Genetic Associations with Weight Gain among South Africans who Initiated Dolutegravir-Containing and Tenofovir-Containing Regimens

Abstract

Background: Excessive weight gain affects some HIV-positive individuals prescribed dolutegravir-containing regimens. Mechanisms underlying such weight gain are unknown.Setting: Data and DNA from antiretroviral therapy-naïve participants who were randomized to initiate dolutegravir with emtricitabine plus either tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) in the ADVANCE study (NCT03122262) were used to characterize associations between human genetic polymorphisms and magnitude of weight gain.Methods: Associations with percent weight gain from baseline to week 48 were assessed using multivariable linear regression models. Primary analyses a priori considered 59 polymorphisms and 10 genes of potential relevance to dolutegravir, TAF, or TDF pharmacokinetics. We also explored genome-wide associations.Results: Among the 314 (92%) of 340 dolutegravir recipients who were successfully genotyped, 160 (47%) and 154 (45%) were randomized to TAF/emtricitabine and TDF/emtricitabine, respectively. In target gene analyses, the lowest P-values for the dolutegravir and tenofovir groups were ABCG2 rs4148149 (P = 7.0 • 10 24 ) and ABCC10 rs67861980 (P = 1.0 • 10 22 ), respectively, which were not significant after correction for multiple testing. In genome-wide analyses, the lowest P-values were rs7590091 in TMEM163 (P = 3.7 • 10 28 ) for dolutegravir, rs17137701 in LOC105379130 (P = 6.4 • 10 28 ) for TAF, and rs76771105 in LOC105371716 (P = 9.7 • 10 28 ) for TDF.Conclusions: Among South African participants in a randomized clinical trial of dolutegravir plus either TAF/emtricitabine or TDF/ emtricitabine, we identified several potential genetic associations with weight gain. Only TMEM163 rs7590091 withstood correction for multiple testing. These associations warrant replication in other cohorts.

Improvements in Patient-Reported Outcomes Following Initiation of Dolutegravir-Based or Low-Dose Efavirenz-Based First-Line Antiretroviral Therapy: A Four-Year Longitudinal Analysis in Cameroon (NAMSAL ANRS 12313 Trial)

“…11,12 Nevertheless, concerns have been raised about the effects of lifelong DTG-based ART, especially given increasing evidence in Europe, North America, and SSA that DTG leads to excessive weight gain and a higher incidence of obesity. 4,5,[13][14][15][16] This adverse effect is a cause for concern because associated metabolic comorbidities may develop (eg, diabetes, hypertension, hypercholesterolemia, cardiovascular disease) in the medium and long term. 17 Accordingly, evidence on the longer-term effects of DTG in the SSA context is needed.…”

Evaluation of kidney function among people living with HIV initiating antiretroviral therapy in Zambia

“…Previous research has found that Dolutegravir (DTG) may be associated with increased body mass index which may be an important upstream risk factor for kidney function PLOS GLOBAL PUBLIC HEALTH impairment [42][43][44]. Though this analysis is limited to those on a non-DTG-based regimen it provides kidney function measures not confounded by the altered, often reduced, creatinine clearance that might contribute to kidney function misclassification among those on a DTGcontaining regimen [45].…”

Final 192-Week Efficacy and Safety Results of the ADVANCE Trial, Comparing 3 First-line Antiretroviral Regimens

“…Data from ADVANCE's pharmacokinetic substudies demonstrated that medium and fast metabolizers of EFV gained weight at the same rate as those taking DTG, while EFV slow metabolizers were the participants who contributed to the slower weight gain in the overall cohort [ 9 , 10 ]. This suggests that EFV is responsible for the lower weight trajectory seen in the TDF/FTC/EFV arm in ADVANCE, over the DTG-containing arms, as opposed to DTG being responsible for the weight gain.…”