The Shift from Wasting to Weight Gain
For decades, HIV was associated with severe weight loss, or wasting syndrome. The early antiretroviral drugs, while effective, were often linked to side effects that suppressed appetite or caused lipodystrophy, an abnormal redistribution of body fat. Today, with highly effective and well-tolerated antiretroviral therapy (ART), people with HIV are living longer, healthier lives. However, a new challenge has emerged: excessive weight gain, particularly with newer drug regimens. The mechanisms behind this are complex and thought to be a combination of a "return to health" effect, the metabolic impact of specific drugs, and the removal of weight-suppressive effects from older medications.
Key Antiretrovirals Linked to Weight Gain
Two specific classes of antiretroviral drugs are most consistently associated with significant weight gain in clinical studies and observational cohorts: integrase strand transfer inhibitors (INSTIs) and the newer formulation of tenofovir, tenofovir alafenamide (TAF).
Integrase Strand Transfer Inhibitors (INSTIs) This drug class is known for its high potency and good tolerability. However, studies show that some INSTIs are more likely to cause weight gain than others.
- Dolutegravir (DTG): Found in combination therapies like Tivicay and Triumeq, dolutegravir has been strongly linked to weight gain. The ADVANCE and NAMSAL studies in Africa both demonstrated that individuals on dolutegravir-based regimens gained substantially more weight than those on efavirenz-based regimens. The effect was particularly pronounced in women and Black individuals.
- Bictegravir (BIC): As a component of the popular single-tablet regimen Biktarvy, bictegravir is another INSTI linked with notable weight gain. Comparative studies show that weight gain with bictegravir is similar in magnitude to dolutegravir.
- Elvitegravir (EVG) and Raltegravir (RAL): While also INSTIs, these are associated with less weight gain than dolutegravir and bictegravir.
Tenofovir Alafenamide (TAF) TAF is the newer, safer version of tenofovir, with fewer side effects related to kidney and bone health than the older version, tenofovir disoproxil fumarate (TDF). However, studies suggest that TAF contributes to weight gain, particularly in combination with INSTIs. The mechanism may be related to TDF's weight-suppressive effect. When patients switch from TDF-based to TAF-based regimens, the removal of this suppressive effect, rather than a direct weight-promoting effect from TAF, may drive the weight increase.
Factors Influencing Weight Gain
Several factors can influence the likelihood and amount of weight gain experienced on ART. These include:
- "Return to Health" Effect: For individuals who experience weight loss due to advanced HIV infection, starting effective ART can lead to weight recovery. This is a positive sign of health improvement but can result in greater overall weight gain, especially in the first few years of treatment.
- Demographic Characteristics: Clinical data consistently show that women and Black individuals are at higher risk for weight gain on certain ART regimens.
- Baseline Health Status: Patients starting ART with a lower CD4 count and higher viral load tend to experience more weight gain, likely due to a more pronounced "return to health" effect.
- Gut Microbiome: Emerging research suggests a connection between the gut microbiome, INSTIs, and weight gain, though the exact mechanisms are still being investigated.
Comparison of Weight Gain Potential by Drug Class
| Antiretroviral Drug Class | Examples | Weight Gain Potential | Key Finding/Mechanism | References |
|---|---|---|---|---|
| Integrase Inhibitors (INSTIs) | Dolutegravir (DTG), Bictegravir (BIC) | High | Newer INSTIs (DTG, BIC) are consistently linked to greater gains than older INSTIs or other classes. | |
| Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) | Tenofovir Alafenamide (TAF) | High (especially with INSTIs) | TAF may cause weight gain by removing the weight-suppressive effect of TDF, its predecessor. | |
| Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs) | Tenofovir Disoproxil Fumarate (TDF) | Low to None | Studies suggest TDF may have a weight-suppressive effect. Switching off TDF can lead to weight gain. | |
| Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | Efavirenz (EFV) | Low to None | Earlier studies suggest EFV may suppress weight gain, influencing weight changes when switching to INSTIs. | |
| Protease Inhibitors (PIs) | Darunavir (DRV), Atazanavir (ATV) | Variable | Older PIs were associated with fat redistribution (lipodystrophy); newer PIs have a more neutral or modest effect on weight compared to INSTIs. |
Managing Antiretroviral-Associated Weight Gain
Managing weight gain requires a holistic approach, often combining lifestyle adjustments with regular medical monitoring. Healthcare providers should discuss these risks with patients and work with them on a strategy.
- Diet and Exercise: The cornerstones of weight management remain a balanced diet and regular physical activity. Regular exercise and a calorie-deficit diet can help control weight and reduce the risk of associated comorbidities.
- Treatment Options: Switching medications to address weight gain is not typically recommended, as its effectiveness is uncertain and could jeopardize viral suppression. However, some studies show modest weight loss upon switching from TAF back to TDF. The decision should be made in close consultation with a specialist, balancing viral control with metabolic health.
- Newer Weight Management Medications: In some cases, healthcare providers might consider anti-obesity medications like GLP-1 receptor agonists (e.g., semaglutide) for patients meeting specific criteria. Bariatric surgery is also an option for some individuals.
Conclusion
The identification of which antiretroviral causes weight gain has highlighted a new consideration in HIV management. While newer regimens containing integrase inhibitors like dolutegravir and bictegravir, often combined with TAF, are associated with greater weight gain, their superior efficacy and tolerability mean they remain the standard of care. The weight gain is likely a complex interplay of a "return to health" effect, metabolic changes, and individual risk factors. Patient care must now include proactive monitoring and management of weight to mitigate the risk of associated metabolic complications like cardiovascular disease and diabetes. Open communication between patient and healthcare provider is key to balancing effective viral suppression with overall long-term health.
