In this long-term, prospective analysis of 816 men with a median of 7 years of follow-up on HAART, past or present hepatitis B infection did not impact long-term response to HAART as measured by HIV RNA suppression, CD4 rise, or ADI incidence. However, even after receiving HAART that included drugs active against HBV, individuals with CH-B had an increased risk for non-AIDS defining illness mortality, primarily due to liver disease. There was also a trend for increased AIDS-related death among those with CH-B. Importantly, isolated core status did not impact the response to HAART or liver-related mortality. These findings are particularly timely as HAART is being made available in countries where hepatitis B is highly endemic.
Another study examined clinical outcomes among HBV-HIV co-infected individuals who were all receiving HAART for greater than 12 months, but, our study differs in important ways [8
]. Omland et al. evaluated similar clinical end points of mortality and liver-related mortality; however, they classified the study subjects based on a single HBsAg test obtained either pre-HAART or on-HAART. This study design can result in misclassification since the serologies can shift over time especially with the initiation of HAART [7
] which can affect the validity of the results. In our analysis, we classified hepatitis B status for each participant by requiring a minimum of two consistent serologic tests separated in time by at least six months. In all cases, at least one of these tests was obtained prior to HI. Second, our study separated subjects without CH-B into isolated core, past infection, and never infected, which other studies, including Omland et al. were not able to do [4
]. Heterogeneity in groups can be problematic because even those with past HBV infection may have active HBV replication [16
]. Our categorization allowed a clear demonstration that HBV infection, past or current, does not impact the immunologic or virologic response to HAART compared to those who were never infected with HBV.
Other studies have evaluated the impact of CH-B in subjects not on HAART [17
] and with heterogenous HAART experience [9
]. The latter includes a study by Konopnicki et al. evaluating the impact of CH-B in the Euro-SIDA cohort for short-term HAART response (to 12 months). The longer term outcomes, such as overall and liver-related mortality, were examined among a mixed population of HAART-naïve and HAART initiator subjects.
Our study is also unique in that we separated CD4 recovery into first and second phases, which has not been previously done in assessing CH-B. Consistent with some reports [8
] and in contrast to other previous reports of attenuated initial CD4 recovery, we found no difference in CD4 response between HBV groups [5
] early during HAART or later during HAART [4
]. Assessing the two phases of CD4 recovery separately enhances the potential of finding a difference in CD4 rise because the different mechanisms believed to lead to the early CD4 rise versus the second phase of rise.
Although HAART response, as measured by CD4 rise and HIV RNA suppression, was not compromised by CH-B in our study, it is notable that AIDS-related mortality rate was higher in this group compared to the HBV uninfected group. After adjustment for baseline CD4, proportion of visits with HIV RNA suppression, and time of HI, a trend remained for increased AIDS-related death, but it was no longer statistically significant. Thus, it is difficult to rule out an effect of CH-B also on AIDS-related death. Men with CH-B started HAART at lower CD4 cell counts which could partially explain an increase in AIDS-related mortality. However, if this explained the entire association, one would expect the association to disappear in the adjusted model.
Unfortunately, liver-related mortality remained significantly increased in patients co-infected with CH-B despite a suppressive HAART regimen that generally included an agent active against HBV, lamivudine or tenofovir DF. A study by Puoti et al. compared risk of liver-related death by ART agent among HIV-HBV co-infected individuals receiving <4 years of HAART [18
]. That study reported a decreased risk of liver-related death with use of lamivudine (adjusted relative risk of 0.73 per year). In our study, the liver attributable mortality rate on HAART was similar to that previously reported from the MACS before and on-HAART (14 per 1000 PYs in an earlier study of the MACS [17
] and 17 per 1000 PYs in this study). There are several possible explanations for this finding that are not inconsistent with the partially protective effect of lamivudine reported by Puoti et al. Firstly, liver-related death was a major cause of death in the Puoti et al. study, accounting for 26% of all deaths. Although there was a slightly decreased risk among patients receiving lamivudine, the incidence remained high. Second, men who died of liver-related disease in our study, and were taking lamivudine, may have developed more lamivudine-resistant hepatitis B due to a longer duration of follow-up than in the Puoti et al. study. Studies of HBV mono-infected people demonstrate that liver disease advances in the setting of lamivudine-resistant virus [19
]. This is a plausible contributing factor since two of the four men with liver-related death in this study had known lamivudine-resistant CH-B. Only one of the men who died of liver disease received tenofovir DF, so it is plausible that with more effective anti-HBV HAART, liver mortality would decrease. In HBV monoinfection, potent anti-HBV therapy improves liver outcomes, but whether this occurs in HIV co-infection needs to be evaluated once sufficient data are available on patients with CH-B who are treated with tenofovir DF-containing HAART. While treatment of HIV-HBV co-infection with tenofovir DF is recommended in the United States, it is not the current practice in many of the regions, such as Africa, with high prevalence of CH-B. Among individuals co-infected with HIV-HBV living in low-income countries, consideration should also be given to including tenofovir DF in first-line regimens. A second plausible explanation for similar liver-related mortality during HAART compared to the pre-HAART era is that these men had more severe liver disease before initiation of HAART and that HAART was not able to reverse their disease; however, the long time on HAART before liver-related mortality, a median of five years, among the men who died of liver-related disease makes this less likely. A third plausible explanation is that immune reconstitution syndrome associated inflammation, which is increased among CH-B co-infected individuals and usually occurs soon after HAART initiation [20
], led to an accelerated long-term progression to liver disease.
Interestingly, there was an increase in mortality among subjects in the isolated core group, which was not attributable to liver disease. We do not anticipate that this was a result of HBV reactivation because (a) reactivation occurs with waning immunity not with the increasing CD4 counts that we observed [21
] and (b) liver disease was not a cause of death for any of the isolated core group. Surprisingly, most of the mortality in this group was from cardiovascular causes, leading to the possibility of differences in behavior rather than an intrinsic property of isolated core status. Differing patterns of drug use, including the possibility of more non-injection cocaine use, could potentially explain increased cardiovascular mortality [22
]. Chronic hepatitis C has also been associated with increased cardiovascular mortality [23
]; however, only one of the four subjects who died of cardiovascular causes had detectable HCV antibody. Significantly increased mortality among isolated core individuals was not reported in the previously described study from Taiwan supporting the possibility that a behavioral or environmental factor, may explain the difference.
In adjusted analysis, we did not observe an increased risk for mortality among the past infection versus the never infected groups. Crude mortality was higher among those with past infection, however, this is explained by the lower CD4 count and older age at HAART initiation amongst those with past infection compared to the never infected group. The absence of a difference in mortality is reassuring, given the high fraction of the population with past HBV infection.
Several limitations to this study are worth noting. An assessment of the potential impact of the HBV suppressive effect of lamivudine, tenofovir DF, or both on liver-related outcomes was not possible due to the small numbers of subjects and the later introduction of tenofovir DF. Second, we did not analyze hepatotoxicity risks because it is usually a transient event that may be missed with the infrequent (every six months) transaminase testing in this cohort. Third, underlying liver disease may have been under-reported on death certificates. This would have lead to an underestimate of the total burden of liver disease in this cohort. However, we do not believe that a systematic bias lead to differential under-reporting by HBV group.
In summary, this study demonstrates that HBV status at HAART initiation does not affect the long-term ability of HIV-infected patients to respond to HAART in terms of HIV RNA suppression and immunological recovery. Thus, CH-B should not diminish enthusiasm for prescribing HAART nor should long-term virologic or immunologic failure on HAART be attributed to CH-B. However, despite effective HAART that includes agents active against HBV, individuals with CH-B did not have an improvement in rate of liver-related mortality and thus remain at considerably higher risk for progressive liver disease, possibly because of incomplete HBV suppression with lamivudine as HBV suppression is an important component of slowing disease progression. Further work is needed to assess the impact of long-term suppressive HBV therapy with agents that are more durable than lamivudine (such as tenofovir DF), earlier HAART initiation in co-infected patients, and screening for liver disease during HAART to improve liver-related outcomes among the large population of individuals co-infected with HIV and CH-B.