Summary of Findings
In this project we described several findings which bring new light to current published literature on HIV/HBV co-infection. In our first specific aim, we found a substantial decrease in more recent calendar years of early mortality following ART initiation among HIV/HBV co-infected patients. HBV-infected patients who began therapy between 1998 and 2001 were over twice as likely to die in the first two years following therapy initiation compared to HBV-uninfected patients, but this difference attenuated in more recent calendar years, with no difference in time to death by HBV infection status among patients starting ART between 2005 and 2008. These findings suggest that during the first two years following ART initiation, HBV co-infection may no longer increase the risk of all-cause mortality among HIV-infected individuals.
In our second specific aim, we found that HIV/HBV co-infected patients who received TDF as part of their initial ART were more likely to achieve and maintain HIV RNA suppression over the first year and a half on therapy. Among patients who achieved and maintained suppressed HIV RNA during this interval, TDF use did not appear to further affect the risk of HIV virologic failure. This is consistent with clinical and clinical trial observations that once virologic suppression is achieved virologic failure is uncommon, even with regimens that may not be considered optimal.120 However, our ability to detect more subtle differences after sustained successful response to initial ART was restricted by
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available sample size and the limited number of HIV virologic failures observed. Consequently any conclusions about longer term effects of TDF use on HIV RNA response would require additional follow-up time in a larger cohort of patients.
These findings are reassuring, particularly since we observed no decrease in the prevalence of HBV co-infection across the study period. However, while we found that HBV co-infection does not contribute to liver-related mortality in the short-term, whether HBV co- infection accounts for some of the rise in liver-related mortality in the long-term remains unknown.
Strengths and Limitations
A major limitation of our analyses was rapid and widespread uptake of ARVs efficacious for treatment of both HIV and HBV, in particular TDF with FTC or 3TC. Even in this large cohort, the small number of HBV co-infected patients and the lack of heterogeneity in treatment over calendar time meant we could not measure the extent to which these anti- HBV agents were responsible for the decrease in early mortality and the improvement in HIV viral control separate from the collective improvements in the management of HIV patients between the late 1990s and late 2000s. However, we ruled out the contribution of several competing explanations, including changes in patient demographic and clinical characteristics over calendar time.
Our studies are, to date, the largest to explore HIV outcomes and mortality among HIV/HBV co-infected individuals. Also, our study population is largely representative of the HIV-infected population in the US, supporting the generalizability of our findings. Finally,
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our studies are, to the best of our knowledge, the first to capture and document the rapid uptake of ARVs efficacious for treatment of both HIV and HBV.
Clinical and Public Health Significance
HBV has been recognized as a significant cause of morbidity and mortality in HIV- infected patients.2,47,145 An effective vaccine against HBV has been available in the US for nearly 30 years; however, a substantial proportion of high-risk individuals have not been immunized.139
As we found in the CNICS cohort with the prevalence of HBV infection steady at 6% between 1998 and 2008, preventive efforts have not yet been successful at reducing HBV infection among HIV-infected individuals. For these reasons, effective HBV treatment remains a high priority for HIV care.
Treatment for HIV/HBV co-infection is more complex than treatment for either HIV or HBV alone. It must balance multiple factors, such as the likelihood of response to anti-HBV therapy, the need to treat HIV, the prevention of drug resistance, minimizing the risk of drug- induced hepatotoxicity and managing rising liver transaminases when they occur. Additional issues complicating treatment for co-infected patients are the limited choice of anti-HBV drugs and that treatment for both infections is suppressive rather than curative, and therefore must be provided for long, often indefinite, periods.36 Though a limitation for our analyses, it is important to recognize that timely and extensive uptake of improved treatment, as we observed in the CNICS cohort, has large clinical and public health benefits.
Our findings support current US treatment guidelines which recommend treating HIV/HBV co-infected patients with combination regimens that include agents efficacious for
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both HIV and HBV, in particular TDF. To date treatment recommendations were largely based on evidence of TDF activity against HBV. These findings suggest that TDF use may also lead to better HIV outcomes and to improvements in short-term mortality among HIV/HBV co-infected patients.
In the US and other developed settings the prevalence of HBV is not high, even among HIV-infected individuals. But in resource limited settings, the story is different. Worldwide two billion people have been infected with HBV and nearly 400 million live with chronic infection.13 The geographic areas with the largest burden of HBV are the same as those with the largest burden of HIV, and given shared risk factors, co-infection is common. Therefore our findings have important implications for prioritizing treatment in these areas. They also provide evidence that increasing the utilization of agents efficacious for both HIV and HBV may substantially improve HIV-related outcomes and short-term mortality for a great number of people.
Future Directions
In the presence of resistance evolution ongoing efforts to identify new agents with activity against both HIV and HBV is necessary.136-138 Further, effective treatment is not a substitute for prevention. Since HBV infection can occur before, after or concurrent with HIV infection, and because HBV vaccine-induced immunity is compromised in HIV-infected patients140, it is vital that efforts continue to achieve wide-spread uptake of HBV vaccination through routine and other immunization opportunities.141
Additional work on mortality by HBV status is necessary to determine whether the
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is sustained for longer periods. This will need to occur in a cohort with longer follow-up of patients who were treated with modern therapy efficacious for both HIV and HBV. Further, additional work is indicated that considers response to agents with activity against both HIV and HBV on HIV RNA suppression, immunologic response, liver disease progression and liver-related mortality. Longer longitudinal follow-up with a larger sample size would support these additional analyses, providing clinical endpoint evidence and strengthening evidence for guidelines in developed and developing regions.
Conclusions
Aging up of the cohort of infants who began receiving HBV vaccine as part of the routine childhood immunization schedule, together with expanding overall coverage of HBV vaccine will hopefully bring the end of HIV/HBV co-infection in the US. Unfortunately, this same outcome will not be seen in resource limited settings for quite some time. Therefore understanding the most efficacious treatment options for HIV/HBV co-infected individuals is necessary in order to enable the least advantaged patients to have the best health outcomes possible. Efforts to expand the use of agents with activity against both HIV and HBV are needed, as well as careful monitoring to ensure the positive benefits seen in our studies, as well as those for HBV-related outcomes, are also seen for HIV/HBV co-infected patients living in resource limited settings.
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APPENDIX A. RESULT OF LOG-LINEAR BINOMIAL REGRESSION MODEL OF