5-on 2-off dosing is inferior to continuous ART in adolescents in BREATHER Plus study

16 July 2025. Related: Early access, Conference reports, Treatment strategies.

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.

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 but more frequent viral load samples were taken every 8-12 weeks and tested retrospectively. The study took place in Kenya (18%), South Africa (7%), Uganda (45%) and Zimbabwe (30%).

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

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.

Study results

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 actually inferior to CT (p=0.034).

Using Kaplan-Meier estimates, the SCT am 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 resuppressed after switching to daily TLD, 10/23 resuppressed on SCT dosing.  In the CT arm, 8/11 resuppressed without changing ART. No participants changes 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 mutations 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%).

By week 96, 20 participants in the SCT arm had changed to daily TLD. Only 6/20 were 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]

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

Further details are needed to explain why the results from BREATHER-Plus were so different to other studies.

For example, 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 much higher efficacy from 5-on 2-off dosing in eight adult studies. [5, 6]

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. 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
6. 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