IAS 2025: 5-on 2-off dosing is inferior to continuous ART in BREATHER Plus – but no differences in clinical outcomes

17 July 2025. Related: Conference reports, Treatment strategies, IAS 13th Kigali 2025.

Adeodata Kekitiinwa at IAS 2025

Simon Collins, HIV i-Base

One of the studies at IAS 2025 with difficult but very clear results reported that taking TLD (tenofovir/lamivudine/dolutegravir) on a 5-on 2-off dosing in the BREATHER Plus study was not as effective as daily dosing. [1]

These results, presented by Adeodata Kekitiinwa from the Baylor Foundation Uganda, were not expected, as the original BREATHER study (PENTA-16), also in adolescents, showed that reduced dosing was both as effective as daily ART and was also preferred by participants. [2]

BREATHER Plus randomised 470 adolescents aged 12-19 (56% female) who were suppressed (< 50 copies/mL) on tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) to either continue continuous treatment (CT) using daily ART (n=231) or switch to short cycle treatment (SCT), with 5 days-on, 2 days-off (n=239). Enrolment criteria included not having a history of drug resistance and the study took place in Kenya, South Africa, Uganda and Zimbabwe.

This was a non-inferiority study using methodology where the confidence interval and non-inferiority margin changed depending on the number of events in the CT arm. Based on a 5% event rate, non-inferiority was based on an 8% upper margin of the 99%CI.

The primary endpoint was two consecutive viral load results >50 copies/mL by week 96. Viral load was monitored in real time every 6-12 months to mirror real-world practice in each country but more frequent viral load samples were taken every 8-12 weeks and tested retrospectively. For example, in Uganda and Kenya, real-time viral load was tested every 6 months (until age 20 when this reduced to every 12 months). In South Africa and Zimbabwe however, viral load was generally only tested every 12 months.

If viral load became detectable on a routine test, the participant was managed closely, ideally with a confirmatory test a week later – and not just left until the next routine test. It is important that a detectable viral load prompted counselling and adherence support, including to allow time before changing ART or dosing strategy.

The median age was 16.5 years (IQR:14.6 to 18.1). Previous time on ART was 11.8 years (IQR: 8.6 to 14.1) with median time on TLD of 2.5 years.

A substudy using MEMS caps estimated adherence between weeks 8-32 and 48-72 in 210 participants in Uganda and Kenya.

Study results and interpretation

At week 96, a higher rate of viral failure occurred in 10% of the SCT (n=23) vs 5% in the CT arm (n=11); diff 5.1% (99%CI: –0.9 to +11.5). The showed that SCT was not non-inferior. The difference was also 5.1% (95%CI: +0.05 to +9.9), which showed that SCT was actually inferior to CT (p=0.034).

Using Kaplan-Meier estimates, the SCT arm had a significantly higher rate of viral rebound: HR 2.1 (95%CI: 1.0 to 4.4).

Outcomes from the SCT viral rebound cases included 9/23 who resuppressed after switching to daily TLD and 10/23 who resuppressed on SCT dosing. In the CT arm, 8/11 resuppressed without changing ART. No participants changed to second-line ART.

Limited data was presented on drug resistance in people with viral rebound, with results only available for 12/23 and 6/11 in the SCT vs CT arms, respectively. The only major mutation related to current ART was one person with dual INSTI/NRTI in the CT arm. Major NNRTI mutations were found in 3/12 and 2/11 other participants.

Retention in the study was high (98%) and only 3 participants changed ART due to side effects (1 SCT and 2 CT), with no differences in side effects overall.

There were also no differences between arms in adherence based on self-report (96%) or using MEMS caps (92%). However, MEMS caps data isn’t always ideal and different participants were enrolled in each of the two assessment time periods.

By week 96, 20 participants in the SCT arm had changed to daily TLD. Only 6/20 were due to confirmed viral failure, with 13/20 due to plans to conceive and 1/20 due to participant choice.

The presentation also referred to several other reduced dosing studies using second-generation INSTIs, including QUATUOR, DUETTO. BICFOTO and BETAF-RED studies. Results have generally been very positive and QUATUOR led to reduced dosing being included in the current French guidelines. [3, 4]

However, the study concluded that reduced dosing with TLD could not be recommended for adolescents when viral load is only monitored every 6-12 months. Daily TLD should therefore continue to be recommended in this population.

comments

Even though the results are disappointing, they show that adolescents on ART should only be recommended to use daily dosing.

They also provide an important and detailed dataset that mirrors clinical management for the majority of people living with HIV, and the results are especially relevant given the uncertainty of international support for universal ART.

Additional information will hopefully help understand why the results from BREATHER Plus were so different to earlier studies, including the original BREATHER study. This might relate to the study design and some to results that are not yet presented.

For example, virological data has not yet been presented on how high VL rebounded. This would help clarify whether viral events were likely low-level blips that could just be a factor of test sensitivity. Similarly, knowing whether there were differences in levels of viral rebound between people who switched to CT rather than continue on SCT will help to determine whether these were blips or viral rebound. These virological data will be included in the full paper, which is already being prepared.

This point is important given the high proportion of participants (10/23 on SCT and 8/11 in CT) who spontaneously resuppressed after adherence support. This suggests natural fluctuation or test sensitivity in addition to any genuine viral rebound. Interestingly, in a post hoc analysis, the proportion of follow-up time with viral load ≥50 copies/mL was higher in the SCT compared to the CT arm, with perhaps a trend ≥200 and ≥1000 copies/mL. [5] 

However, because these are small numbers and therefore underpowered to show statistical significance, perhaps an alternative primary endpoint would have produced very different results. Although BREATHER Plus mirrored the current standard of care for monitoring in these countries, it didn’t use the standard of care for management, rather using the approach to viral failure in a high-income setting. The lack of clinical failure in the study together with no differences based on the WHO >1000 copies/mL criteria for viral failure might the following sensitivity analysis important.

In an ITT sensitivity analysis, using a viral load threshold of >1000 copies/mL to avoid viral blips, there was no difference between arms – with 5 (2%) SCT vs 5 (2%) CT at week 96. This is difficult to interpret because it cannot adjust for degree of adherence support following the initial detectable viral load. [5]

The original PENTA-16 BREATHER study reported that 5-on 2-off dosing was highly effective in 199 adolescents using TDF/FTC/efavirenz in 11 countries. Results were not only highly effective but the strategy was also very popular.

Many of the differences between BREATHER and BREATHER Plus might explain these results, including adherence, frequency of monitoring, pharmacokinetic differences of ART and study design, where small differences could disproportionally affect the reduced dose arm (See Table 1).

A systematic review and meta-analysis of reduced dosing studies, presented as a late-breaker earlier in the conference and recently published in AIDS, reported 5-on 2-off dosing to be as safe and effective as daily dosing. [6, 7]

Table 1. Differences between BREATHER and BREATHER Plus

References

1. Kekitiinwa A et al for the BREATHER Plus study group. Short cycle antiretroviral therapy (ART) with weekends off is inferior to continuous ART in adolescents living with HIV receiving tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) in sub-Saharan Africa: BREATHER Plus 96-week results. IAS 2025. Oral late-breaker abstract OAS0104LB.
   https://programme.ias2025.org/Abstract/Abstract/?abstractid=6712
2. The BREATHER (PENTA 16) Trial Group. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial.  Lancet HIV. 2016. 3: e421-430.
   https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(16)30054-6/fulltext
3. French HIV Treatment Guidelines. Published online December 2024. https://anrs.fr/fr/actualites/actualites/recommandations-has-traitement-antiretroviral-vih
4. Landman R et al. A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial. Lancet HIV. 2023. 9: e79-90.
   https://pubmed.ncbi.nlm.nih.gov/35120640
5. Personal communication, BREATHER Plus study team.
6. Fairhead C et al. Systematic review and meta-analysis of the efficacy of intermittent antiretroviral therapy dosing: a crisis response to the sudden cuts in USAID and PEPFAR funding. IAS 2025. Oral late-breaker abstract OAB0106LB.
   https://programme.ias2025.org/Abstract/Abstract/?abstractid=6516
7. Hill A et al. Could reduced dosing maintain more people on antiretrovirals after the sudden cuts in USAID funding? A crisis response. AIDS DOI:10.1097/QAD.0000000000004212. (22 April 2025).
   https://journals.lww.com/aidsonline/abstract/9900/could_reduced_dosing_maintain_more_people_on.692.aspx