Structured ART interruptions have been associated with increased rates of AIDS and non-AIDS related morbidity and mortality [11
]. This post-hoc substudy conducted in SMART demonstrates that ART interruption may be particularly problematic among HIV-HBV coinfected individuals. Such patients in the DC arm of SMART 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+ and non-HBV+ participants in SMART indicate that HBV-specific management issues did not drive more rapid reinitiation of ART. HBV+ 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 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
]. Such rebounds have been associated with flares in liver enzymes and occasionally with hepatic decompensation. HBV DNA rebounds following development of lamivudine resistance have also led to hepatic inflammation and worsening of liver function [16
A smaller study of ART interruption (STACCATO) recently documented HBV DNA rebounds and ALT flares following interruption of HBV-active containing ART regimens [18
]. 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 counts. The mechanisms underlying such an interaction between HBV viraemia and immune status are unclear. HIV is associated with higher HBV DNA and faster liver disease progression [1
], but so far there is no evidence that HBV influences HIV disease progression [20
]. CD4 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 [22
]. Furthermore, HIV suppression following ART initiation is not affected by HBV coinfection [22
]. 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 [24
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
]. 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 [27
], 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
]. 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 immortalised T-cell line [30
]. 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 increased 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 subjects, 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+ 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+ and HCV+ participants had increased AIDS and non-AIDS morbidity and mortality in the DC arm compared to non-hepatitis coinfected participants, indicating that ART interruption is particularly hazardous for hepatitis coinfected individuals [31
]. 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
]. 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 viraemia or markers of disease activity such as presence of HBeAg, elevated liver enzymes and/or significant liver fibrosis. 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 [32
]. The nucleotide analogue adefovir produces sustained HBV DNA suppression in a large proportion of HIV-HBV coinfected individuals [33
], has no significant HIV activity at the 10 mg daily HBV therapeutic dose, and does not seem to select for HIV mutations (including K65R) [35
]. Education of HIV clinicians on the importance of maintaining HBV viral control is required, as only 2 of 72 SMART HBV+ 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, albeit 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 the HBV prevalence was relatively low and therefore impaired the generalization of the study findings.
In conclusion, 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.