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Reconstitution of Hepatitis B Virus Specific T Cell Responses with Treatment of Human Immunodeficiency Virus/HBV Coinfection
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R. Monica Lascar,1,4 Richard J. Gilson,1,4 A. Ross Lopes,1,2,3 Antonio Bertoletti,2 and Mala K. Maini1,2,3,4
1Department of Sexually Transmitted Diseases, 2Institute of Hepatology, and 3Division of Infection and Immunity, University College London, and 4Mortimer Market Centre, Camden Primary Care Trust, London, United Kingdom
ABSTRACT/SUMMARY
Liver-related mortality is an increasing problem in human immunodeficiency virus (HIV)/hepatitis B virus (HBV)coinfected patients receiving highly active antiretroviral therapy (HAART).
In HIV-negative patients, HBV chronicity is associated with a reduction in specific T cell responses that can be partially restored by treatment with lamivudine. We studied 5 HIV/HBV-coinfected patients treated with HAART, either with or without addition of a drug with specific anti-HBV activity.
Our data show that reconstitution of some HBV-specific T cell responses can also occur in HIV-positive patients after a reduction in HBV load. This potential to recover T cell responses, which has been thought to be critical for HBV control, provides support for the addition of anti-HBV therapy in the treatment of HIV/HBV-coinfected patients.
BACKGROUND
A large proportion of patients infected with human immunodeficiency virus (HIV) have also been infected with hepatitis B virus (HBV) because of their shared transmission routes, and at least 10%15% remain coinfected. Recent evidence has confirmed that HIV/HBV-coinfected patients, especially those with low CD4 cell counts, are at significantly increased risk of mortality due to liver disease. Since the advent of highly active antiretroviral therapy (HAART), the overall improvement in survival of patients has been associated with an apparent increase in liver diseaserelated mortality in coinfected patients. This increase in mortality has been attributed not only to potential hepatotoxicities of these drugs but also to prolonged survival, which allows time for slowly progressive viral hepatitis to become clinically relevant. Therefore, in the era of HAART, there is a need to reexamine the use of specific anti-HBV drugs in this coinfected population. It is unclear whether the immune reconstitution associated with HAART is sufficient to either restore control of HBV infection (as occurs with several other opportunistic infections) or allow specific anti-HBV therapy to be effective.
An important consideration is the effect that HAART regimens with and without an anti-HBV drug have on HBV-specific T cell responses in coinfected patients. Recent studies of HIV-negative patients have revealed that the hyporesponsiveness of both CD4 and CD8 T cells that is associated with HBV chronicity can be partially overcome by treatment with lamivudine. We studied patients coinfected with HIV and HBV to examine whether HAART with and without an anti-HBV drug is capable of inducing HBV-specific immune responses in the setting of HIV infection.
RESULTS
The kinetics of HBV-specific CD8 cell responses were studied and showed that recovery of T cell reactivity was preceded by a reduction in HBV DNA level and surface-antigen titers; in patient 3, the level of HBeAg also became undetectable. HBV-specific CD8 cell responses were maximal between 12 and 24 weeks after the start of treatment, which is similar to the time course in HIV-uninfected patients starting anti-HBV therapy.
Discussion By Authors
Here we have presented the first analysis of HBV-specific T cell responses in HIV/HBV-coinfected patients in whom the effect of HAART with or without an anti-HBV drug can be examined. We have found evidence for reconstitution of functionally active HBV-specific CD8 cell responses when HIV/HBV-coinfected patients are treated. The fact that low-level responses were detected in only 2 of the 11 HIV/HBVcoinfected patients studied cross-sectionally adds weight to the increase in detectable responses after treatment. Our preliminary findings from this longitudinal study of 5 patients need to be confirmed in larger studies, but, from our sample, it appears that HAART alone may be insufficient for reconstitution of HBV-specific responses. However, some reconstitution of specific T cell responses can certainly occur with reduction of HBV load, even in the context of advanced immunosuppression or ongoing HIV viremia. These observations are consistent with the fact that HBV-specific T cell responses are difficult to detect in HIV-negative patients with HBV infection until HBV load is reduced. The increase in HBV-specific CD8 cell responses after treatment contrasts with the situation observed for HIV-specific CTLs, which are easily detectable in patients with high virus loads and typically decrease after the reduction in virus load that is induced by HAART.
One patient who had a marked reduction in HBV viremia on the addition of the novel anti-HBV drug adefovir dipivoxil showed reconstitution of HBV-specific CD4 cell responses to HBcAg and HBsAg. Although he was receiving only a dual nucleoside regimen and had incomplete suppression of HIV load, he was the only patient who had never been severely immunosuppressed and might therefore be expected to most closely mimic an HIV-negative patient with chronic HBV infection. Such CD4 cell responses are thought to play a critical role in maintaining functionally active CTLs, and it is of note that this patient also had the highest peak CD8 cell response while receiving treatment.
The reconstituted HBV-specific CD8 cell responses were mostly low frequency after 10 days of in vitro expansion, and all were envelope specific, even though all patients were screened repeatedly for responses to epitopes within core and polymerase as well. Reconstituted responses in HIV-negative patients have also been reported to be frequently envelope specific, with a notable absence of the core-specific CD8 cells that are immunodominant in response to acute infection associated with viral control. However, these responses were only measured from the peripheral blood; the recent identification of other CD8 cell specificities in secondary lymphoid organs during treatment with lamivudine in HIV-negative patients with HBV infection suggests the potential for a more complete reconstitution of the multispecific response associated with viral control. Recent reports have highlighted the potential benefits of additional anti-HBV drugs, such as adefovir dipivoxil and tenofovir disoproxil fumarate, for HIV/HBV-coinfected patients. Whether more-potent anti-HBV therapy or therapeutic immunization will ultimately be able to further enhance reconstitution of HBV-specific T cell responses, even in the setting of HIV disease, remains to be established.
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