The research team, led by Jingwei Tian and Yaokai Chen of Chongqing Public Health Medical Center together with collaborators at Zunyi Medical University and other Chinese institutions, followed 2,379 virologically suppressed people living with HIV for 144 weeks, nearly three years. All participants began the observation period on a classic first-line combination: tenofovir disoproxil fumarate plus lamivudine plus efavirenz, abbreviated TDF/3TC/EFV. This regimen served Chinese treatment programs for years, but it carries well-documented drawbacks, including kidney and bone toxicity from tenofovir disoproxil fumarate and central nervous system side effects from efavirenz. Some patients in the cohort continued on this older combination, while others switched to one of two modern alternatives: the single-tablet regimen bictegravir/emtricitabine/tenofovir alafenamide, known as BIC/FTC/TAF, or the two-drug combination dolutegravir plus lamivudine, known as DTG/3TC.

Because patients were not randomly assigned to their treatment paths, the investigators faced the fundamental challenge of any observational study: people who switch medications often differ systematically from those who do not. To address this, the team applied propensity score overlap weighting, a statistical technique that reweights the comparison groups so that baseline characteristics such as age, sex, body measurements, and laboratory values are balanced across them. This approach allows the analysis to approximate, though never perfectly replicate, the conditions of a randomized trial. The primary endpoint was the longitudinal change in body weight and body mass index from baseline to weeks 24, 48, 96, and 144. Secondary endpoints captured a broader metabolic picture, including changes in blood lipids, fasting blood glucose, the triglyceride-glucose index known as TyG, and serum uric acid.

The headline finding was unambiguous: weight and body mass index increased in every group over the 144 weeks, but the gains were markedly larger among those who switched to INSTI-based regimens. Patients moving to BIC/FTC/TAF gained more weight than those moving to DTG/3TC at weeks 24, 48, and 144, with the bictegravir-based regimen showing the steepest trajectory. This pattern echoes signals from international trials and cohort studies that have linked INSTI initiation and switching to clinically meaningful weight gain, but the Chinese data are particularly valuable because most prior evidence came from North American, European, and African populations, where baseline body composition and dietary patterns differ considerably.

The lipid results revealed a more nuanced picture. Compared with patients who stayed on TDF/3TC/EFV, both switch groups experienced increases in total cholesterol and low-density lipoprotein cholesterol, the fraction commonly labeled bad cholesterol because of its association with atherosclerotic cardiovascular disease. However, high-density lipoprotein cholesterol, the protective fraction, declined only in the BIC/FTC/TAF group, while triglycerides remained stable among those taking DTG/3TC. The direction of these changes matters clinically: a rise in LDL-C paired with a fall in HDL-C, as seen with bictegravir-based switching, shifts the lipid profile in a direction generally considered atherogenic, whereas the dolutegravir two-drug regimen appeared metabolically gentler on this front.

Beyond weight and lipids, the study tracked two additional metabolic markers that are gaining attention in HIV care. Fasting blood glucose rose in both switch groups, and serum uric acid also climbed in both, with significantly larger uric acid increases among patients on BIC/FTC/TAF. Elevated uric acid is the biochemical hallmark of hyperuricemia, the precursor state for gout, and has emerged as a recurrent finding in INSTI pharmacovigilance. The triglyceride-glucose index, a simple surrogate for insulin resistance calculated from fasting triglycerides and glucose, provided a window into early metabolic dysfunction without requiring formal glucose tolerance testing.

When the researchers translated these continuous laboratory changes into clinical diagnoses using multivariable Cox proportional hazards models, the differences between the two switch strategies became striking. Patients who switched to BIC/FTC/TAF faced more than double the hazard of developing overweight or obesity compared with those continuing the older regimen, with an adjusted hazard ratio of 2.47 and a 95 percent confidence interval of 1.96 to 3.10. They also carried a modestly elevated risk of dyslipidemia, at an adjusted hazard ratio of 1.18, and a substantially increased risk of hyperuricemia, at 2.23. The DTG/3TC group also fared worse than those who stayed on TDF/3TC/EFV, with adjusted hazard ratios of 1.56 for overweight or obesity and 1.76 for hyperuricemia, but the magnitude of risk was consistently lower than for the bictegravir-based triple-drug regimen. Notably, neither switch strategy significantly changed the risk of developing type 2 diabetes over the follow-up period.

The mechanistic story behind these observations remains incomplete, but several hypotheses circulate in the field. Integrase inhibitors may influence adipocyte biology and appetite regulation, potentially through effects on melanocortin signaling pathways, while the reversal of efavirenz-related toxicity could unmask baseline metabolic differences. Tenofovir alafenamide, the prodrug used in the BIC/FTC/TAF regimen, achieves high intracellular concentrations with lower plasma tenofovir exposure, sparing kidneys and bones, but some studies suggest it contributes more to weight gain than the older disoproxil fumarate salt. The uric acid signal may reflect changes in renal tubular handling as patients transition away from tenofovir disoproxil fumarate, which has mild uricosuric properties that lower serum urate. Disentangling drug-specific effects from the metabolic recovery that follows viral suppression and from the removal of older drugs remains one of the central analytical challenges in this literature.

For clinicians, the study’s practical message is one of vigilance rather than alarm. The authors emphasize that switching from TDF/3TC/EFV to either INSTI regimen was associated with significant increases in body weight and selected lipid parameters, and that BIC/FTC/TAF displayed a more pronounced adverse metabolic profile than DTG/3TC. They argue that metabolic monitoring after any switch to INSTI-based therapy deserves routine incorporation into HIV care, with particular attention for patients moving to bictegravir-based regimens. This is especially relevant in China and other Asian settings, where populations may have different baseline metabolic risk profiles and where the threshold at which weight gain becomes clinically consequential may differ from Western populations.

The study’s retrospective design imposes limits that the authors and the broader field acknowledge. Overlap weighting balances measured confounders but cannot account for unmeasured variables such as diet, physical activity, or the clinical reasons that prompted a switch in the first place. The 144-week horizon, while long by observational standards, may still underrepresent the cumulative metabolic burden of decades on therapy. Nevertheless, with 2,379 participants and nearly three years of longitudinal laboratory data, the analysis offers one of the clearest head-to-head real-world comparisons of these two widely used switch strategies in an Asian population. As INSTI regimens continue to displace older combinations globally, findings like these will shape how clinicians weigh the undeniable tolerability and convenience advantages of modern therapy against a metabolic cost that is now difficult to ignore.

Subject of Research: Long-term metabolic effects of switching from TDF/3TC/EFV to INSTI-based antiretroviral regimens in people living with HIV

Article Title: Long-term metabolic changes after switching from TDF/3TC/EFV to BIC/FTC/TAF or DTG/3TC in people living with HIV: a retrospective comparative cohort study in China

Article References: Tian, J., Zhou, Y., Qin, Y., Lu, Y., Wang, Q., Liu, P., Kong, F., Harypursat, V., & Chen, Y. (2026). Long-term metabolic changes after switching from TDF/3TC/EFV to BIC/FTC/TAF or DTG/3TC in people living with HIV: a retrospective comparative cohort study in China. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14425-w

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14425-w

Keywords: HIV, antiretroviral therapy, bictegravir, dolutegravir, tenofovir alafenamide, weight gain, dyslipidemia, hyperuricemia, integrase inhibitors, metabolic syndrome, cohort study, China

The impetus for these recommendations lies in the growing recognition that PWH experience accelerated aging-related comorbidities, notably ASCVD, with rates surpassing those of the general population. Chronic immune activation and inflammation, residual viral replication, and antiretroviral therapy (ART) side effects compound traditional risk factors, necessitating nuanced cardiovascular risk stratification and prevention strategies tailored specifically to PWH. REPRIEVE’s rigorous investigation enrolled thousands of individuals across multiple continents, assessing pitavastatin’s capacity to attenuate major adverse cardiovascular events (MACE), which encompasses myocardial infarction, stroke, and cardiovascular death.

The trial’s striking outcome—a 36% relative reduction in MACE among the pitavastatin arm compared to placebo—underscores the potential of statin therapy as a cornerstone of primary prevention in the HIV-infected demographic. Statins’ pleiotropic effects, including anti-inflammatory properties and endothelial function stabilization, are believed to underlie these benefits, complementing their lipid-lowering actions. Such findings have informed the HHS Antiretroviral Treatment Guidelines Panel to endorse moderate-intensity statin use, specifically citing pitavastatin at 4 mg daily, atorvastatin at 20 mg daily, or rosuvastatin at 10 mg daily as viable options.

Crucially, the panel delineates initiation thresholds standardized to the 10-year ASCVD risk score, advocating statin therapy in PWH exhibiting a calculated risk of 5% or greater. For those with risk scores below this threshold, the recommendation is more nuanced—favoring statin consideration informed by individualized clinician–patient discussions highlighting HIV-specific variables that could heighten ASCVD susceptibility beyond conventional metrics. Such factors include chronic inflammation biomarkers, ART history, and non-traditional risk enhancers intrinsic to HIV pathobiology. In younger patients under 40, the panel advises tailored decision-making predicated on familial history and cumulative risk exposures, acknowledging gaps in existing data.

The recommendations emphasize moderate-intensity statins partly because of their safety profile and minimal pharmacokinetic interactions with antiretroviral regimens. Pitavastatin, distinctively metabolized via pathways less involved in cytochrome P450 enzyme systems, offers a reduced risk of drug-drug interactions, making it especially suitable for PWH who often receive complex polypharmacy. Despite these advances, the panel underscores the urgent need for continued research dissecting absolute cardiovascular risk and exploring nonischemic cardiac manifestations common in HIV, such as cardiomyopathies and arrhythmias, which remain poorly characterized.

These clinical guidelines represent a vital paradigm shift given the historical underrepresentation of PWH in cardiovascular prevention trials and the prior absence of HIV-focused primary prevention protocols. They advocate for an integrative approach merging cardiology and HIV specialty care to optimize statin utilization and mitigate cardiovascular morbidity. Physicians are encouraged to incorporate comprehensive risk assessments that transcend traditional lipid measurements, incorporating inflammatory markers and potential subclinical atherosclerosis imaging that may reveal early vascular disease in PWH.

As PWH live longer due to advances in ART, managing comorbid conditions like ASCVD becomes paramount to preserving quality of life. This guideline update arrives at a critical juncture, aligning with a broader shift in HIV care that prioritizes aging-related comorbidity management. It also illuminates unresolved questions about statins’ broader impact in HIV beyond lipid modulation, including potential antiviral activity and immunomodulatory effects that may influence HIV reservoir dynamics and systemic inflammation.

The panel’s work was a collaborative effort involving the American College of Cardiology, the American Heart Association, and the HIV Medicine Association, bringing multifaceted expertise to balance efficacy, safety, and patient-centered care considerations. The development process incorporated rigorous evidence appraisal and deliberations of trial data quality, benefit-harm balance, and implementation feasibility in diverse healthcare settings.

In tandem with guideline dissemination, educational initiatives are crucial to enhance clinician awareness regarding the distinct cardiovascular risk profile in PWH and the modern nuances of statin therapy. Stigma, healthcare access disparities, and comorbid substance use remain barriers necessitating multidisciplinary efforts to ensure equitable statin uptake. Moreover, patient engagement in shared decision-making fosters adherence and empowers PWH to participate actively in their cardiovascular health management.

Future investigative directions recommended by the panel include long-term observational cohort studies and mechanistic trials elucidating statins’ effects on inflammation, immune activation, and viral persistence. Additionally, head-to-head comparisons of different statin agents in the HIV population could further refine therapeutic choices. Integration of advanced cardiovascular imaging modalities and biomarker panels may enhance personalized risk stratification, enabling precision prevention strategies.

This evolving guidance marks a pivotal step toward closing a critical gap in HIV care, positioning statin therapy as a foundational preventive measure against cardiovascular disease, which remains a leading cause of morbidity and mortality in the HIV community. As the body of evidence consolidates, the routine incorporation of statins into primary prevention paradigms for PWH promises to advance health outcomes and sustain the gains achieved through antiretroviral therapy.

Subject of Research: People

Article Title: Statin Therapy as Primary Prevention for Persons with HIV: Recommendations from the U.S. HHS Antiretroviral Treatment Guidelines Panel

News Publication Date: 27-May-2025

Web References: http://dx.doi.org/10.7326/ANNALS-24-03564

Keywords: Statins, Human immunodeficiency virus, Antiretrovirals