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 × 10-4) and ABCC10 rs67861980 (P = 1.0 × 10-2), 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 × 10-8) for dolutegravir, rs17137701 in LOC105379130 (P = 6.4 × 10-8) for TAF, and rs76771105 in LOC105371716 (P = 9.7 × 10-8) 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.

Conflict of interest statement

Research reported in this publication was supported by the Fogarty International Center (FIC) of the National Institutes of Health (NIH) under Award Number D43 TW010559 and National Heart, Lung, And Blood Institute of the NIH and the FIC, under Award Number UG3HL156388. Furthermore, this work was supported by National Research Foundation through the Thuthuka Grant [113983] and Black Academic Advancement Program Grant [120647], the South African Medical Research Council (SAMRC) through self-initiated research grant (P.S.), the Wellcome Trust (WT) through an investigator award [212265/Z/18/Z], the National Research Foundation (NRF) of South Africa (Grant Number 119078), and core funding for the Wellcome Centre for Infectious Diseases Research in Africa [203135/Z/16/Z] (G.M.). Grant support included TW010559, AI110527, AI077505, TR000445, and AI110527 (D.W.H.). Gilead Sciences and ViiV Healthcare donated study drugs for the conduct of the parent study. F. Venter reports grants from USAID, Unitaid, SAMRC, and ViiV; personal fees and nonfinancial support from ViiV Healthcare and Gilead Sciences, during the conduct of the study; and personal fees from Mylan, Merck, Adcock-Ingram, Aspen, Abbott, Roche, and Johnson and Johnson, outside the submitted work. SS reports grants from USAID, Unitaid, SAMRC, and ViiV Healthcare during the conduct of the study. N. Chandiwana reports personal fees and nonfinancial support from Johnson and Johnson, grants from USAID, Unitaid, SAMRC, and ViiV Healthcare during the conduct of the study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, WT, NRF, SAMRC, or other funders. The remaining authors have no funding or conflicts of interest to disclose.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Figures

Figure 1:. Disposition of study participants.

Of 1053 participants enrolled in the ADVANCE study, 314 who had been randomized to dolutegravir-containing regimens were evaluable for genetic associations.

Figure 2.. Genome-wide associations with weight gain from baseline to week 48 in ADVANCE study participants.

Manhattan plots and QQ-plot for genome-wide associations with percentage weight gain from baseline to week 48. Analyses controlled for age, sex, first three MDS coordinates, and, in the dolutegravir analysis, concomitant NRTI. Red lines indicate a genome-wide significance threshold of P<5.0×10−8. Panel A: Associations among 314 participants in the dolutegravir arm. A polymorphism in TMEM163 (rs7590091) achieved genome-wide significance (P = 3.7×10−8).Panel B: Associations among 160 participants in the tenofovir alafenamide fumarate (TAF) arm. Two polymorphisms, LOC105379130 rs17137701, and rs76794506 in an intergenic region on chromosome 10, had P- vales approaching statistical significance (P = 6.4×10−8 and P = 8.8×10−8, respectively).Panel C: Associations among 154 participants in the tenofovir disoproxil fumarate arm. The polymorphism LOC105371716 rs76771105 had the lowest p-value (P = 9.7×10–8).