What is the risk of weight gain with antiretroviral therapies like Biktarvy (Bictegravir/Emtricitabine/Tenofovir alafenamide), Juluca (Dolutegravir/Rilpivirine), Dovato (Dolutegravir/Lamivudine), and Cabenuva (Cabotegravir/Rilpivirine)?

Weight Gain with Modern Antiretroviral Regimens

Direct Answer

All four regimens—Biktarvy, Juluca, Dovato, and Cabenuva—are associated with weight gain, with Biktarvy carrying the highest risk due to its combination of an integrase inhibitor (bictegravir) plus tenofovir alafenamide (TAF). 1, 2

Weight Gain Risk Hierarchy

Highest Risk:

• Biktarvy (bictegravir/emtricitabine/TAF): This combination poses the greatest weight gain risk because it contains both an INSTI and TAF, which have additive effects on weight gain 1, 3. Bictegravir specifically shows higher weight gain profiles among INSTIs 1.

Moderate-High Risk:

• Dovato (dolutegravir/lamivudine): Contains dolutegravir, an INSTI associated with significant weight gain 1, 4. However, the absence of TAF reduces the overall risk compared to Biktarvy 3.
• Cabenuva (cabotegravir/rilpivirine): Contains cabotegravir (an INSTI) and rilpivirine (an NNRTI). While rilpivirine is associated with more weight gain than efavirenz among NNRTIs 4, the overall risk is lower than dolutegravir-containing regimens 1.

Moderate Risk:

• Juluca (dolutegravir/rilpivirine): Contains dolutegravir but lacks TAF, placing it in a moderate risk category 1, 4.

Mechanistic Understanding

INSTI Class Effects:

• INSTIs cause the most weight gain among all antiretroviral drug classes, exceeding protease inhibitors and NNRTIs 1, 5.
• Dolutegravir and bictegravir specifically show higher weight gain profiles within the INSTI class 1, 4.
• INSTIs can directly alter adipose tissue through inhibition of fat beiging, resulting in fat fibrosis and hypertrophy 3.

TAF vs. TDF:

• Greater weight gain occurs with TAF-containing regimens compared to TDF, regardless of the third agent class 1, 2.
• Weight gain with TAF typically occurs within the first year following initiation or switch 2.
• TDF and efavirenz are associated with weight suppression, and their removal from regimens leads to weight gain 3, 6.
• Switching from TAF back to TDF results in weight loss, demonstrating the medication-related nature of this effect 1, 2.

Additive Effects:

• The effects of INSTIs and TAF are additive, making INSTI + TAF combinations particularly problematic 3.

High-Risk Populations

Demographic Risk Factors:

• Women: At significantly higher risk for weight gain with INSTI and TAF-containing regimens 2, 4, 3.
• Black individuals: Consistently show greater weight gain across studies 4, 3.
• Lower baseline CD4 count and higher viral load: Associated with more weight gain in treatment-naive patients 4, 7.

Clinical Management Algorithm

Monitoring:

• Document weight and BMI every 6 months for all patients on INSTI- or TAF-based regimens to identify excessive weight gain 8, 2.
• Focus monitoring particularly during the first year of treatment when most weight gain occurs 2, 3.

Prevention Strategy:

• Avoid INSTI + TAF combinations (like Biktarvy) if weight gain is a primary concern 1.
• Consider alternative regimens with lower weight gain profiles for high-risk patients (women, Black individuals) 1, 2.

Management of Established Weight Gain:

• Emphasize lifestyle changes including diet and exercise for all patients on these regimens 8, 2.
• Switching regimens solely because of weight gain is not currently recommended due to known toxicities of alternatives like TDF (renal and bone toxicity) and lack of benefit when changing from INSTIs to boosted protease inhibitors 8.
• GLP-1 receptor agonists show similar efficacy for weight loss in people with HIV as in the general population, though loss of muscle mass is a concern in older patients at risk for sarcopenia 8, 2.
• Switching from TAF to TDF can reverse weight gain but must be balanced against TDF's renal and bone toxicities 1, 2.

Critical Caveats

Reversibility is Limited:

• The reversibility of INSTI- and TAF-associated weight gain is limited, with return to pre-therapy weight rarely observed 2, 3.
• Most weight gain occurs during the initial 12-month period, and the trajectory differs between agents 3.

Weight Gain is Not Universal:

• The majority of patients experience weight changes of less than 5% of body weight, but a minority gain more than 10% 2, 7.
• Excessive weight gain is uncommon overall but occurs more frequently in specific high-risk populations 3.

Not Solely "Return to Health":

• Weight gain with these regimens is not solely a "return to health" phenomenon but appears to be medication-related, as demonstrated by weight loss when switching away from these agents 2, 3.