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Initial ART and Weight Gain: Where Do We Stand at the End of 2021?

Brenda E. Crabtree Ramírez, MD

Assistant Professor, HIV Program
Department of Infectious Diseases
Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán
Mexico City, Mexico

Brenda E. Crabtree Ramírez, MD, has disclosed that she has received consulting fees from Janssen, MSD, and ViiV Healthcare.

View ClinicalThoughts from this Author

Released: November 5, 2021

Initiation of antiretroviral therapy (ART) often leads to weight gain. Although some of this weight gain is appropriate and considered to be part of the “return to health” associated with HIV suppression, excessive increases in weight may lead to obesity and other negative metabolic consequences. In that sense, a key question for HIV care providers and people with HIV (PWH) is whether the weight gain observed with ART leads to permanent metabolic changes or if the effects might be reversible. Answering this question is crucial to optimizing ART and the health of PWH.

Weight Gain Differences With INSTIs and TAF
Back in 2017-2018, results from 4 observational cohort studies suggested that the use of integrase strand transfer inhibitor (INSTIs) was associated with greater increases in body weight compared with other antiretrovirals, particularly among women. More recently, results from the ADVANCE trial demonstrated significantly more weight gain with the dolutegravir (DTG)-containing regimens of DTG plus emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) or DTG plus FTC/tenofovir alafenamide (TAF) vs efavirenz (EFV)/FTC/TDF in a South African population. Weight gain was highest when DTG was combined with FTC/TAF. In another study, Sax and colleagues analyzed information from 8 randomized clinical trials of initial ART and found that weight gain was greater with the use of newer ART regimens. In particular, INSTI use was associated with more weight gain than use of protease inhibitors or nonnucleos(t)ide reverse transcriptase inhibitors, and DTG and bictegravir (BIC) were associated with more weight gain than elvitegravir/cobicistat or raltegravir. When nucleos(t)ide reverse transcriptase inhibitors (NRTIs) were compared, use of TAF was associated with greater weight gain vs other NRTIs (TDF, abacavir [ABC], zidovudine). The pooled analysis also demonstrated that several baseline demographic factors were associated with weight gain: lower baseline CD4+ cell count, higher baseline HIV-1 RNA level, absence of injection drug use, female sex, and Black race. Such findings highlight the need for increased clinical attention to the maintenance of healthy body weight and incorporation of appropriate lifestyle modifications for PWH. However, the long-term magnitude and clinical significance of these weight change differences are yet not clear.

Metabolic Outcomes Similar for BIC and DTG
Recent data presented at IDWeek 2021 have added to our understanding of the metabolic effects of different ART regimens. One study in particular analyzed the incidence of metabolic changes over 144 weeks in 2 blinded phase III noninferiority first-line ART clinical trials, one that compared BTC/FTC/TAF vs DTG/ABC/lamivudine (3TC) and another that compared BIC/FTC/TAF vs DTG plus FTC/TAF. At 144 weeks, there were no significant differences between arms for treatment-emergent diabetes, hypertension, changes in BMI, or fasting blood glucose. Surprisingly, BIC/FTC/TAF was associated with a greater increase in BMI through Week 96 vs DTG/ABC/3TC, but no difference was found after 144 weeks. Changes in BMI did not differ according to sex or race, and requirements for use of lipid-lowering therapy over 144 weeks were similar across all 4 treatment arms. These findings suggest that there are no differences in metabolic outcomes with BIC vs DTG.

Putting ART-Associated Weight Gain in Context
In the context of emerging data on weight gain differences across ART regimens, it is important to consider that comorbidities among PWH generally develop at younger ages and with higher frequency compared with people without HIV, including cardiovascular disease, diabetes, obesity, and dyslipidemia. The differential burden of metabolic comorbidities underscores the importance of gaining a better understanding of the implications of ART-associated weight gain differences.

Although weight gain has been identified as a potential problem for future clinical outcomes associated with newer antiretrovirals, expert guidelines do not advise restricting the use of these otherwise optimized drugs, even in people who may be more vulnerable to weight gain and the development of obesity after ART initiation because available data continue to support that the benefits of highly effective ART in extending life expectancy by rapidly controlling HIV outweigh the potential risks of increased weight gain.

Remaining Unknown: Is ART-Associated Weight Gain Reversible?
In addition to understanding more about the metabolic implications of ART-associated weight gain, a burning question in the HIV community remains: Is ART-associated weight gain reversible upon a switch away from the offending agent(s) (ie, INSTIs and/or TAF)? Ongoing studies are evaluating this question, including the randomized, open-label phase IV Do IT and DEFINE studies that are currently enrolling PWH who have experienced significant weight gain on regimens that include an INSTI plus TAF. In the Do IT trial, patients will be randomized to switch to doravirine (DOR) plus (FTC or 3TC)/TAF, switch to DOR plus (FTC or 3TC)/TDF, or continue their baseline regimen of an INSTI plus (FTC or 3TC)/TAF. The primary endpoint is weight change over 48 weeks. In the DEFINE study, patients will be randomized to an immediate or delayed (after 24 weeks) switch to darunavir/cobicistat/FTC/TAF, with a primary endpoint of weight change over 24 weeks.

Your Thoughts?
How are you currently managing excess or unwanted weight gain following ART initiation in PWH? Answer the polling question and join the discussion by posting a comment. For more discussion of HIV treatment, comorbidities, prevention, and COVID-19–related issues, download the slides and watch the videos from our recent HIV Annual Update symposium.

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