Highlights
- Dolutegravir-based ART shows no evidence of excessive weight gain or increased adiposity compared to efavirenz or protease inhibitor-based regimens in children and adolescents over a five-year period.
- Metabolic health parameters, including total cholesterol, triglycerides, and glucose levels, were significantly more favorable in participants receiving dolutegravir.
- Findings provide robust evidence supporting the World Health Organization recommendation of dolutegravir as the preferred antiretroviral for pediatric populations.
Background: Addressing the Weight Gain Concern in Pediatric HIV
The transition to dolutegravir (DTG)-based antiretroviral therapy (ART) has revolutionized HIV management due to its high genetic barrier to resistance and superior virological efficacy. However, data from adult trials—most notably the ADVANCE and NAMSAL studies—raised significant concerns regarding substantial weight gain and increased risk of obesity associated with integrase strand transfer inhibitors (INSTIs), particularly when combined with tenofovir alafenamide (TAF). In pediatric populations, where growth and development are dynamic, the impact of DTG on body composition and metabolic health is of paramount importance. The ODYSSEY trial (PENTA20) previously established the clinical efficacy of DTG in children. This ancillary analysis provides a much-needed long-term evaluation of whether the weight gain observed in adults translates to children and adolescents, and how DTG influences their metabolic trajectory over approximately five years.
Study Design and Methodology
The ODYSSEY trial was an open-label, randomized, non-inferiority trial conducted across 29 centers in Europe, Africa, and Southeast Asia. The study enrolled children and adolescents living with HIV, weighing at least 3 kg, who were either starting first-line ART (ODYSSEY-A) or switching to second-line ART (ODYSSEY-B). Participants were randomized to receive DTG-based ART or the standard of care (SOC) available at the time.
Cohorts and Comparators
The analysis was stratified into two cohorts based on weight at enrollment: those weighing 14 kg or more and those weighing less than 14 kg. In the 14 kg or more cohort, the SOC for first-line therapy was predominantly efavirenz (92%), while for second-line therapy, it was boosted protease inhibitors (98%). In the smaller cohort (less than 14 kg), lopinavir-ritonavir was the primary SOC.
Outcome Measures and Statistical Rigor
The primary outcomes for this ancillary analysis included anthropometric measures (weight, height, BMI-for-age Z scores), body composition (mid-upper-arm circumference [MUAC], waist/hip circumference, body fat percentage), and metabolic markers (fasting lipids and glucose). To address the challenge of treatment switches in the SOC arm during the extended follow-up—often necessitated by changes in global guidelines—the researchers employed inverse-probability-of-censoring-weights (IPCW). This methodology allows for a robust estimation of the treatment effect as if participants had remained on their randomized allocation, providing a clearer comparison of the long-term biological effects of the drugs.
Key Findings: Growth and Body Composition
The study followed 792 children (392 DTG, 400 SOC) for a median of nearly five years. The demographic profile was predominantly Black African (88%), with a median age of 12.2 years in the larger cohort.
Weight Trajectories in Children 14 kg or More
In the cohort weighing 14 kg or more, the results were largely reassuring. By week 240, children on DTG-based ART showed a mean weight increase that was only 1.0 kg greater than those on SOC (95% CI -0.2 to 2.2; p=0.095). While a small difference in MUAC was noted (+0.4 cm; p=0.030), this did not translate into clinical markers of obesity. Crucially, there were no significant differences between the groups in BMI-for-age Z scores, body fat percentage, or waist-to-height ratios. This suggests that the weight gain observed was likely a reflection of healthy growth or a return-to-health effect rather than pathological adiposity.
Specifics of the Less Than 14 kg Cohort
For the youngest children, weight and BMI-for-age Z scores remained similar between the DTG and SOC groups through 192 weeks. A small but statistically significant difference in height was observed, with the DTG group being approximately 2.5 cm shorter than the SOC group (p=0.016). However, the researchers noted that this finding requires cautious interpretation given the smaller sample size and the known variability in growth rates in early childhood.
Metabolic Superiority of Dolutegravir
One of the most striking findings of the ODYSSEY ancillary analysis was the superior metabolic profile of participants on DTG.
Lipid Profiles
Participants in the DTG arm exhibited significantly lower levels of total cholesterol and triglycerides compared to those on SOC. At week 240, the adjusted mean difference for total cholesterol was -15.3 mg/dL (p<0.0001) and for triglycerides was -14.4 mg/dL (p=0.0089). This benefit was particularly pronounced when comparing DTG to protease inhibitor-based regimens, which are traditionally associated with dyslipidemia.
Glucose Metabolism
Glucose levels were also significantly lower in the DTG group (-4.4 mg/dL; p=0.0004) compared to SOC. These findings suggest that DTG is not only safe regarding weight but may actually offer a protective cardiovascular and metabolic advantage over older antiretroviral classes in the long term.
Expert Commentary and Clinical Implications
The ODYSSEY trial results provide a critical evidence base for pediatric HIV care. The fear of integrase-induced obesity, which has shaped adult clinical practice and led to complex discussions about switching regimens, appears less applicable to the pediatric population.
Mechanical Insights and Biological Plausibility
The lack of excessive adiposity in children compared to adults might be attributed to different physiological stages. Children have higher metabolic rates and different hormonal milieus that may buffer against the adipogenic effects seen in older populations. Furthermore, the SOC in ODYSSEY often involved efavirenz, which is known to suppress weight gain in some individuals potentially due to its neuropsychiatric side effects or metabolic interference. Therefore, the slight increase in weight on DTG might represent a normalization of growth rather than a drug-specific toxicity.
Global Health Impact
For health policy experts and clinicians in high-burden settings, these results are highly encouraging. DTG is easier to administer (once daily, dispersible tablets available) and more effective at achieving viral suppression than many SOC alternatives. Knowing that it also preserves metabolic health and does not drive an obesity epidemic among HIV-positive youth solidifies its position as the gold standard for pediatric ART.
Conclusion
The 5-year ancillary analysis of the ODYSSEY trial confirms that dolutegravir-based ART is a safe and metabolically favorable option for children and adolescents. While small increases in absolute weight and MUAC were noted, they were not accompanied by increases in BMI Z-scores or central adiposity. The significant improvements in lipid and glucose profiles further underscore the benefits of DTG over protease inhibitors and efavirenz. As we strive for the 95-95-95 targets, these data provide clinicians with the confidence to continue scaling up DTG-based regimens in the most vulnerable populations.
Funding and Registration
The ODYSSEY trial was funded by Fondazione Penta ETS, ViiV Healthcare, and the UK Medical Research Council. It is registered with ClinicalTrials.gov (NCT02259127), EUDRACT (2014-002632-14), and ISRCTN (ISRCTN91737921).
References
1. Turkova A, White E, Violari A, et al. Weight gain, body composition, and metabolic parameters of dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: an ancillary analysis of the ODYSSEY trial. Lancet Child Adolesc Health. 2026;10(3):189-202.
2. Venter WD, Moorhouse M, Sokhela S, et al. Dolutegravir plus Two Antiretrovirals in First-Line HIV Treatment. N Engl J Med. 2019;381(9):803-815.
3. World Health Organization. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV. Geneva: WHO; 2018.