Concentration–response relationships of dolutegravir and efavirenz with weight change after starting antiretroviral therapy

Abstract

Dolutegravir is associated with more weight gain than efavirenz in people starting antiretroviral therapy (ART). We investigated the concentration–response relationships of efavirenz and dolutegravir with weight gain. We determined concentration–response relationships of dolutegravir and efavirenz (both combined with tenofovir disoproxil fumarate and emtricitabine) with changes in weight and fat distribution, derived from dual‐energy x‐ray absorptiometry scans, in a nested study of ART‐naïve participants from a randomised controlled trial. Pharmacokinetic parameters used in analyses were efavirenz mid‐dosing interval concentrations and estimated dolutegravir area under the concentration–time curve using a population pharmacokinetic model developed in the study population. Study outcomes were percentage changes from baseline to week 48 in weight, and visceral and subcutaneous adipose tissue mass. Pharmacokinetic data were available for 158 and 233 participants in the efavirenz arm and dolutegravir arms respectively; 57.0% were women. On multivariable linear regression there were independent negative associations between efavirenz concentrations and changes in both weight (P < .001) and subcutaneous adipose tissue mass (P = .002). Estimated dolutegravir area under the concentration–time curve up to 24 hours was not associated with change in weight (P = .109) but was negatively associated with change in visceral adipose tissue mass (P = .025). We found an independent negative concentration–response relationship between efavirenz concentrations and weight change in ART‐naïve participants. Dolutegravir concentrations were not independently associated with weight change. These findings suggest that weight gain differences between efavirenz and dolutegravir are driven by efavirenz toxicity impairing weight gain rather than by off‐target effects of dolutegravir causing weight gain.

Change in body weight and risk of hypertension after switching from efavirenz to dolutegravir in adults living with HIV: evidence from routine care in Johannesburg, South Africa

“…Data from ADVANCE strongly suggests this is the case, reporting that weight gain among moderate and fast metabolizers of efavirenz was the same as that among those on the dolutegravir arm, containing the same nucleoside backbone. 26 , 27 This is supported by other studies on the impact of efavirenz concentrations on weight gain. 28 …”

Effect of obesity on dolutegravir exposure in Black Southern African adults living with HIV

“…It has been postulated that dolutegravir could cause weight gain by off-target effects through inhibition of the melanocortin-4 receptor pathway, affecting appetite and energy balance. 19 , 20 However, in vitro studies have shown that the concentrations needed for the direct inhibition of the melanocortin-4 receptor that would explain clinically important weight gain are much higher than those achieved with the currently recommended daily dose of 50 mg. 21 In a sub-study of ADVANCE, our group has recently shown that weight gain differences between dolutegravir and efavirenz are driven by impaired weight gain in participants who are genetically slow metabolisers of efavirenz 22 – this finding suggests that dolutegravir is not causing weight gain but that efavirenz is impairing weight gain in slow metabolisers who have high efavirenz concentrations. The reason for the contributory effect of TAF on weight gain is still unclear and may reflect weight loss effects of TDF.…”

Body mass index, proteinuria and total lymphocyte counts in predicting treatment responses among ART naïve individuals with HIV initiated on antiretroviral treatment in Dar es Salaam, Tanzania, 2019: a cohort study

“…Weight loss may be due to HIV itself, opportunistic infections or HIV-associated tumours. Failure to gain weight has been associated with efavirenz toxicity over time as was observed in a study in South Africa 30. Weight loss in both ART naïve and exposed patients has been associated with increased morbidity and mortality 31 32.…”

“…Failure to gain weight has been associated with efavirenz toxicity over time as was observed in a study in South Africa. 30 Weight loss in both ART naïve and exposed patients has been associated with increased morbidity and mortality. 31 32 A study in England observed that each log10 increase in HIV viral load was associated with a 0.92 kg decrease in body weight.…”