Viral suppression maintained with alternate-day dosing of efavirenz/tenofovir/emtricitabine

Krishen Samuel
Published: 01 April 2019

No significant differences in viral suppression between groups on daily dosing versus alternate-day dosing of combination fixed-dose tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV, better known with the brand name of Atripla) were found in a randomised clinical trial published in AIDS by Dr Rita Bellagamba and colleagues at the Italian National Institute of Infectious Diseases.

While levels of efavirenz in plasma concentrations showed a significant decrease in the alternate-day dosing group, this did not significantly affect viral suppression.

Researchers are looking at the possibility of reduced doses of antiretrovirals with long half-lives, such as TDF/FTC/EFV. While efavirenz-based treatment is not as widely used in high-resource settings – due to concerns over neuropsychological symptoms and possible suicidal ideation/suicide – it is still widely used in developing countries, and with pregnant women.

Previous research included two randomised studies investigating treatment interruption using the FOTO strategy (five days on, two days off) in virally suppressed adults and young people on efavirenz-based treatment. When compared with standard schedules, there were no virological failures at 48 weeks. A proof of concept study looking at reduced dosing of TDF/FTC/EFV to three days a week showed no virological failure at 24 weeks. A recent double-blind, placebo-controlled randomised trial reported that a reduced dose of 400mg EFV was as successful at maintaining an undetectable viral load as the standard dose of 600mg at 48 and 96 weeks.

The study

The current randomised clinical trial aimed to investigate the effects of reducing combined TDF/FTC/EFV dosing to alternate days versus the standard of care regimen (taking one pill daily) after 48 weeks. Some inclusion criteria comprised: being on fixed-dose TDF/FTC/EFV, with persistent virological suppression (less than 40 copies of HIV per ml) for 6 months or more. People were excluded if they had previous virological failure, resistance to any of the medications, or if they were pregnant.

A total of 197 people from an Italian treatment centre were randomised, with 98 allocated to the daily treatment group and 99 allocated to the reduced dosing group. Of the entire sample, a large percentage of people were male (90%), with a median age of 43.2. Most of these had acquired HIV through homosexual contact (68%). The median CD4 cell count was 677 (IQR: 525-814), with the median time being on Atripla 38.3 months (IQR: 23.3-55). Individuals had been living with HIV for a median of 6.8 years. The two groups were not significantly different, except that there was a higher proportion of males on the TDF/FTC/EFV regimen for a longer duration in the daily treatment group. Baseline efavirenz plasma concentrations in both groups were similar with a median of 2421ng/ml.

The study included therapeutic drug monitoring to measure efavirenz concentrations in plasma at baseline and at 48 weeks. Participants were sent text messages with reminders to take their doses. The main outcome was virological failure at week 48 (defined by a viral load of more than 40 copies/ml) or treatment interruption.


A high percentage in both groups showed successful viral suppression at 48 weeks (97% in the daily group and 94% in the alternate-day dosing group), with a -3% overall risk difference (95% CI: -8.86-2.86%). This was not a statistically significant difference.

Virological failure was reported in one person from the daily dosing group (1%) and three people from the alternate day dosing group (3%). In addition, five people had withdrawn from the study.

Of those who experienced treatment failure, all four cases had a low level viral load rebound (less than 250 copies/ml); all reported more than 95% adherence. The three people in the alternate-day group were switched to daily TDF/FTC/EFV with adherence recommendations. The person in the daily dosing group had experienced low efavirenz plasma levels (less than 1000ng/ml) at failure and was prescribed a new drug regimen of TDF/FTC/elvitegravir/cobicistat (despite not being resistant to efavirenz). At 12 month follow-up, all these four people were virally suppressed.

Secondary outcome differences were noted in terms of CD4 levels and efavirenz plasma concentrations: median CD4 cell increase from baseline to week 48 was 29.4 cells/mm3 (95% CI: 2.5-56.4) in the daily dosing group and 61 cells/mm3 (95% CI: 32.1-89.9) in the alternate-day dosing group. More research is required to understand the larger increase of CD4 cells in the alternate-day group, but it could be linked to reduced EFV toxicity.

Median change of efavirenz concentration at week 48 from baseline was -6.5 ng/ml (95% CI: -103--55) in the daily dosing group and -1124 ng/ml (95% CI: -1375--928) in the alternate-day group.

There were no significant differences between the groups in terms of cholesterol or triglyceride changes and neuropsychological symptoms (such as sleep quality, anxiety and dizziness).

Self-reported adherence was higher for the alternate-day group (86% vs 73% for the daily dosing group), with significant differences at 12, 24 and 36 weeks.


Despite a significant decrease in efavirenz levels in the alternate-day dosing group, both groups were able to maintain high levels of viral suppression. Of the people who experienced virological failure, only one required a complete change of regimen and all were virally suppressed at 12 month follow-up. Adherence was significantly better in the alternate-day dosing group.

As many people living with HIV, especially in low-resource settings, continue to take medications with long half-lives such as TDF/FTC/EFV, these findings are encouraging as they suggest that alternate-day dosing may be a realistic option for many individuals who fit the profile of participants in this study. Benefits include reduced costs and potentially better adherence.

Participants will be followed up to 96 weeks for further results. It is important to note that researchers excluded pregnant women from this study, and thus further research needs to be done on this group.


Bellagamba R et al. Randomized clinical trial on efficacy of fixed-dose efavirenz/tenofovir/emtricitabine on alternate days versus continuous treatment. AIDS. 33: 493-502, 2019.



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