Initiating non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy in patients recently infected with HIV-1 reduces the size of latent viral ‘reservoirs’ to a greater degree than in chronically infected patients, according to a study published in the July 1st edition of the Journal of Acquired Immune Deficiency Syndromes.
The study also shows that early treatment reduces these reservoirs to the size of those in treatment-naïve long-term non-progressors.
After infection, HIV’s genetic information is incorporated into the DNA of its host cells. While only active cells produce new virus particles, resting memory or naïve CD4 T-cells harbour a long lasting ‘reservoir’ of HIV’s genetic information. This reservoir is not diminished by antiretroviral therapy, but can become a source of new viral production if therapy is stopped.
In this study, the authors “show for the first time that initiation of NNRTI-based antiretroviral therapy during recent infection reduces peripheral blood mononuclear cell HIV-1 DNA copies to levels comparable to those seen in long-term non-progressors, which is not apparent if therapy is started during chronic infection.” They conclude that “when administered during recent infection, antiretroviral therapy may prevent further de novo infections of healthy CD4+ T cells and thus result in lower levels of HIV-1 proviral DNA.”
The investigators, from Chelsea and Westminster Hospital and Imperial College London, recruited 39 treatment-naïve patients for their study. Sixteen of these initiated antiretroviral therapy (efavirenz [Sustiva] plus two or three nucleoside analogues) during recent infection (between 60 days and one year post-infection), whereas ten started therapy during chronic infection (over two years). The remaining group of 13 patients were long-term non-progressors, who had been infected with HIV-1 for over eight years, but with controlled viral loads in the absence of antiretroviral therapy.
The researchers used a polymerase chain reaction (PCR)-based technique to measure the amount of HIV proviral DNA in the peripheral blood mononuclear cells taken from the patients. Thirty-six weeks of therapy reduced HIV proviral DNA levels in the recently infected group from a median of 266 to 33 copies/µg (p
HIV-1 proviral levels also decreased in the chronically infected group from 395 copies/µg to 218 copies/µg over 36 weeks (p = 0.053). However, the final size of the HIV reservoir remained higher in this group than in both the recently infected group (p
In contrast, reduction of HIV viral loads to below the limit of detection occurred more rapidly in the chronically infected group. After twelve weeks, 80% of this group were had undetectable viral loads, compared with 41% in the recently infected group (p
Both groups showed a increase in CD4 cell counts, with recently infected patients increasing from a median of 493 cells/mm3 at baseline to 617 cells/mm3 at week 36 (p = 0.005), a comparable level to that in the long-term non-progressors (726 cells/mm3; p = 0.36). The chronically infected group started at a lower CD4 cell count (311 cells/mm3; p 3 by week 36 (p
Despite their findings, the authors acknowledge that early treatment of HIV infection may not always be the best option for patients. “The high cost and adverse side-effects still make the timing of initiation of antiretroviral therapy a controversial issue,” they warn. “The physical and psychological effects of antiretroviral therapy must still be considered when deciding the ideal timing for the initiation of therapy, in addition to larger and more extensive studies that must be carried out before ascertaining the true clinical significance of the size of this reservoir.”
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Reference
Pires A et al. Initiation of antiretroviral therapy during recent HIV-1 infection results in lower residual viral reservoirs. J Acquir Immune Defic Syndr 36: 783-790, 2004.