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Renal Safety Similar With Dolutegravir, Raltegravir, and Efavirenz in Antiretroviral Naive
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
Regimens including dolutegravir, an investigational integrase inhibitor, proved similar in renal safety to raltegravir and efavirenz regimens after 48 weeks in phase 3 trials that enrolled previously untreated people [1].
Dolutegravir stifles creatinine secretion by inhibiting the renal organic transporter 2 (OCT2), but it has no impact on estimated glomerular filtration rate (eGFR) (measured by iohexol plasma clearance) or renal plasma flow (assessed by para-aminohippurate clearance) [2]. In phase 1/2a studies, people taking dolutegravir had small, nonprogressive increases in creatinine, and those increases declined when dolutegravir stopped.
To analyze renal changes with dolutegravir more closely, researchers assessed an array of renal markers in antiretroviral-naive people who enrolled in two phase 3 trials of dolutegravir. SPRING-2 compared dolutegravir (50 mg once daily) with raltegravir plus investigator-selected nucleosides. SINGLE compared the same dose of dolutegravir (plus abacavir/lamivudine) with efavirenz (plus tenofovir/emtricitabine, as Atripla). Renal assessments included (1) serial serum creatinine measures, (2) eGFR by the Cockroft-Gault method), (3) spot urine albumin/creatinine ratio, and (4) renal toxicity.
Median age across the four treatment arms was about 36, and 15% of study participants were women. Blacks made up about 10% of the SPRING-2 population and 24% of the SINGLE population. About 60% of SPRING-2 participants took tenofovir/emtricitabine with dolutegravir or raltegravir.
In the first 2 weeks of both trials, serum creatine rose by an approximate average 12 umol/L in both dolutegravir arms and stayed around that level through 48 weeks. At week 48 creatinine elevations averaged 12.3 umol/L in the dolutegravir arms and 4.7 umol/L in the comparison arms.
Through 48 weeks creatinine clearance fell an average 16.5 and 13.1 mL/min in the two dolutegravir arms, fell 5.4 mL/min in the raltegravir arm, and rose 2.1 mL/min in the Atripla arm. Median urine albumin/creatinine ratio did not change through 48 weeks in the dolutegravir or raltegravir arms and changed minimally in the Atripla arm.
There were three kidney-related adverse events among people taking dolutegravir in SPRING-2, but none were judged related to study drug or resulted in withdrawal. There was one such adverse event in a person taking dolutegravir in SINGLE (a grade 1 creatinine elevation); it was judged not related to study drug and resulted in withdrawal.
The researchers conclude that "analysis of adverse events and lab data do not suggest that dolutegravir has an adverse effect on renal function." The investigators attributed "likely benign," nonprogressive, mild creatinine increases with dolutegravir to inhibition of creatine secretion.
References
1. Curtis LD, Min S, Nichols G, et al. Once-daily dolutegravir (DTG; S/GSK1349572) has a renal safety profile comparable to raltegravir (RAL) and efavirenz in antiretroviral (ART)-naive adults: 48 week results from SPRING-2 (ING113086) and SINGLE (ING114467). 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract TUPE282.
2. Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexal and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol. 2013;75:990-996.
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