In adolescents living with HIV, a 5-days-on and 2-days-off dosing of antiretroviral therapy (ART) with tenofovir disoproxil fumarate, lamivudine, and dolutegravir fails to match the efficacy of continuous dosing for maintaining viral suppression, as shown in the BREATHER Plus trial conducted in Africa.
By week 96, the primary outcome of viral rebound—defined as the first of two consecutive plasma HIV RNA measurements of ≥50 copies/mL—had occurred in 9.9 percent of participants in the short-cycle ART group vs 4.8 percent in the continuous ART group (estimated difference, 5.1 percent, 99 percent confidence interval [CI], –0.8 to 11.5). [Lancet HIV 2026;13:e367-e379]
The upper limit of the confidence interval for the estimated difference exceeded the 8-percent margin required for noninferiority.
“BREATHER Plus is the first trial to consider short-cycle ART in the context of viral load monitoring every 6−12 months, aligning with standard of care in Africa, and only the second trial to consider short-cycle ART on a three-drug regimen with dolutegravir, which is now the predominant anchor drug globally,” noted chief investigator Dr Adeodata Kekitiinwa from Baylor College of Medicine Children’s Foundation in Kampala, Uganda, and colleagues.
“Reassuringly, in both treatment groups in the BREATHER Plus trial, most participants (approximately 80 percent) who had confirmed viral rebound by week 96 had virological suppression at close-out, with no change to ART regimen. Only one participant (in the continuous ART group) had a major resistance mutation to integrase strand transfer inhibitors,” Kekitiinwa and colleagues added.
Daily ART remains essential
Short-cycle ART regimens provide individuals weekend-long breaks from their medication while keeping the virus suppressed, with the aim of reducing long-term toxicities and costs and potentially improving quality of life, according to the investigators. This could be especially beneficial to adolescents living with HIV, “who face adherence challenges and treatment fatigue, and require ART across their lifespan.”
In the original BREATHER study, a 5-days-on-and-2-days-off dosing schedule using efavirenz-based ART was found to be noninferior to continuous ART in terms of virologic suppression in children and young adults aged 8–24 years. [PLoS One 2018;13:e0196239]
Similarly, several randomized trials of short-cycle ART regimens involving adults yielded reassuring results for various primary outcomes, including virologic suppression, safety, and toxicity. [Lancet HIV 2022;9:e79-e90; J Antimicrob Chemother 2025;80:2179-2186]
In light of the findings from BREATHER Plus, Kekitiinwa and colleagues urged caution in recommending dosing 4–5 days per week across the general population in low-to-middle income countries to extend ART supplies. “Vulnerable populations living with HIV, including children, adolescents, and female individuals of childbearing potential, should continue daily ART.”
Indeed, results of an exploratory analysis suggested that participants in the short-cycle ART group were at risk of onward transmission of HIV (viral load ≥200 copies/mL) for a higher proportion of follow-up than those in the continuous ART group (≥200 copies/mL: 2.4 percent vs 1.4 percent of time to week 96; ≥1,000 copies/mL: 1.5 percent vs 0.8 percent of time to week 96).
“Although short-cycle ART might be desirable in terms of cost reduction and quality of life, the importance of virological suppression for long-term health and the prevention of onward HIV transmission remains fundamental to population health,” Kekitiinwa and colleagues pointed out.
Not for everyone
In an accompanying editorial, Drs Romain Palich from Paris Cité University and Jean-Jacques Parienti from the University of Caen Normandy, both in France, discussed potential factors explaining why the results from studies of short-cycle ART regimens in adults living with HIV were not replicated in the adolescent population of BREATHER Plus. [Lancet HIV 2026;13:e358-e359]
“First, we suspect that adherence to treatment was not as high as described in the trial. Although self-reported adherence to treatment was 96 percent, this subjective measure is affected by social desirability,” Palich and Parienti noted.
They added that the BREATHER Plus investigators collected data on the opening of pill bottle caps with an embedded electronic device in a random but consenting subpopulation, which likely represented participants with the highest adherence. “Even in this sub-study, around one in five adolescents in the short-cycle ART group opened their pill bottle less than 5 days per week.
“Second, biological observations in adults living with HIV cannot be extrapolated to adolescents living with HIV acquired through vertical transmission. These adolescents have lived with HIV since birth and often received ART since early childhood, experiencing chronic immune activation, cumulative drug exposure, and sometimes undocumented episodes of previous virological failure,” Palich and Parienti continued.
In BREATHER Plus, the median time on ART was 11.8 years, and baseline HIV DNA resistance testing was omitted by design to reflect real-world practice. Palich and Parienti pointed to the possibility that archived mutations undermined the cushion of safety under a reduced dosing protocol.
“Despite the disappointing headline result of the BREATHER Plus trial, Kekitiinwa and colleagues offer valuable lessons, showing that even well-conceived, biologically sound innovations cannot be assumed to work across all populations,” they said.
Palich and Parienti argued that short-cycle ART regimens “are only efficacious when adherence, pharmacology, immunology, and virology align—a scenario rarely achieved in adolescents with perinatally acquired HIV. For this patient population, the path to durable viral suppression and freedom from daily medication might differ to that of adults.”
The BREATHER Plus trial
The trial was conducted in five clinical research centres across Kenya, South Africa, Uganda, and Zimbabwe, including a total of 470 adolescents living with HIV with an HIV-1 RNA of <50 copies/mL over the previous 12 months and no documented history of treatment failure.
The participants were randomly assigned to receive an oral, fixed-dose combination of tenofovir disoproxil fumarate (300 mg), lamivudine (300 mg), and dolutegravir (50 mg) either as short-cycle regimen (n=239) or continuous daily regimen (n=231). Those in the short-cycle ART group could choose their two consecutive days off (ie, Friday and Saturday or Saturday and Sunday).
The median age of the participants was 16.5 years, 56 percent were female, and all were Black. Nearly everyone (97 percent) had acquired HIV vertically, and the median CD4 T-cell count was 878 cells/μL. The median duration of exposure to ART before trial enrolment was 11.8 years, including 2.5 years on dolutegravir. The median follow-up was 117 weeks.
By the end of follow-up, 16 serious adverse events (AEs) occurred in 15 participants in the short-cycle ART group (including one death unrelated to HIV or ART) and 22 serious AEs in 16 participants in the continuous ART group.
On the modified HIV/AIDS-Targeted Quality of Life questionnaire, 98 percent in the short-cycle ART group and 99 percent in the continuous ART group reported that taking their medications had not made it difficult to live a normal life.