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ARV Update

By Michael Carter

January 2004


Restoring Anti-HBV Immunity in HIV/HBV-Coinfected Patients

Antiretroviral therapy can partially restore specific immune responses against hepatitis B virus (HBV) in patients coinfected with HIV and HBV, even if their antiretroviral regimen does not include drugs with a specific anti-HBV effect, according to a small study published in the December 15, 2003, Journal of Infectious Diseases.

Investigators in London studied five HIV/HBV-coinfected patients for 24 weeks after either starting antiretroviral therapy or adding an antiretroviral drug to the regimen that was also active against HBV. The researchers wished to see whether antiretroviral therapy, with or without an anti-HBV drug, was capable of inducing HBV-specific immune responses. The research was prompted by studies showing that HIV-negative patients infected with HBV were able to recover some HBV-specific CD4 and CD8 immune response after treatment with lamivudine (3TC), which is active against both HIV and HBV.

After 24 weeks of antiretroviral therapy, which did not include any drugs active against HBV, two patients saw a return of HBV-specific CD8 cell response. A third patient, who was initially taking dual nucleoside reverse transcriptase inhibitor (NRTI) therapy, experienced a return of HBV specific CD8 cell response after the addition of the NRTI adefovir (which, although effective against both HIV and HBV, is only licensed for the treatment of HBV because the dose needed for HIV treatment causes toxicities). This patient also had a return of HBV specific CD4 cell response.

The recovery of immune responses to HBV was preceded by a reduction in HBV viral load and levels of HBV surface antigen. A fall in HBV viral load was accompanied by an improvement in ALT levels. CD4 counts increased significantly in three patients in the study, but only one of these experienced a restoration of HBV-specific immune response. Although HIV viral load fell significantly in three patients, this was only accompanied by specific immune responses against HBV in one patient.

"Our preliminary findings from this longitudinal study of five patients need to be confirmed in larger studies," cautioned the investigators. However, they added that, "it appears that [antiretroviral therapy] alone may be insufficient for reconstitution of HBV-specific responses." However, some reconstitution of specific responses can occur with a reduction in HBV viral load, even if a patient has a high HIV viral load.

Editor's Note: Reprinted with permission from www.aidsmap.com (first e-published December 22, 2003).


TMC 125 Possibly Effective Against NNRTI-Resistant HIV

TMC 125, a new non-nucleoside reverse transcriptase inhibitor (NNRTI), reduces viral load in HIV-infected patients with high-level phenotypic NNRTI resistance, European investigators reported in a fast-track article published in the December 5, 2003, issue of AIDS. Published in the same issue was a concise communication in which another group of European researchers claimed that monotherapy with TMC 125 in previously untreated patients leads to a rate of decline of plasma HIV RNA no less than that associated with a five-drug regimen during one week of therapy.

TMC 125 is a diarylpyrimidine derivative with molecular flexibility to accommodate mutational changes in the binding pocket of the reverse transcriptase. Brian G. Gazzard et al. (Chelsea and Westminster Hospital, London) explained that in vitro studies of TMC 125 showed activity against more than 1,000 NNRTI-resistant HIV mutants.

In a proof-of-concept study, Gazzard et al. administered TMC 125 at 900 mg twice daily for seven days to 15 patients previously treated with NNRTI-containing regimens, specifically efavirenz (EFV) or nevirapine (NVP). The median number of NNRTI mutations was two; three patients had three mutations, and one had four. They also had nucleoside reverse transcriptase inhibitor (NRTI) mutations, and all but one had protease mutations.

When TMC 125 was substituted for the previous NNRTI, viral load decay rate was 0.13 log10 HIV RNA copies/mL per day. Median decrease at day 8 was 0.89 log 10 copies/mL, and seven patients had a decrease of >1 log10. There were no severe adverse events. Most commonly reported mild or moderate events were diarrhea and headache.

If further studies confirm these findings, the authors suggest that TMC 125 may be of benefit following failure with a current NNRTI, and may even be used in NNRTI-naive patients.

In the concise communication, Joep MA Lange et al. (University of Amsterdam, The Netherlands) compared treatment efficacy during one week of therapy with TMC 125 or with a five-drug regimen (lamivudine [3TC], abacavir [ABC], indinavir [IDV], NVP, and zidovudine [ZDV] or stavudine [d4T]) in antiretroviral therapy-naive patients.

In the 12 patients on TMC 125, the median plasma HIV RNA decline was 1.92 log 10 copies/mL, compared with 1.76 log 10 copies/mL in 11 patients on the five-drug regimen. Median increases in CD4 cells were 119 and 60 cells/L in the two groups, respectively.

Lange et al. suggest that, "starting treatment with a TMC 125-containing regimen could give a better suppression of HIV replication in the long run."

Editor's Note: This Reuters Health article was first e-published January 9, 2004.




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