Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors in Randomized Comparative Clinical Trials

Paul E Sax, Kristine M Erlandson, Jordan E Lake, Grace A Mccomsey, Chloe Orkin, Stefan Esser, Todd T Brown, Jürgen K Rockstroh, Xuelian Wei, Christoph C Carter, Lijie Zhong, Diana M Brainard, Kathleen Melbourne, Moupali Das, Hans-Jürgen Stellbrink, Frank A Post, Laura Waters, John R Koethe, Paul E Sax, Kristine M Erlandson, Jordan E Lake, Grace A Mccomsey, Chloe Orkin, Stefan Esser, Todd T Brown, Jürgen K Rockstroh, Xuelian Wei, Christoph C Carter, Lijie Zhong, Diana M Brainard, Kathleen Melbourne, Moupali Das, Hans-Jürgen Stellbrink, Frank A Post, Laura Waters, John R Koethe

Abstract

Background: Initiation of antiretroviral therapy (ART) often leads to weight gain. While some of this weight gain may be an appropriate return-to-health effect, excessive increases in weight may lead to obesity. We sought to explore factors associated with weight gain in several randomized comparative clinical trials of ART initiation.

Methods: We performed a pooled analysis of weight gain in 8 randomized controlled clinical trials of treatment-naive people living with human immunodeficiency virus (HIV) initiating ART between 2003 and 2015, comprising >5000 participants and 10 000 person-years of follow-up. We used multivariate modeling to explore relationships between demographic factors, HIV disease characteristics, and ART components and weight change following ART initiation.

Results: Weight gain was greater in more recent trials and with the use of newer ART regimens. Pooled analysis revealed baseline demographic factors associated with weight gain including lower CD4 cell count, higher HIV type 1 RNA, no injection drug use, female sex, and black race. Integrase strand transfer inhibitor use was associated with more weight gain than were protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), with dolutegravir and bictegravir associated with more weight gain than elvitegravir/cobicistat. Among the NNRTIs, rilpivirine was associated with more weight gain than efavirenz. Among nucleoside/nucleotide reverse transcriptase inhibitors, tenofovir alafenamide was associated with more weight gain than tenofovir disoproxil fumarate, abacavir, or zidovudine.

Conclusions: Weight gain is ubiquitous in clinical trials of ART initiation and is multifactorial in nature, with demographic factors, HIV-related factors, and the composition of ART regimens as contributors. The mechanisms by which certain ART agents differentially contribute to weight gain are unknown.

Keywords: ART; HIV; antiretroviral therapy; obesity; weight gain.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Weight trends in participants initiating antiretroviral therapy. A, Baseline median CD4 cell count and median weight in the indicated clinical trials, which are ordered by date of trial initiation. Error bars represent the first through third quartiles. B, Mean weight change observed at the 48-week time point for the indicated trials, which are organized by date of initiation. Red bars are the investigational regimen, and gray bars are the comparator. *P < .05 by analysis of variance. C, Median weight (red) and median weight change (blue) over time in 8 pooled clinical trials. D, Body mass index category distributions over time in 8 pooled clinical trials. Abbreviations: 3TC, lamivudine; ABC, abacavir; ATV/r, ritonavir-boosted atazanavir; B, bictegravir; C, cobicistat; D4T, stavudine; DTG, dolutegravir; E, elvitegravir; EFV, efavirenz; F, emtricitabine; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine.
Figure 2.
Figure 2.
Effect of sex and race on weight change in individuals initiating antiretroviral therapy. A, Least squares mean (LSM) weight change over time, stratified by sex. *P < .05 vs the comparator. B, LSM weight change over time, stratified by race (black vs non-black). *P < .05 vs the comparator. C, LSM weight change over time, stratified by both sex and race. *P < .05 for black females vs non-black females; **P < .05 for black females vs non-black females and for black females vs black males. P values for these comparisons are found in Supplementary Table 3.
Figure 3.
Figure 3.
Weight change and absolute weight in participants initiating antiretroviral therapy. A and B, Least squares mean (LSM) weight change (A) and absolute weight (B) over time in all participants, stratified by third antiretroviral agent. C and D, LSM weight change (C) and absolute weight (D) in participants taking integrase strand transfer inhibitors (INSTIs), stratified by INSTI used. E and F, LSM weight change (E) and absolute weight (F) in all participants taking nonnucleoside reverse transcriptase inhibitors (NNRTIs), stratified by NNRTI used. G and H, LSM weight change (G) and absolute weight (H) in participants taking a nucleoside reverse transcriptase inhibitor (NRTI), stratified by NRTI used. Error bars depict the 95% confidence interval. Asterisks are color-coded to match the respective comparator and denote P ≤ .05 compared with NNRTIs (A and B), EVG/c (C and D), EFV (E and F), or ZDV (G and H). P values for these comparisons are found in Supplementary Table 3. Abbreviations: ABC, abacavir; BIC, bictegravir; DTG, dolutegravir; EFV, efavirenz; EVG/c, cobicistat-boosted elvitegravir; PI, protease inhibitor; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine.

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