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Earlier ART in primary infection leads to bigger drop in cellular HIV DNA
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CROI 2015, February 23-26, 2015, Seattle, Washington
Mark Mascolini
The earlier antiretroviral therapy (ART) starts during primary HIV infection, the faster cell-associated HIV DNA drops in the first 8 months of therapy, according to results of 327-person analysis in France [1]. Researchers working with the ANRS PRIMO cohort estimated that HIV DNA levels would be significantly lower after 5 years of uninterrupted ART begun within 15 days of infection than when ART began only within the first 3 months.
HIV establishes a latent reservoir in resting CD4 cells in the earliest weeks of primary infection. Previous research found that ART begun during primary HIV infection leads to bigger drops in cell-associated HIV DNA than ART started during chronic infection [2,3]. And macaque studies found greater declines in the SIV DNA reservoir when ART began between 7 and 10 days of infection than when it began between 10 and 42 days [4].
To determine the impact of early ART on HIV DNA decay in humans, an APHP/Inserm team focused on 327 people who enrolled in the PRIMO cohort during primary infection, began ART within the month of enrollment, and reached a plasma viral load below 50 HIV RNA copies/mL within 6 months. Moussa Laanani and colleagues made 1305 HIV DNA measurements with a method that permits detection to a level as low as 5 HIV DNA copies per million peripheral blood mononuclear cells (PBMCs). They used a 3-slope linear mixed-effects model to calculate decay of cell-associated HIV DNA during suppressive ART.
Most study participants, 83%, were men, and 91% had symptomatic primary HIV infection. Median age at cohort entry stood at 36 (interquartile range [IQR] 29 to 43), and median year of inclusion was 2002 (IQR 1999 to 2005). Median time between HIV infection and starting ART measured 41 days (IQR 33 to 54).
Median CD4 count at cohort entry stood at 450 and median intracellular HIV DNA at 3.46 log10 copies per million PBMCs. Median entry plasma HIV RNA measured 5.3 log10 copies/mL. Most study participants, 82%, started a protease inhibitor regimen, median duration of uninterrupted ART measured 2.3 years (IQR 1.0 to 4.6), and each participant had a median of 3 HIV DNA measures (IQR 2 to 4).
Laanani and colleagues calculated that HIV DNA declined fastest in the first 8 months of ART among cohort members who started ART within 15 days of infection. HIV DNA decay rates were slower in people who started ART only within 1 month of infection and slower still in those who started within 3 months of infection:
-- ART within 15 days: -0.171 DNA log10 copies/million PBMCs/month
-- ART within 1 month: -0.131 DNA log10 copies/million PBMCs/month
-- ART within 3 months: -0.068 DNA log10 copies/million PBMCs/month
The difference between the 15-day slope and the other slopes was highly statistically significant (P < 0.0001).
After the first 8 months of ART, HIV DNA continued to decline significantly with ongoing therapy but at a slower rate than during the first 8 months of therapy. The APHP/Inserm team calculated that predicted average intracellular HIV DNA after 5 years of uninterrupted suppressive ART would be 1.62 log10 copies/million PBMCs in the group that started ART within 15 days of infection and 2.24 log10 copies/million PBMCs in the group that started ART within 3 months of infection (P = 0.0006).
The APHP/Inserm investigators concluded that starting ART sooner during primary HIV infection results in a faster drop in cell-associated HIV DNA during the first 8 months of therapy and that HIV DNA decay continues through the first several years of treatment. The researchers believe their findings provide "strong arguments in favor of cART initiation at the earliest possible time point after HIV infection, and thus in favor of early screening."
References
1. Laanani M, Ghosn J, Essat A, et al. The earlier cART is initiated during PHI, the more intracellular HIV-DNA decreases. CROI 2015. February 23-26, 2015. Seattle, Washington. Abstract 373.
2. Hocqueloux L, Avettand-Fenoel V, Jacquot S, et al. Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts. J Antimicrob Chemother. 2013;68:1169-1178.
3. Buzon MJ, Martin-Gayo E, Pereyra F, et al. Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells. J Virol. 2014;88:10056-10065.
4. Okoye A, Rohankhedkar M, Reyes M, et al. Treatment in acute SIV infection limits the size and distribution of the viral reservoir. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). March 3-6, 2014. Boston. Abstract 136LB.
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