Which has a higher risk of weight gain, Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) or Protease Inhibitors (PIs)?

Weight Gain Risk: NNRTIs vs Protease Inhibitors

Integrase strand transfer inhibitors (INSTIs) cause the most weight gain, followed by protease inhibitors, with NNRTIs causing the least weight gain among antiretroviral drug classes. 1

Direct Comparison of Weight Gain Risk

INSTIs Have the Highest Risk

• INSTI-based regimens are associated with greater weight gain than either NNRTI- or PI-based regimens, though this is primarily observed with longer therapy duration than the 28 days typically used for post-exposure prophylaxis 1
• Among INSTIs, bictegravir (BIC) and dolutegravir (DTG) show higher weight gain profiles 1

Protease Inhibitors Show Moderate Weight Gain

• PI therapy is associated with weight gain (mean 1.54 kg, P < 0.0001) and increased body mass index (0.50 kg/m², P < 0.0001) 2
• The weight gain with PIs is mainly fat mass accumulation, with no change in lean body mass (skeletal muscle) 2
• PI class-specific metabolic complications include insulin resistance, diabetes, dyslipidemia, and lipodystrophy 1
• Patients who respond to PI therapy with decreased viral load experience significantly greater weight gain per month than non-responders 2

NNRTIs Have the Lowest Weight Gain Risk

• NNRTIs are not specifically associated with weight gain as a class effect 1
• The primary adverse effects of NNRTIs are CNS toxicity (especially efavirenz), rash, and hyperlipidemia—not weight gain 1
• Efavirenz is actually associated with less weight gain as initial therapy, and switching to efavirenz can result in weight loss 3

The TAF Factor: An Important Nuance

Tenofovir Formulation Matters More Than Drug Class

• Greater weight gain occurs with regimens containing tenofovir alafenamide (TAF) compared to tenofovir disoproxil fumarate (TDF), regardless of the third agent class 3
• Weight gain with TAF typically occurs within the first year following initiation or switch 3
• Women and Black individuals are at higher risk for weight gain with TAF-containing regimens 3
• Switching from TAF back to TDF results in weight loss, demonstrating the medication-related nature of this effect 3

Clinical Algorithm for Minimizing Weight Gain

When Selecting Initial Regimen:

1. Avoid INSTI + TAF combinations if weight gain is a primary concern 1, 3
2. Consider NNRTI-based regimens (particularly efavirenz or doravirine) with TDF as they have the lowest weight gain profile 1, 3
3. If using PI-based therapy, expect moderate weight gain primarily as fat mass 2

Monitoring Strategy:

• Document weight and BMI every 6 months for patients on TAF-based regimens 3
• Monitor more frequently (monthly) during the first year when weight gain risk is highest 3

Management of Established Weight Gain:

• Emphasize lifestyle changes including diet and exercise 3
• Consider glucagon-like peptide-1 receptor agonists for significant weight gain 3
• Switching from TAF to TDF can reverse weight gain, though this must be balanced against TDF's known renal and bone toxicities 3
• Changing regimens solely for weight gain is not currently recommended due to toxicities of alternative agents 3

Common Pitfalls to Avoid

• Do not assume weight gain is simply "return to health"—it is medication-related, particularly with INSTIs and TAF 3
• Do not overlook the NRTI backbone—TAF vs TDF choice may matter more than the third agent class for weight outcomes 3
• Do not ignore metabolic complications with PIs—weight gain is accompanied by insulin resistance, dyslipidemia, and lipodystrophy 1
• Be aware that PI-associated weight gain is predominantly fat mass, not muscle restoration 2