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Starting ART Above 500 CD4s Cuts HIV DNA in PBMCs, Prompts Bigger CD4 Rebound
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
"....results support early ART in people with a high CD4 count..."
Starting antiretroviral therapy (ART) at a CD4 count above 500 promoted a deeper drop in HIV DNA in peripheral blood mononuclear cells (PBMCs), a bigger CD4-cell rebound, and a better CD4/CD8 ratio, according to results of a 309-person retrospective study in Orleans, France [1]. The findings follow earlier research by this group indicating that starting ART during primary HIV infection leads to a sharp decline in the PBMC HIV DNA reservoir and that this decline persists and sometimes improves after people stop therapy [2]. After that study, VISCONTI, the Orleans team asked whether starting ART during chronic infection-but at a CD4 count above 500-would yield similar PBMC reservoir results.
The new study aimed to see how CD4 count when ART begins affects a composite endpoint: (1) reaching a normal CD4 count (at or above 900), (2) reaching a normal CD4/CD8 ratio (above 1), and reaching an HIV DNA level below 200 copies per million PBMCs. The researchers used Cox proportional hazards regression analysis to identify factors leading to the composite endpoint.
The study included antiretroviral-treated adults with chronic (Fiebig VI) HIV infection divided into three groups by pretreatment CD4 count: 500 or higher, 200 to 499, and below 200. All study participants reached and maintained a plasma viral load below 50 copies, though they could have viral blips between 50 and 200 copies. No one met the primary endpoint before starting ART. The investigators measured HIV DNA in PBMCs before ART (if possible), then at least once a year.
The Orleans team found 309 eligible patients seen at some point from 2005 through 2012. Median follow-up was 3.7 years (interquartile range 1.5 to 6.8). HIV DNA in PBMCs could be measured in 77 of these 309 people (25%).
There was 30 people (73% men) in the 500+ nadir CD4 group, 155 (52% men) in the 200-499 group, and 124 (56% men) in the under-200 group. Gender differences between groups were not significant (P = 0.11). Average age was significantly younger in the 500+ group (34) than in the other two groups (39 and 40) (P = 0.047). Of course nadir (lowest-ever) CD4 was highest in the 500+ group (577 versus 292 versus 101, P < 0.0001), while peak viral load was lowest in the 500+ group (4.6 versus 5.0 versus 5.3 log, P = 0.0004). Time from HIV diagnosis to ART was brief in all three groups but lower in the under-200 group (0.2 years) than in the 500+ group (0.9 years) or the 200-499 group (1.5 years) (P = 0.02). The researchers did not report how long each group had an undetectable plasma viral load after starting ART.
HIV DNA in PBMCs correlated negatively with CD4 count during suppressive ART--the higher the current CD4 count, the lower the HIV DNA level (rho = -0.145, P < 0.0001). Median HIV DNA was significantly lower in the 500+ group than in the 200-499 or under 200 groups (2.51 versus 2.78 versus 2.91 log copies per million PBMCs, P = 0.0009). The 500-or-over group also had the highest most recent median CD4 count (1011 versus 662 versus 515, P < 0.0001) and the best median CD4/CD8 ratio (1.25 versus 0.88 versus 0.66, P < 0.0001).
A significantly higher proportion of people who started ART with at least 500 CD4s met each of the primary endpoint components:
Proportions with CD4 nadir >500, 200-499, and <200:
-- Current CD4 count at or above 900: 67% versus 12% versus 6% (P < 0.0001)
-- CD4/CD8 ratio above 1: 73% versus 36% versus 16% (P < 0.0001)
-- HIV DNA below 200/million PBMCs: 39% versus 21% versus 11% (P = 0.001)
-- Primary endpoint (all three components): 30% versus 3% versus 0% (P < 0.0001)
In the Cox model accounting for other relevant variables, only a nadir CD4 count at or above 500 predicted reaching the primary endpoint, raising chances 56 times (hazard ratio 56, 95% confidence interval 15 to 209, P < 0.0001).
In the subgroup of 77 people with HIV DNA determined before ART began, 18 people had a CD4 nadir at or above 500 and 59 had a lower nadir. A 500+ CD4 nadir was associated with slightly lower HIV DNA levels before treatment started (P = 0.06). But median HIV DNA decline after 1 year of viral suppression was similar in these two subgroups at about 0.5 log10 copies per million PBMCs (P = 0.8).
The investigators noted that the proportion of people reaching a CD4 count at or above 900 in the 500-or-over group was similar to the proportion among people they treated during primary HIV infection. They proposed that a lower pretreatment HIV DNA level probably explains part of the good immunologic and virologic response in people who started ART with at least 500 CD4s. The researchers suggested their results support early ART in people with a high CD4 count.
References
1. Hocqueloux L, Avettand-Fenoel V, Prazuck T, et al. In chronically HIV-1-infected patients long-term antiretroviral therapy initiated above 500 CD4/mm3 achieves better HIV-1 reservoirs' depletion and T cell count restoration. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract WEAB0102.
IAS: In chronically HIV-1-infected patients long-term antiretroviral therapy initiated above 500 CD4/mm3 achieves better HIV-1 reservoirs' depletion (HIV-DNA) and T cell count restoration - (07/05/13)
2. Saez-Cirion A, Bacchus C, Hocqueloux L, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9:e1003211. http://www.natap.org/2013/HIV/031513
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