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Pre-ART Load, Time to Suppression, and Regimen Predict Rebound
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15th European AIDS Conference, October 21-24, 2015, Barcelona
Mark Mascolini
A higher pretreatment viral load and slower time to viral suppression predicted virologic rebound in 7500 people starting their first antiretroviral therapy (ART) in France [1]. Starting ART with an integrase inhibitor (INSTI) or a nonnucleoside (NNRTI) rather than a protease inhibitor (PI) lowered rebound risk.
University of Nantes researchers and colleagues across France noted that previous research in the United Kingdom linked pre-ART viral load and time to viral control to rebound risk in a cohort including 75% starting an NNRTI and 25% starting a PI. To update those findings, the French team focused on people starting one of the most potent antiretrovirals in recent years: the NNRTI efavirenz, an INSTI, or the ritonavir-boosted PI lopinavir, atazanavir, or darunavir.
Study participants were members of the French Dat'AIDS cohort, a 42,000-person group of people in care for HIV, HBV, and/or HCV. This analysis included people older than 16 who started one of the regimens noted above between January 2007 and December 2013. The main outcome was viral rebound, defined as 2 consecutive viral loads above 50 copies after viral suppression. Statistical models to identify rebound predictors adjusted for type of regimen, nucleoside backbone, baseline CD4 count, age, gender, HIV transmission group, AIDS at baseline, and coinfection with HBV or HCV.
The analysis included 8351 ART starters who had adequate follow-up data, 7592 of whom (91%) reached a viral load below 50 copies on their first regimen. Suppressors had a median age of 39 years, 71% were men, 43% men who have sex with men (MSM), and 46% heterosexual. While 15.5% had an AIDS history, 12.6% had hepatitis coinfection. Median pre-ART CD4 count measured 308 and median viral load 4.8 log10 copies (about 63,000 copies). Most suppressors, 69%, started a boosted-PI regimen, 26% started an NNRTI, and 5% started an INSTI. Three quarters of suppressors backed up their main antiretroviral with tenofovir/emtricitabine and 15% with abacavir/lamivudine.
Over the first year of treatment, time to viral suppression was significantly faster with an INSTI than with a PI or an NNRTI (P < 0.001) and faster in people with a pretreatment load below 100,000 copies (P < 0.001). Cox regression analysis determined that men had about a 10% lower chance of viral suppression than women (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.83 to 0.94, P < 0.001), but MSM had almost a 20% higher chance of suppression than heterosexuals (aHR 1.19, 95% CI 1.12 to 1.26, P < 0.001).
People with an AIDS diagnosis had a 20% lower chance of viral suppression (aHR 0.81, 95% 95% CI 0.76 to 0.87, P < 0.001), while people with a pretreatment HIV load above 100,000 copies had a one-third lower chance of suppression (aHR 0.67, 95% CI 0.64 to 0.71, P < 0.001). Cohort members starting an NNRTI (efavirenz) had a 12% better chance of viral suppression than those starting a PI (aHR 1.12, 95% CI 1.06 to 1.18, P < 0.001), while those starting an INSTI had almost a twice higher chance of reaching an undetectable viral load than the PI group (aHR 1.92, 95% CI 1.72 to 2.14, P < 0.001). Age, nucleoside backbone, and hepatitis coinfection did not affect chances of getting the viral load below 50 copies.
Among the 7592 people who reached a sub-50-copy viral load, 990 (13%) had a rebound during a median follow-up of 41.2 months. Time to rebound was faster in people with a pre-ART viral load above 100,000 copies than in those with a lower baseline viral load (P < 0.001). And people who took longer than 6 months to achieve viral suppression had a faster time to rebound (P < 0.001).
Cox modeling identified 10 predictors of virologic rebound at the following adjusted hazard ratios (and 95% CI):
Lower rebound risk
-- Age 40 or older: aHR 0.85 (0.74 to 0.96), P = 0.012
-- MSM versus heterosexual risk group: aHR 0.66 (0.56 to 0.77), P < 0.001
-- Starting NNRTI (efavirenz) vs PI: aHR 0.74 (0.63 to 0.87), P < 0.001
-- Starting INSTI vs PI: aHR 0.53 (0.33 to 0.83), P = 0.006
Higher rebound risk
-- Hepatitis virus coinfection: aHR 1.25 (1.05 to 1.50), P = 0.013
-- AIDS category B vs A: aHR 1.31 (1.07 to 1.60), P = 0.010
-- AIDS category C vs A: aHR 1.63 (1.40 to 1.90), P < 0.001
-- Backbone other than ABC/3TC or AZT/3TC vs TDF/FTC: aHR 1.69 (1.18 to 2.42), P = 0.004
-- Pretreatment load above 100,000 copies: aHR 1.49 (1.31 to 1.71), P < 0.001
-- Time to suppression 6 months or longer: aHR 2.14 (1.88 to 2.44), P < 0.001
Among people starting an NNRTI (efavirenz), pretreatment load above 100,000 copies, 6 or more months to viral suppression, baseline AIDS, and "other" nucleoside backbone independently raised rebound risk. Among people starting a PI, independent rebound predictors were age 40 or older (lower risk), MSM (lower risk), and (all higher risk) hepatitis coinfection, AIDS category B or C, pretreatment load above 100,000 copies, and 6 or more months to viral suppression. Among people starting an INSTI, only one factor independently predicted virologic rebound: Taking 6 months or more to reach viral suppression more than tripled the risk (aHR 3.47, 95% CI 1.08 to 11.16, P = 0.037).
The Dat'AIDS team noted that their analysis is limited by the small number of people starting ART with an integrase inhibitor. With that limitation in mind, they concluded that rebound risk after viral suppression is significantly lower with an integrase inhibitor or with efavirenz than with a PI. For people starting therapy with efavirenz or a PI, rebound risk depended mainly on baseline viral load or taking 6 months or longer to reach viral suppression. In people starting an integrase inhibitor, rebound risk depended only on taking 6 months or longer to reach viral suppression. The researchers are now comparing results with the three PI regimens studied.
Reference
1. Khatchatourian L, Hanf M, Jovelin T, et al. Impact of baseline viral load and time to viral suppression on subsequent virologic rebound according to first-line antiretroviral therapy (cART). 15th European AIDS Conference, October 21-24, 2015, Barcelona. Abstract PS10/1.
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