positive participants, 12 in the drug conservation arm and one in the virological suppression arm. In the drug conservation arm, a more than 3 log HBV DNA rebound was more common among HBV-positive participants on baseline TDF-containing regimens (7/17) as compared with 3TC only-containing regimens (3/27) and no HBV-active ART (2/21) (P = 0.013). The one participant in the virological suppression arm was on a 3TC only-containing regimen. Among HBV-positive participants on HBV-active ART in the drug conservation arm, time to reach a more than 3 log HBV DNA increase varied from 1 to 10 months.
Following reinitiation of TDF-containing regimens in seven drug conservation participants with a more than 3 log HBV DNA increase, there were generally rapid reductions in plasma HBV DNA. Only two HBV-positive participants in the drug conservation arm received non-HIV active/HBV-active agents (adefovir in both cases) during ART interruption.
Univariate and multivariate factors associated with HBV DNA changes from baseline through month 12 are shown in Table 2. In the multivariate model, factors associated with a HBV DNA rebound were drug conservation arm (P = 0.0002), nondetectable HBV DNA at baseline (P = 0.007), and black race (P = 0.03). Being on a TDF-containing ART regimen at baseline was marginally associated with a HBV DNA rebound (P = 0.06).
Retrospective ALT data including baseline and at least one follow-up level at months 4, 8, or 12 was available in 32 of 72 (44%) HBV-positive participants in the drug conservation arm. A hepatic flare (increase in ALT level from baseline to above 200 U/ml) was uncommon during follow-up, with only two participants developing flares at month 12. The rate of hepatic flare was low in HBV-positive participants in the drug conservation arm with and without an HBV DNA rebound of more than 1 log (1/10 and 1/22, respectively).
During the SMART study follow-up, there were no episodes of hepatic decompensation or liver disease mortality events recorded among HBV-positive participants in either the drug conservation or virological suppression arm.
Reinitiation of antiretroviral therapy in the drug conservation group
Median time to ART reinitiation was considerably shorter (7.5, 15.6, and 17.8 months; P < 0.0001) and the proportion of participants reinitiating higher (62.5, 46.5, and 39.7%; P = 0.0002) among HBV-positive participants in the drug conservation arm as compared with HCV-positive and non-HBV/HCV participants (Fig. 1, Table 3). The median CD4 cell count at time of reinitiation was similar across the three groups (ranging from 233 to 241 cells/μl). As the CD4 cell count was comparable among the groups when ART was interrupted, these findings suggest that depletion of CD4+ T cells occurred more rapidly among HBV-positive participants.
Over the initial 4 months follow-up off ART in the drug conservation arm, the median CD4 cell count decline (slope) per month was 70.9, 50.6, and 53.0 cells/μl for HBV-positive, HCV-positive, and non-HBV/HCV participant groups (P = 0.14). The reasons for ART reinitiation were similar across the groups, with CD4 cell count of less than 250 cells/μl and low CD4 cell percentage being the most common reasons in each group (Table 3).
Factors associated with ART reinitiation in multivariate analysis were HBV infection (compared with no HBV/HCV infection) hazard ratio = 1.71, (95% confidence interval 1.27–2.31), baseline CD4 cell count (per 100 cells/μl lower) 1.14 (1.11–1.18), nadir CD4 cell count (per 100 cells/μl lower) 1.50 (1.42–1.58), age (per 10 years older) 1.13 (1.06–1.20), prior AIDS 1.41 (1.24–1.61), baseline plasma HIV RNA ≤ 400 copies/ml 1.19 (1.04–1.37), and highest recorded log10 HIV RNA (per 1 log higher) 1.19 (1.11–1.28) (Table 4).
The extent of HBV DNA rebound moderately correlated with the degree of CD4 cell count decline at several follow-up time points: correlation coefficients were −0.19 (P = 0.40) for month 1, −0.31 (P = 0.06) for month 2, −0.40 (P = 0.02) for month 4, −0.49 (P = 0.003) for month 6, −0.28 (P = 0.11) for month 8, −0.54 (P = 0.001) for month 10, and −0.26 (P = 0.06) for month 12. HBV DNA rebounds also correlated significantly with plasma HIV RNA increases at several follow-up time points, with coefficients varying from 0.38 to 0.51.
Structured ART interruptions have been associated with increased rates of AIDS and non-AIDS-related morbidity and mortality . This post-hoc substudy conducted in SMART trial demonstrates that ART interruption may be particularly problematic among HIV–HBV-coinfected individuals. Such patients in the drug conservation arm of SMART trial experienced considerable HBV DNA rebound and had to reinitiate ART more often and more rapidly than the rest. Similar reasons for reinitiation and CD4 distribution at reinitiation among HBV-positive and non-HBV-positive participants in SMART trial indicate that HBV-specific management issues did not drive more rapid reinitiation of ART. HBV-positive participants with baseline HBV DNA suppression on TDF-containing regimens were at particularly high risk of HBV DNA rebound following ART interruption. HBV DNA rebound following ART interruption was associated with CD4 cell count decline and HIV RNA increase, although the explanation for this relationship is unclear.
Plasma HBV DNA rebound following cessation of HBV antiviral therapy has been documented in both HBV monoinfected and HIV–HBV-coinfected individuals [12–15]. Such rebounds have been associated with flares in liver enzymes and occasionally with hepatic decompensation. HBV DNA rebounds following development of 3TC resistance have also led to hepatic inflammation and worsening of liver function [16,17].
A smaller study  of ART interruption (STACCATO) recently documented HBV DNA rebounds and ALT flares following interruption of HBV-active-containing ART regimens. However, this SMART substudy is the first to indicate that such rebounds among HIV–HBV-coinfected individuals may lead to accelerated immune deterioration in terms of drop in CD4 cell counts. The mechanisms underlying such an interaction between HBV viremia and immune status are unclear. HIV is associated with higher HBV DNA and faster liver disease progression [1,3,19], but so far, there is no evidence that HBV influences HIV disease progression [20,21]. CD4 cell count recovery following ART initiation may be marginally impaired in the initial few months of therapy among HBV-coinfected individuals, but by 12 months, responses are similar to non-HBV-coinfected individuals . Furthermore, HIV suppression following ART initiation is not affected by HBV coinfection [22,23]. In the EuroSIDA cohort study , around 500 HIV–HBV-coinfected participants (8.7% of the total cohort) had a higher rate of liver disease-related and overall mortality, but no increased HIV disease progression or AIDS-related mortality.
In contrast to stable chronic HBV infection, a rapid increase in HBV replication following treatment cessation as observed in this study may potentially alter HIV replication and CD4+ T-cell turnover by several mechanisms. First, a rapid increase in HBV replication may have led to an increased number of activated HBV-specific T cells as observed following acute HBV infection and hepatic flare [25,26]. An increase in activated CD4+ T cells could provide a larger pool of target cells for HIV replication leading to accelerated CD4+ T-cell decline. Second, an acute increase in HBV replication may have potentially led to altered T-cell trafficking with recruitment of both HBV-specific and non-HBV-specific T cells to the liver from the periphery ; however, in the absence of hepatic flare, this explanation seems less likely. Finally, although primarily a hepatotropic virus, HBV can infect lymphocytes at low levels and, therefore, could potentially interact directly with HIV [28,29]. The HBV genome encodes a 17-kDa protein, termed HBx, that acts synergistically with the HIV protein, Tat, to induce HIV replication and cellular activation in Jurkat cells, an immortalized T-cell line . It is possible that this direct interaction between HBV x protein and HIV may occur in primary CD4+ T cells in vivo.
Potential consequences of HBV DNA rebound and accelerated immune deterioration include both enhanced HBV and HIV disease morbidity. HBV DNA rebound could lead to increase hepatic inflammation and liver disease progression as well as enhanced susceptibility to HBV drug resistance. Although ALT data collection was only undertaken retrospectively and available in a minority of participants, the low rate of hepatic flare even in those with significant HBV DNA rebound is somewhat reassuring. The subsequent HBV DNA declines following reinitiation of TDF-containing regimens and a lack of reported major liver disease events among HBV-positive participants provides further reassurance that adverse HBV clinical outcomes will be limited if HBV therapy is subsequently resumed. In a separate post-hoc SMART analysis , both HBV-positive and HCV-positive participants had increased AIDS and non-AIDS morbidity and mortality in the drug conservation arm as compared with nonhepatitis-coinfected participants, indicating that ART interruption is particularly hazardous for hepatitis-coinfected individuals. Despite this association, liver disease-related events were limited and not the explanation for the increased non-AIDS-related morbidity.
The major clinical implication of our study findings, along with previously reported adverse outcomes following cessation of HBV antiviral therapy, would appear to be that ART interruption, particularly of regimens containing HBV-active therapy, should be avoided in HIV–HBV-coinfected individuals. A higher rate of HBV DNA rebound following interruption of TDF-containing regimens is consistent with greater baseline HBV DNA suppression as a result of the high potency and genetic barrier for resistance of this agent [5,6,9]. If ART interruption is required for any reason, a non-HIV-active HBV drug should be commenced, particularly, if there is previously documented evidence of HBV viremia or markers of disease activity such as presence of hepatitis B e antigen, elevated liver enzymes, significant liver fibrosis, or all. The recent demonstration of HIV suppression and associated M184V mutation development in HIV–HBV-coinfected individuals receiving entecavir but no ART has reduced the choices available . The nucleotide analogue adefovir produces sustained HBV DNA suppression in a large proportion of HIV–HBV-coinfected individuals [33,34], has no significant HIV activity at the 10 mg daily HBV therapeutic dose, and does not seem to select for HIV mutations (including K65R) . Education of HIV clinicians on the importance of maintaining HBV viral control is required, as only two of 72 SMART HBV-positive participants who interrupted ART were commenced on HBV-active therapy during interruptions.
Several limitations of the study must be recognized. First, is the post-hoc nature of the analyses, although within a well characterized population from a randomized controlled trial population. Second, the lack of prospective and systematically collected ALT data limited evaluation of the impact of HBV DNA rebound on hepatic disease parameters. Third, the exclusion of HBV-coinfected individuals from the SMART study, if they were assessed as requiring ongoing ART for management of chronic HBV infection, meant that the HBV prevalence was relatively low and, therefore, impaired the generalization of the study findings.
ART interruption among HIV–HBV-coinfected participants in the SMART study was associated with frequent plasma HBV DNA rebound and more rapid and higher rates of ART reinitiation. Such outcomes indicate that ART interruption may be particularly hazardous for this subpopulation of HIV-infected individuals.
We would like to acknowledge the SMART participants, the SMART study team (see N Engl J Med 2006; 355:2294–2295 for list of investigators) and the INSIGHT Executive Committee. The National Centre in HIV Epidemiology and Clinical Research is funded by the Australian Government Department of Health and Ageing and is affiliated with the Faculty of Medicine, University of New South Wales. Support provided by NIAID and NIH grants #U01AI042170 and U01AI46362. G.D. is supported by a NHMRC Practitioner Fellowship. Clinical Trials.gov identifier: NCT00027352.
There are no conflicts of interest.
Preliminary findings were presented at the Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention; Sydney, Australia; July 2007.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; coinfection; hepatitis B virus; HIV; tenofovir