Atripla three days a week for two years: pilot switch study reports undetectable viral load with better bone, kidneys and sleep
1 October 2016. Related: Conference reports, Treatment strategies, Lipodystrophy Workshop (IWADRH) 18 New York 2016.
Simon Collins, HIV i-Base
A small pilot study that switched people with undetectable viral load to reduced dosing of Atripla reported no viral load rebounds with follow-up results out to two years. 
The initial study randomised 61 participants with a long history of viral suppression (entry criteria included viral load <37 copies/mL for more than two years) to either switch to taking Atripla three times a well (on Mondays, Wednesdays and Fridays) or to continue with daily dosing.
The primary endpoint of viral suppression at week 24 was reported for all 30 participants in the reduced dose group (100%, 95%CI 98.3 to 100). Additionally, no viral loads blips (>37 copies/mL) were reported from more than 330 viral load samples. Analysis using a viral load test with a 2 copy/mL cut-off showed no differences between baseline and week 24 samples in either arm.
Secondary endpoints favoured the reduced dose strategy with small but significantly better markers of renal function and bone health and for better quality sleep, indicating potential benefits from reducing exposure to both tenofovir-DF and efavirenz. Median urine albumin to creatinine ratio reduced by 1 vs 0 mg/g (p=0.047) and Beta-2 microglobulin reduced by – 158 ug/g vs + 312 (p=0.003) in the reduced vs daily groups respectively. Although sleep quality was reported as normal at baseline using the Pittsburgh Sleep Quality Index (median 4 on a scale of 1 to 10, when lower is better), by week 24 this improved more for the reduced dose arm, by –1.0 vs –0.5 (p=0.003).
A small but statistically significant increase in total cholesterol in the reduced dose group of + 4vs –5 mg/dL (p=0.019) was explained by the lipid impact of reducing levels of tenofovir-DF.
A three-year study extension that then allowed those on daily dosing to switch to reduced dosing at week 24 was accepted by all participants, with follow up results now presented for 61 people out to 24-30 months.
Viral suppression has been maintained throughout the 24 to 30 month extension phase with no study discontinuations. The single reported complication was one non-AIDS related neoplasia with this participant continuing on the reduced dose schedule.
Concern about the difficulty of remembering dosing with less than daily regimens was discussed in questions after the presentation. Although data was not presented formally on adherence, the study included additional adherence support to overcome these initial difficulties.
No participant accepted the option to switch back to daily dosing and the lack of drop-out or discontinuations for any reason supports further evaluation of this strategy in larger studies.
Although this is a small study, the durability reported in these results makes further research important given the likely continued pressure to widely use generic components of Atripla in first-line therapy, even when guidelines recommended better and newer options.
The benefits from reduced dose tenofovir-DF suggest this might even be preferable compared to the strategy of reducing the daily efavirenz dose to 400 mg.
Previous studies have suggested that daily dosing might not be needed given the long half-lives of efavirenz, tenofovir-DF and emtricitabine (ranging from 39->60 hours). For example, ten years ago the FOTO study (Five-On, Two Off) reported no viral blips >50 copies/mL when 30 for over a year. 
The BREATHER study in young people (age 8 to 24) reported non-inferiority from dropping weekend doses compared to daily dosing with 75% of participant reported significant improvement in quality of life. The BREATHER study was reported at CROI 2015 and published in Lancet HIV in June 2016. [3, 4]
At IAS 2016 in Durban this year, a French study reported three cases of viral rebound over a year in 100 participants with suppressed viral load switching to a reduced dose strategy of taking only four continuous doses each week, all of who resuppressed when returning to daily dosing.
More importantly, all combinations of 2NRTIs + either a PI or NNRTI were included. Although 40 people were using efavirenz-based ART, 26 were using rilpivirine and 5 were using etravirine. There were 29 people using PI-based ART: 15 with darunavir/r, 13 using atazanavir/r and 1 using lopinavir/r. 
While these small studies are intriguing with tentative results that look promising, together with other reduced-dose maintenance strategies – including dolutegravir with and with 3TC – this might warrant a large well powered randomised study in order to really access both safety and efficacy.
Given the potential savings if this is successful, perhaps this could be a new focus for the INSIGHT research network that so effectively produced definitive data on controversial aspects of care in both the SMART and START studies.
- Rojas J et al. Three-day per week Atripla maintains viral suppression and decreases sub-clinical toxicity: a pilot study. 18th International Workshop on Comorbidities and Adverse Drug Reactions in HIV, 12-13 September 2016, New York. Oral abstract O22.
- 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.
- 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.
- 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.
- de Truchis P et al. Efficacy of a maintenance four-days-a-week regimen, the ANRS162-4D trial. AIDS 2016. Poster THPEB063.
http://programme.aids2016.org/PAGMaterial/eposters/0_5947.pdf (PDF poster)