The study compared two three-drug regimens. Participants assigned to the experimental group received doravirine, a nonnucleoside reverse transcriptase inhibitor, together with lamivudine and tenofovir disoproxil fumarate. Those in the comparison group received dolutegravir, an integrase strand transfer inhibitor, with emtricitabine and tenofovir alafenamide. Both regimens combine agents that interrupt different stages of HIV replication, limiting the virus’s ability to produce new copies and reducing the risk that resistance will emerge when treatment is taken consistently.

The trial focused on adults with HIV who were at risk of gaining weight after starting treatment. Weight gain has become an important consideration in HIV care as modern antiretroviral therapy has transformed HIV infection into a manageable chronic condition. Although restoring health after the initiation of therapy can itself lead to weight gain, accumulating evidence has also linked some treatment combinations—particularly regimens containing certain integrase inhibitors and tenofovir alafenamide—with greater increases in body weight in some populations.

At 48 weeks, 89.0% of participants receiving doravirine, lamivudine, and tenofovir disoproxil fumarate had achieved viral suppression, defined as an HIV RNA level below 50 copies per milliliter. In the dolutegravir, emtricitabine, and tenofovir alafenamide group, 90.7% reached the same threshold. The difference between the groups met the trial’s prespecified noninferiority margin of minus 10 percentage points, meaning the alternative regimen was considered sufficiently close to the comparator in its ability to suppress HIV.

Noninferiority trials are designed to determine whether a new or alternative treatment performs no worse than an established treatment by more than a clinically acceptable amount. In this case, the analysis did not seek to show that the doravirine-based regimen was superior for viral suppression. Instead, it tested whether any reduction in suppression would remain within a predefined range while allowing researchers to examine potential advantages, including its effect on weight.

The results indicated that participants assigned to the doravirine-based regimen experienced less weight gain than those assigned to the dolutegravir-based regimen containing tenofovir alafenamide. The study summary did not provide numerical differences in weight gain, but the direction of the finding is clinically relevant because body-weight changes can influence metabolic health, cardiovascular risk, quality of life, and long-term treatment decisions.

The pharmacology of the drugs may help explain the observed difference. Dolutegravir blocks HIV integrase, the viral enzyme that inserts HIV genetic material into the DNA of human cells, while bictegravir and other drugs in the same class have also been associated in previous research with treatment-related weight increases. Tenofovir alafenamide is a newer formulation that delivers tenofovir efficiently to cells at a lower circulating dose than tenofovir disoproxil fumarate, improving some aspects of tolerability but potentially contributing to differences in weight outcomes when the two formulations are compared.

Doravirine works through a separate mechanism. As a nonnucleoside reverse transcriptase inhibitor, it binds directly to HIV reverse transcriptase and interferes with the enzyme’s ability to convert viral RNA into DNA. Lamivudine and tenofovir disoproxil fumarate are nucleoside or nucleotide reverse transcriptase inhibitors that act as faulty building blocks during viral DNA synthesis. Used together, the three agents create a combination blockade against replication rather than relying on a single antiviral mechanism.

The findings do not mean that every person taking an integrase inhibitor or tenofovir alafenamide will gain excessive weight, nor do they establish that the doravirine-based regimen is the best option for all adults with HIV. Treatment selection must account for viral resistance, kidney and bone health, coexisting conditions, drug interactions, pregnancy considerations, adherence, access, and national treatment guidelines. The study instead provides evidence that clinicians may be able to consider weight-related priorities without sacrificing short-term virologic efficacy in an appropriate population.

The paper is scheduled for presentation at the International AIDS Society conference. It will be published in JAMA under the DOI 10.1001/jama.2026.14762. The investigators said the full article contains additional information about the study methods, participant characteristics, authorship, funding, and potential conflicts of interest. Longer follow-up will be important to determine whether the difference in weight gain persists beyond 48 weeks and whether it translates into measurable differences in metabolic or cardiovascular outcomes.

Subject of Research: First-line antiretroviral therapy for HIV, viral suppression, and treatment-associated weight gain.

Web References: International AIDS Society conference: https://www.iasociety.org/conferences/aids2026

References: JAMA. DOI: 10.1001/jama.2026.14762

Keywords: HIV, antiretroviral therapy, viral suppression, doravirine, dolutegravir, tenofovir disoproxil fumarate, tenofovir alafenamide, weight gain, integrase strand transfer inhibitors, randomized clinical trial, noninferiority trial, HIV treatment.

The investigators constructed a sophisticated lifetime simulation model integrating comprehensive datasets, notably the Systolic Blood Pressure Intervention Trial (SPRINT) and the National Health and Nutrition Examination Survey (NHANES), alongside meta-analytic inputs from the broader cardiovascular literature. The model projected long-term cardiovascular outcomes including incidences of myocardial infarction, ischemic stroke, and heart failure under different systolic blood pressure targets: less than 140 mm Hg, less than 130 mm Hg, and less than 120 mm Hg. Importantly, this analytical framework did not overlook the consequential spectrum of treatment-associated adverse events such as falls, acute kidney injury, hypotension, and bradycardia, thereby providing a balanced perspective on intensive antihypertensive therapy.

A critical innovation of this study lies in the explicit incorporation of real-world measurement inaccuracies in systolic blood pressure readings. Blood pressure measurement is notoriously prone to variability due to operator technique, device calibration, patient positioning, and biological fluctuations. By integrating these error rates observed in everyday clinical settings, the researchers added a vital layer of ecological validity to their cost-effectiveness analysis, ensuring that their findings remain applicable outside tightly controlled trial environments.

The simulation revealed that even when accounting for these common measurement errors, the aggressive target of <120 mm Hg consistently prevented a greater number of debilitating cardiovascular events compared to the more lenient <130 mm Hg target. This outcome signifies a paradigm shift, implying that achieving stringent blood pressure control confers profound long-term benefits that substantially outweigh the concerns raised by potential overtreatment or clinical measurement variability.

However, the intensification of therapy to reach the lowest systolic parameters was not without trade-offs. Adverse events related to intensified pharmacotherapy saw an uptick in the simulation, including an increased risk for falls in older adults—a clinically significant concern given the morbidity associated with fall-related fractures—alongside episodes of renal hypoperfusion manifesting as kidney injury, instances of symptomatic hypotension, and incidences of bradycardia. These nuances highlight the necessity for personalized clinical judgment, tailoring treatment intensity to the individual risk profiles and preferences of patients.

Economic considerations further enrich the study’s implications. While the <120 mm Hg treatment goal unavoidably increased healthcare utilization—reflected in greater antihypertensive drug consumption and more frequent clinical monitoring visits—cost-effectiveness analyses using quality-adjusted life years (QALYs) demonstrated the intervention’s value. Specifically, the cost per QALY gained at the intensive target was approximately $42,000, a figure well within commonly accepted thresholds for healthcare interventions, thereby affirming that tighter blood pressure control yields not only clinical but also economic benefits.

Karen Smith, PhD, an investigator at Brigham and Women’s Hospital and the study’s lead author, highlights the clinical confidence these findings should inspire. “Our data suggest that for patients at elevated cardiovascular risk, pursuing a systolic blood pressure target below 120 mm Hg is both clinically advantageous and economically rational,” Smith states. “This conclusion holds even under typical measurement error conditions, reinforcing the robustness of intensive blood pressure management strategies in real-world practice.”

Nevertheless, Smith cautions that the research focuses on population-level analysis and cost-effectiveness rather than individualized treatment recommendations. The increased incidence of adverse effects with more aggressive therapy means that “intensive blood pressure control will not be optimal for every patient.” She advocates for shared decision-making between clinicians and patients, emphasizing a nuanced appraisal of risks, benefits, and patient values when choosing an appropriate therapeutic target.

Additional contributors to the study include Thomas Gaziano, Alvin Mushlin, David Cutler, Nicolas Menzies, and Ankur Pandya, who collectively brought expertise in epidemiology, biostatistics, health economics, and clinical medicine to bear on this multifaceted investigation. The interdisciplinary nature of the research underscores the complexity inherent in balancing treatment intensity and adverse event risk in hypertension management, a challenge central to public health policy.

Funding for this important research was provided by the U.S. National Science Foundation and the National Institute of Neurological Disorders and Stroke, signaling robust support from leading scientific institutions dedicated to advancing cardiovascular health. Their involvement reinforces the study’s methodological rigor and relevance to national health priorities.

This publication arrives at a pivotal moment in cardiovascular medicine, where guidelines continue to evolve amid emerging evidence. By quantifying the real-world impact of intensive blood pressure targets and factoring in common clinical challenges such as measurement error and safety concerns, the study offers a comprehensive perspective that could influence future hypertension guidelines and inform clinical practice at large.

In conclusion, while intensified systolic blood pressure control to levels below 120 mm Hg comes with a nuanced risk-benefit profile, this research substantiates its superiority in preventing major cardiovascular events and offers a cost-effective strategy for managing high blood pressure. Importantly, these findings advocate for personalized therapeutic plans that consider patients’ unique clinical contexts and treatment goals, heralding a more refined approach to hypertension care in the years ahead.

Subject of Research: People
Article Title: Effect of systolic blood pressure measurement error on the cost-effectiveness of intensive blood pressure targets
News Publication Date: 18-Aug-2025
Web References: https://www.acpjournals.org/doi/10.7326/ANNALS-25-00560
References: Smith KC et al. “Effect of systolic blood pressure measurement error on the cost-effectiveness of intensive blood pressure targets” Annals of Internal Medicine DOI: 10.7326/ANNALS-25-00560
Keywords: Hypertension, Blood pressure, Cost effectiveness