CROI 2025: Reducing Biktarvy from daily to only once, twice or three times a week

17 March 2025. Related: Early access, Conference reports, Antiretrovirals, Treatment strategies, .

Simon Collins, HIV i-Base

A pilot study that compared daily Biktarvy to three reduced dosing strategies, including to as low as once-weekly dosing, generated a lot of discussions at CROI 2025. [1]

Even though the rationale for the study referenced the potency and long half-lives of bictegravir, emtricitabine and TAF to support less than daily dosing, the results were controversial as the lowest doses resulted in sub-optimal drug levels when viral failure would commonly be expected.

However, the results are also very timely though if less frequent dosing is shown to be safe in other settings, given the current uncertainty over continued funding for PEPFAR.

The BETAF-RED study was a phase 2, open-label, pilot, randomised, controlled trial. Participants at a single centre were consecutively randomised (n=10 per arm) to: daily (OD) or to taking ART three times a week (3W: Mon/Wed/Fri), twice weekly (2W: Tue and Fri), or once-weekly (1W: Wednesdays) for 48 weeks. [2]

Entry criteria included having undetectable viral load for at least 6 months on daily Biktarvy, a CD4 count >350 cells/mm3, no resistance to current ART and no active hepatitis B or C.

Primary endpoints were viral load <50 copies/mL at 12 and 48 weeks using FDA snapshot in OT and ITT analyses. Monitoring at baseline and weeks 4, 12, 24, 36 and 48 also included ultrasensitive viral load (<5 copies/mL), total and intact HIV reservoir, CD4 and CD8 cells, hsCRP and IL-6, and plasma and intracellular trough drug levels.

Baseline characteristics included 92% men (36/40), diagnosed a median of 8 years (IQR: 4 to 12), with median CD4 count of 635 (IQR: 517 to 762) and CD4:CD8 of 0.98 (0.83 to 1.14). Previous duration of suppression on ART was not reported, although this could be a factor in continued viral suppression.

Results were available for 33/40 participants with 7/40 discontinuations (n=3 participant decision, n=1 lost to follow-up, n=3 with viral failure. The three cases of viral failure included two from the 1W arm at 4 weeks (with viral load at 780 and 29,800 copies/mL) and one from the 3W arm (at 60 copies/mL). No resistance was detected in these participants and all resuppressed to undetectable after switching back to daily dosing.

PK levels of all three drugs were significantly lower in alll three reduced dosing groups compared to daily dosing. Although the poster reports that PK levels generally remained above target levels in the 3W and 2W groups, these data were difficult to varify because the target PJ levels were not reported. PK levels were all reported as suboptimal for the 1W group.

There were no significant differences between arms at 12 and 48 weeks in terms of ultrasensitive plasma viral load, HIV reservoir, or inflammatory markers. There were also no significant changes in weight, sleep quality (Pittsburgh Sleep Quality Index), quality of life (EQ-5D-5L), glucose, lipids, estimated glomerular function, or liver enzymes.

There were positive increases in CD4/CD8 ratio in OD and 3W at 48 weeks but no significant differences in CD4 count, CD8 count, or CD4/CD8 ratio between each of the three reduction dose arms compared to the OD arm at 12 or 48 weeks.

commentS

These results support further research in settings currently facing the insecurity of continued PEPFAR funding for national HIV programmes and where drug costs perhaps account for most than half the annual HIV budget.

Important cautions however include that B/F/TAF might have different properties compared to TDF/lamivudine/dolutegravir (TLD) that is currently used globally in low- and middle-income countries and recommended in WHO guidelines. This also includes differences in baseline characteristics, standard of care (including limited CD4 and viral load testing) and that intermittent ART might also bring adherence challenges.

However, if shown to be safe this might however enable alternative strategies compared to closed clinics and no access to ART.

Further research is also supported by a growing number of other randomised and observational studies that used less than daily dosing, although these have also generally been in high-income countries. [3, 4, 5, 6, 7, 8, 9]

The 2024 update to the French HIV treatment guidelines also included the option to switch to intermittent triple therapy (four or five days per week) based on the Quatuor study, for people who have undetectable viral load using standard daily dosing. [10] 

The randomised ANRS Quatuor trial included included having a CD4 nadir >250 cells/mm3, no history previous viral failure or drug resistance and not having chronic HBV co-infection.  Similar rates of maintaining viral suppression at week 48 in the reduced dose (96%, 304/318) vs daily (97%, 308/318) groups [adjusted difference: –1·3% (95% CI –4·2 to 1·7)], showed intermittent dosing to be non-inferior to daily ART. [11]

References

  1. Chivite I et al for the BETAF-RED Study Team. Safety, Tolerability, and Efficacy of a BIC/FTC/TAF Dose Reduction Strategy. CROI 2025. Poster abstract 659.
    www.croiconference.org/abstract/2386-2025/ (abstract)
    www.croiconference.org/wp-content/uploads/sites/2/posters/2025/659-2025.pdf (poster)
  2. ClinicalTrials.gov. Safety, Tolerability, and Efficacy of a Dose Reduction Strategy Based on Bictegravir/​Emtricitabine/​Tenofovir Alafenamide in Virologically Suppressed HIV-infected Adults (BETAF-RED).
    clinicaltrials.gov/study/NCT05602506
  3. Five days on two days off: Biktarvy in pilot FOTO study. HTB (August 2024).
    i-base.info/htb/48358
  4. Atripla three days a week for two years: pilot switch study reports undetectable viral load with better bone, kidneys and sleep. HTB (October 2016).
    i-base.info/htb/30601
  5. Bellagamba R et al for the ATAD Study Group. Randomized clinical trial on efficacy of fixed-dose efavirenz/tenofovir/emtricitabine on alternate days versus continuous treatment. AIDS. 2019 Mar 1;33(3):493-502. doi: 10.1097/QAD.0000000000002067.
    pubmed.ncbi.nlm.nih.gov/30702517
  6. Rojas J et al. A maintenance 3-day-per-week schedule with the single tablet regimen efavirenz/emtricitabine/tenofovir disoproxil fumarate is effective and decreases sub-clinical toxicity. AIDS. 2018 Jul 31;32(12):1633-1641. doi: 10.1097/QAD.0000000000001843.
    pubmed.ncbi.nlm.nih.gov/30702517/
  7. Butler KM et al. ART with weekends off is noninferior to continuous ART in young people on EFV+2NRTI. 2015 Conference on Retroviruses and Opportunistic Infections (CROI 2015), 23-26 February 2015, Seattle. Oral abstract 38LB.
    http://www.croiconference.org/sessions/art-weekends-noninferior-continuous-art-young-people-efv2nrti
  8. PENTA Study 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. The Lancet HIV , Volume 3 , Issue 9 , e421 – e430. DOI: http://dx.doi.org/10.1016/S2352-3018(16)30054-6.
    http://thelancet.com/journals/lanhiv/article/PIIS2352-3018(16)30054-6/abstract
  9. Cohen C et al. The FOTO study: The 48 week extension to assess durability of the strategy of taking efavirenz, tenofovir and emtricitabine Five days On, Two days Off (FOTO) each week in virologically suppressed patients. IAS 2009, Cape Town. Abstract MOPEB063.
    http://library.iasociety.org/AbstractView.aspx?confID=2009&abstractId=3046
  10. Cabié A et al for the ANRS. Key changes to the French national HIV treatment guidelines. October 2024.
    https://anrs.fr/fr/actualites/actualites/recommandations-has-traitement-antiretroviral-vih/
  11. 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. 2022;9(2):e79-e90.
    www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(21)00300-3/fulltext

Links to other websites are current at date of posting but not maintained.