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Immediate ART in START Trial Linked to Better Kidney Function
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21st International AIDS Conference (AIDS 2016), July 18-22, 2016, Durban, South Africa
Mark Mascolini
Estimated glomerular filtration rate (eGFR) proved higher (better) in international START trial participants who began antiretroviral therapy (ART) immediately at a CD4 count above 500 than in those who delayed ART until their CD4s dipped to 350 [1]. This large analysis with a median 2.1 years of follow-up shed light on the impact of race, tenofovir disoproxil fumarate (TDF), and boosted protease inhibitors (PIs) on kidney function in people starting ART with high CD4s.
Through 3 years of follow-up involving 4685 people starting their first antiretroviral regimen, START found that immediate treatment at a CD4 count above 500 cut the risk of a serious AIDS or non-AIDS event or death by 57% (P < 0.001) compared with delaying ART [2]. Immediate ART lowered the risk of a non-AIDS diagnosis 39% (P = 0.04). Because little is known about how ART affects kidney function in people with high CD4 counts, START investigators analyzed eGFR in study participants.
The primary aim of the kidney function analysis was to evaluate changes in eGFR determined by the CKD-EPI equation in START participants randomized to immediate or deferred ART. The analysis included 2294 people randomized to immediate ART and 2335 randomized to deferred ART. The immediate and deferred groups were similar in median age (36 years in both groups), proportion of women (26.6% and 27.0%), proportion of blacks (30.1% and 30.2%), baseline CD4 count (651 in both groups), and baseline eGFR (112 and 111 mL/min).
eGFR fell over time in both START arms. But through a median 2.1 years of follow-up, eGFR remained higher in the immediate arm. In a random effects linear regression model adjusted for baseline eGFR and years since randomization, eGFR was an average 0.56 mL/min higher in the immediate arm (P = 0.049). In a model adjusted for those factors plus age, gender, race, injection drug use, proteinuria, and other variables, eGFR remained 0.55 mL/min higher with immediate ART (P = 0.037). And in a model adjusted for all those variables plus current TDF or boosted PI, eGFR was 1.72 mL/min higher in the immediate ART group (P < 0.001). If the researchers stopped follow-up when a person started TDF or a boosted PI, eGFR rose in the immediate arm through 36 months and fell slightly in the deferred arm.
Among blacks, eGFR was significantly higher in the immediate-ART group than in the deferred group (average difference 2.43 mL/min, P < 0.001). After adjustment for current TDF or boosted PI, the eGFR difference between immediate and deferred therapy grew larger and remained significant (average difference 3.90 mL/min, P < 0.001). Among nonblacks, the difference between the immediate and deferred arms was small and not significant (average difference -0.23 mL/min, P = 0.49). But after adjustment for TDF or boosted PI use, eGFR proved significantly higher in the immediate-ART arm (average difference 1.05 mL/min, P = 0.004).
During follow-up 10 CKD adverse events arose, 4 in the immediate-ART group and 6 in the deferred group. End-stage renal disease developed in 1 person in each study arm. Immediate ART was associated with almost a 25% lower risk of 1+ or greater proteinuria in a trend that reached statistical significance (incidence rate ratio 0.74, 95% confidence interval 0.55 to 1.00, P = 0.049).
The START team believes their findings "illustrate the complex relationship between decreasing renal function, genetic disposition for renal decline, the use of renal toxic antiretrovirals and uncontrolled HIV." They called for further study to examine the mechanism of the short-term kidney benefit with immediate ART in people with high CD4 counts.
References
1. Mocroft A, Achra AC, Ross M, et al. Deferred antiretroviral therapy is associated with lower estimated glomerular filtration rate in HIV-positive individuals with high CD4 counts. 21st International AIDS Conference (AIDS 2016). July 18-22, 2016. Durban, South Africa. Abstract WEPDB0101.
2. INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807. http://www.nejm.org/doi/full/10.1056/NEJMoa1506816
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