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ClinicalThought: Weight and Metabolic Complications
Weight Gain and Metabolic Complications With ART From IDWeek 2021

Released: October 28, 2021

Expiration: October 27, 2022

Darcy Wooten
Darcy Wooten, MD, MS
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Managing weight gain and associated metabolic complications is increasingly important for HIV healthcare professionals. These conditions are prevalent among individuals with HIV in part due to the success of antiretroviral therapy (ART), which enables people to live longer. In addition, many of our preferred antiretrovirals (ARVs) for most individuals, namely second-generation integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF), have been associated with weight gain and metabolic complications. Several key studies from IDWeek 2021 focused on these issues.

Weight Gain, Metabolic Complications, and Polypharmacy
A study by Kumar et al reviewed claims data from Optum research from tens of thousands of individuals with HIV in the United States between 2014-2018. They examined changes by year in the number and type of comorbid conditions and the number of non-ARV medications prescribed. The percentage of individuals with 3 or more comorbid conditions increased from 25.8% to 37.2%, and the percentage of individuals prescribed 5 or more non-ARV medications increased from 70.4% to 76.3%. The most prevalent comorbid conditions included hypertension, hyperlipidemia, and neuropsychiatric disease, all of which significantly increased over the study period. Also observed were a concurrent decrease in the percentage of individuals receiving non-nucleoside reverse-transcriptase inhibitors (from 51.2% to 29.5%) and protease inhibitors (from 29.6% to 17.3%) and an increase in the percentage of individuals receiving INSTIs (from 27.1% to 62.6%). This study highlights the important role of healthcare professionals in managing comorbidities and polypharmacy in people with HIV in the coming years.

Predicting Risk of Weight Gain
It would be ideal to be able to predict who is at highest risk for weight gain—especially excessive weight gain—when starting ART. Phupitakphol et al presented a retrospective study investigating predictors of excessive weight gain (top 20%) after 2 years among treatment-naive individuals who were virologically suppressed on therapy from 2005-2018. The multivariate analysis showed that only low baseline CD4+ cell count and high HIV viral load were significantly associated with excessive weight gain after 2 years, potentially representing a “return-to-health” phenomenon. Age, sex at birth, baseline BMI, and ART class were not significantly associated with excessive weight gain.

There was a moderate correlation between early weight gain (within the first 2 months) and excessive weight gain at 2 years. Although limited by the observational nature of this study, these data on early weight gain suggest that the opportune time to intervene to prevent excessive weight gain might be early, when individuals are diagnosed and started on therapy. These interventions include counseling on weight gain, diet, and exercise.

Weight Gain in Patients Receiving PrEP
Although much of the conversation surrounding ART-associated weight gain has focused on second-generation INSTIs, TAF also has been associated with significantly more weight gain compared with other nucleoside reverse-transcriptase inhibitors, including tenofovir disoproxil fumarate (TDF). What has not been clear is whether TAF causes weight gain or there are weight-mitigating effects from TDF. Shah et al conducted a pooled analysis of pre-exposure prophylaxis (PrEP) randomized clinical trials that compared TDF or emtricitabine (FTC)/TDF with control (either placebo or cabotegravir) to look at the impact of TDF on weight changes. The rationale for studying this in individuals without HIV was to remove the potential impact of the “return to health” phenomenon.

The analysis included 7 PrEP studies with more than 19,000 participants. Individuals who received TDF-containing PrEP were significantly more likely to lose weight during the study period compared with those receiving control. The effect was largely driven by trials comparing TDF-containing PrEP with placebo; when cabotegravir was the control, there was no difference in weight gain between the 2 regimens. Although TDF-containing PrEP was well tolerated overall with low rates of adverse events, higher rates of vomiting were observed with TDF compared with placebo. There were no differences in rates of nausea, diarrhea, or loss of appetite.

These data suggest that the weight differences observed between TAF and TDF may be primarily related to TDF-associated weight loss. There is ongoing debate on how to balance the weight loss effect of TDF with its known renal and bone toxicities. Shared decision-making and individualized care through in-depth, one-on-one discussions with patients will be critical in this regard. 

Weight Gain and Metabolic Complications Increasing Comorbidities
We continue to look at the role ART is playing with respect to weight gain and metabolic complications that drive the development of multimorbidity. Daar et al presented data on treatment-emergent diabetes and hypertension, weight gain, and lipid changes in 2 parallel randomized, controlled trials: Study 1489 (bictegravir/FTC/TAF vs dolutegravir/abacavir/lamivudine) and Study 1490 (bictegravir/FTC/TAF vs dolutegravir plus FTC/TAF). The median age of participants in the study was 33 years; 90% were male, and 67% were White. After 3 years, there was no significant difference between the regimens with respect to treatment-emergent diabetes, fasting glucose, treatment-emergent hypertension, or fasting lipids. Similarly, there were no differences in median change in BMI from baseline or categorical BMI shifts.

These data support the conclusion that, in this relatively young and healthy population, there were low rates of incident metabolic complications with some of our most commonly used first-line regimens. Although this is reassuring, it will be important to look at these outcomes at even later time points and in older populations.

The studies presented at IDWeek 2021 expand our understanding of weight gain, metabolic complications, and the role of ART within these areas among people with HIV. At the same time, we still have many unanswered questions, including:

  1. Can we predict who is at highest risk for weight gain and metabolic complications when starting or switching to specific therapies?
  2. Can behavioral or other types of interventions applied early on help mitigate potential weight gain?
  3. If patients do gain weight and develop metabolic disease after starting or switching to certain ARVs, what interventions (including possibly changing to a different ART regimen) are successful in reducing weight and stabilizing metabolic complications?

Your Thoughts?
How often does weight gain influence ART selection for your patients? Join the discussion by posting a comment. For more details on this and other key HIV issues from IDWeek 2021, review more CCO Conference Coverage, including Capsule summary slidesets, video recaps with expert faculty, and other ClinicalThought commentaries highlighting US and global perspectives.

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