Small study finds no need for double-dosing dolutegravir after switching from failing efavirenz-based regimen

On the whole, additional dolutegravir doses are not needed in people who are switching from a failing efavirenz-based regimen, a small study in South Africa showed. However, the research noted some important exceptions in cases where a person is taking concomitant medications or adherence is a concern.

About This Study

“Pharmacokinetics of Single Versus Double-Dose Dolutegravir After Switching From a Failing Efavirenz-Based Regimen” was published online on Feb. 15, 2024, in Journal of Acquired Immune Deficiency Syndromes. The lead author is Rulan Griesel, MBChB, MMed, of the Division of Clinical Pharmacology in the Department of Medicine, and of the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, both at the University of Cape Town, South Africa. Griesel is also an employee of ViiV Healthcare, the manufacturer of the study drug.

Key Research Findings

This pharmacokinetic sub-study of a clinical trial in Southern Africa evaluated an additional dolutegravir dose after switching treatment from efavirenz. At baseline, HIV in all 35 participants (77% women) was poorly controlled (median CD4 count 254 cells/mm³, median viral load 4.0 log10 copies/mL). Researchers were concerned that an initial reduction in dolutegravir exposure due to the residual effects of efavirenz might cause resistance to the new regimen.

Participants were randomized 2:1 to get a double dose of the study drug (n=24) or placebo (n=11) during the first 14 days after switching treatment. Drug concentrations were measured at days three and seven, at the end of double dosing, and two weeks later (i.e., day 28).

By day three, study drug trough concentrations were above the 90% inhibitory concentration of dolutegravir (0.064 µg/mL) in all but one participant, who was in the double-dose arm. By day seven and thereafter, sufficient trough concentrations were maintained in all participants. One participant developed study-drug-related renal impairment but remained on their regimen.

At day 14, residual efavirenz concentrations differed by metabolizer genotype (slow: 0.901 µg/mL, intermediate: 0.261 µg/mL, extensive: 0.149 µg/mL) but by day 28 there was no significant differences among the groups. There was no association between efavirenz genotype and dolutegravir concentration.

Discussion Highlights and Implications for Practice

Study limitations reported included the inability to monitor meals while taking dolutegravir, which is fat-soluble, as well as the small sample size and a lack of slow efavirenz metabolizers in the control group.

Results show that supplemental dolutegravir doses are not generally needed when switching from a failing efavirenz-based regimen, the researchers said. However, they also pointed out that supplemental doses may be necessary when certain concomitant medications (antacids, mineral supplements) are taken or when there are adherence challenges.

By Barbara Jungwirth