Why do women on Antiretroviral Therapy (ART) experience more significant weight gain?

Why Women Experience Greater Weight Gain on Antiretroviral Therapy

Women on ART experience significantly more weight gain than men due to sex-specific biological factors that interact with certain antiretroviral medications, particularly integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF), with this disparity occurring predominantly within the first year of treatment. 1

Sex as an Independent Risk Factor

• Female sex is an independent predictor of weight gain following ART initiation, even after controlling for other demographic and clinical variables 2
• Women have higher odds of experiencing >10% body weight increase at two years compared to men (adjusted odds ratio = 1.37,95% CI: 1.20 to 1.56) 3
• This sex difference persists across multiple randomized controlled trials and observational cohorts, indicating a consistent biological phenomenon rather than a statistical artifact 2

Medication-Specific Contributions

The magnitude of weight gain in women is amplified by specific ART components:

• INSTI-based regimens cause more weight gain than NNRTI-based regimens, with women being disproportionately affected 1, 3
• Among INSTIs, dolutegravir shows the highest weight gain (mean +7.2 kg at two years), followed by raltegravir (+5.8 kg) and elvitegravir (+4.1 kg) 3
• TAF-containing regimens produce greater weight gain than TDF-containing regimens, with women showing more pronounced increases 1, 4
• The combination of INSTI plus TAF appears to have synergistic effects on weight gain, particularly in women 5

Timing and Pattern of Weight Gain

• Weight gain occurs predominantly within the first year following ART initiation or regimen switch 1
• The majority of patients experience weight changes <5% of body weight, but a minority (including disproportionately more women) gain >10% 1
• This is not solely a "return to health" phenomenon, as the weight gain exceeds what would be expected from immune reconstitution alone 1

Intersectionality with Race

• Black women face the highest risk, as both female sex and Black race are independent risk factors for ART-associated weight gain 1, 2
• This creates a compounded vulnerability in Black women, who experience the most substantial weight increases on INSTI- and TAF-based regimens 1

Mechanisms Under Investigation

While the exact mechanisms remain incompletely understood, several factors are being studied:

• Sex hormones likely play a role in differential fat metabolism and weight regulation on ART 1
• Women may have different pharmacokinetic responses to certain antiretroviral agents 5
• Baseline factors associated with greater weight gain include lower CD4 counts and higher HIV RNA levels, though sex remains an independent predictor even after adjusting for these variables 2

Clinical Implications for Management

Despite the weight gain concerns, changing regimens solely because of weight gain is not currently recommended (evidence rating: BIa) 1

However, proactive management is essential:

• Document weight and BMI every 6 months for all individuals on TAF-based regimens (evidence rating: AIIa) 4
• Provide counseling about potential weight gain before initiating ART, especially for women starting INSTI- and TAF-based regimens (evidence rating: AIII) 1
• Emphasize lifestyle modifications including diet and exercise at ART initiation, particularly for women at high risk (evidence rating: AIII) 1
• Monitor for cardiometabolic complications, as >10% weight gain is associated with increased risk of diabetes (HR 2.01), metabolic syndrome (HR 2.24), and cardiometabolic outcomes (HR 1.54) 6

Reversibility Considerations

Weight gain with ART is rarely reversible, with return to pre-therapy weight being uncommon 1:

• Switching from TAF back to TDF can produce weight loss (-1.84 kg at 12 months), but this comes with TDF's known renal and bone toxicities 7
• Women in the ADVANCE trial who switched from TAF/FTC/DTG to TDF/3TC/DTG experienced weight reductions, likely due to TDF's weight-suppressive effect 1
• Switching to other regimens (DTG/3TC or long-acting CAB/RPV) does not lead to significant weight reduction 7

Common Pitfalls to Avoid

• Do not dismiss weight gain as simply "return to health"—it represents a medication-related metabolic effect that requires monitoring 1
• Do not automatically switch regimens due to weight gain alone, as alternative agents may have worse toxicity profiles 1
• Do not fail to counsel women preemptively about this risk, as early lifestyle intervention may mitigate some weight gain 1
• Do not neglect cardiovascular risk assessment in women who gain substantial weight on ART 6