A Randomized Open-Label Study of 3- Versus 5-Drug Combination Antiretroviral Therapy in Newly HIV-1–Infected Individuals

Abstract

Background To understand whether combination antiretroviral therapy (cART) has been optimized, we asked whether 3-drug protease inhibitor (PI)-based cART intensified with raltegravir and maraviroc and initiated during early infection would improve outcomes when compared to similarly applied 3-drug PI-based cART. Methods 40 newly HIV-1 infected patients were randomized 1:2 to receive 3-drug (N=14) or 5-drug (N=26) therapy. The primary endpoint was the percent of subjects with undetectable plasma viremia using standard RT-PCR and the single copy assay (SCA) after 48 weeks. Secondary endpoints included levels of cell-associated HIV-1 DNA and RNA and levels of infectious virus in resting CD4+ T cells at week 96 and quantitative and qualitative immunologic responses. Results At 48 weeks, 34 subjects remained on study and are included in the as-treated analysis. Three of 11 (27.3%) in the 3-drug arm and 9 of 21 (42.9%) in the 5-drug arm had plasma HIV-1 RNA levels below detection by both standard RT-PCR and SCA (P= 0.46, Fishers exact test). No significant differences in absolute levels of proviral DNA or changes in cell-associated RNA were seen during 96-weeks of therapy. Mean levels of infectious HIV-1 in resting CD4+ T cells at week 96 in 7 subjects treated with 3-drugs and 13 with 5-drugs were 0.67 and 0.71 IUPM respectively (P= 0.81). No differences were seen in quantitative or qualitative immunologic determinations including markers of immune activation. Conclusions Intensified 5-drug cART initiated during early infection fails to significantly further impact virologic or immunologic responses beyond those achieved with standard 3-drug PI-based cART.

Treatment intensification followed by interleukin-7 reactivates HIV without reducing total HIV DNA

“…The addition of RAL and MVC alone to suppressive cART did not result in decreases or increases of either cell-associated HIV DNA or ultrasensitive HIV RNA, consistent with prior intensification studies using RAL or MVC[10,12,30]. We did not investigate the level of preintegration episomal DNA (2-LTR circles), but some studies did find transient accumulation of 2-LTR circles with RAL or MVC.…”

Virologic failure is uncommon after treatment initiation during acute HIV infection

“…This has been previously described and was not found to be associated with any differences in the measurable HIV reservoir after 24 weeks of therapy [9]. Similarly, addition of raltegravir and maraviroc to protease inhibitor-based regimens has been shown to result in rapid reduction of plasma viremia without long-term effect on HIV reservoirs when ART is initiated during primary HIV infection [24,25]. In prior studies, adherence to the intensified five-drug regimens tended to be worse and virologic failure was more common [24,25].…”

“…Similarly, addition of raltegravir and maraviroc to protease inhibitor-based regimens has been shown to result in rapid reduction of plasma viremia without long-term effect on HIV reservoirs when ART is initiated during primary HIV infection [24,25]. In prior studies, adherence to the intensified five-drug regimens tended to be worse and virologic failure was more common [24,25]. Interestingly, three of the four participants with virologic failure at week 24 in this study were prescribed the intensified five-drug regimen.…”

Enhanced Antiretroviral Therapy in Rhesus Macaques Improves RT-SHIV Viral Decay Kinetics

“…Therefore, increasing the combination of drugs administered may not be sufficient to eradicate viral reservoirs. Recently, a randomized open-label study of three-versus fivedrug PI-based combination HAART in newly HIV-1-infected individuals also found no significant long-term impact on virologic or immunologic responses at 48 weeks beyond those achieved with standard three-drug PI-based HAART (40). Unlike this recent clinical study, which was limited to monitoring the viral load after 12 weeks of treatment, our studies demonstrated an immediate impact on viral decay kinetics during the first 10 weeks of treatment, which arguably could be of benefit to the infected individuals in preserving their functional immunity.…”