By Liz Highleyman

The availability of antiretroviral agents with long half-lives provides a rationale for evaluating less-than-daily dosing, Cal Cohen from the Community Research Initiative of New England and colleagues with the FOTO (Five On, Two Off) study noted as background.

As previously reported, 24-week results from a randomized study demonstrated that using specific antiretroviral drugs for 5 consecutive days each week followed by 2 days off was non-inferior to standard 7 days per week therapy with regard to maintaining virological suppression. In the present study, this strategy was extended and the researchers assessed its durability over 48 weeks.

They hypothesized that "Brief treatment interruption will positively address aspects of 'pill-fatigue' and costs associated with daily treatment, and may address long-term toxicity issues."

FOTO enrolled 60 patients with stable CD4 count of at least 200 cells/mm3 and virological suppression (< 75 copies/mL for at least 3 months, < 50 copies/mL at study screening). All were taking efavirenz, tenofovir, and emtricitabine -- the drugs in the Atripla combination pill -- for at least 3 months. Most (83%) were men, 70% were white, 22% were black, and the mean age was 44 years. People with hepatitis B coinfection were excluded because stopping tenofovir and emtricitabine, which are active against both viruses, could have detrimental effects.

Participants were randomly assigned to stay on daily therapy or switch to the FOTO schedule, with most taking the 2-day treatment breaks on weekends. If no virological failure occurred, patients initially assigned to the daily treatment arm could cross over to the FOTO schedule after week 24.

The primary endpoint compared rates of virological suppression at week 24; with 60 patients, the study had 80% power to demonstrate non-inferiority (<15% difference in viral suppression rates). Durability was assessed at 48 weeks.

Results

	50 patients (23 initially assigned to the FOTO arm and 27 who crossed over from the daily arm) were followed through week 48.
	The 10 patients who discontinued the study prior to week 48 all had a viral load < 50 copies/mL at their last visit.
	At week 24, 100% of patients in the FOTO arm and 86% in the daily therapy arm had HIV RNA < 50 copies/mL.
	Among the 50 participants who remained in the study, no cases of virological failure (confirmed viral load > 400 copie/mL) were observed during 48 weeks.
	At week 48 on FOTO, 45 of 50 patients (90%) had viral load < 50 copies/mL.
	5 individuals on FOTO experienced viral "blips" (viral loads between 50 and 500 copies/mL) at week 48, but all were back below 50 copies/mL on their next test.
	Overall, efavirenz levels were higher among patients taking daily therapy.
	However, efavirenz trough levels (lowest level between doses) measured in a subset of participants during the 2 days off treatment showed that most had sustained levels above the therapeutic target of 1000 ng/mL.
	Patients with efavirenz levels that fell below this target 1 or more times still maintained viral suppression.
	A small number of patients who reported missing Monday doses, thus taking 3 days off, also still maintained viral suppression.
	Adverse events were uncommon and mild, including 3 reports of sleep disturbances in the FOTO arm.
	Similar proportions of patients in the FOTO and daily therapy arms (8% vs 11% at week 24) reported missing 1 or more medication doses (in the FOTO group, about the same number mistakenly took an extra dose on an off day).
	The median score on a preference questionnaire -- on a scale of 0 (prefer daily therapy) to 10 (prefer taking days off) -- after 4 weeks on FOTO was 9.5.
	The cost savings of the FOTO strategy was 28.5%.

The FOTO strategy "successfully maintained virologic suppression in all patients through 48 weeks," the researchers concluded.

"There was a strong preference to take 2-days off treatment per week even when on a simple one-pill once-daily regimen," they stated. "The 28% cost savings for this strategy has broad potential implications for the developed and developing world."

Community Research Initiative of New England, Boston, MA, and Springfield, MA; AIDS Research and Treatment Center of the Treasure Coast, Fort Pierce, FL; Orlando Immunology Center, Orlando, FL; Kinder Medical Group, Miami, FL; Whitman-Walker Clinic, Washington, DC; Baystate Medical Center, Springfield, MA; University of Liverpool, Liverpool, UK.

8/7/09

Reference
C Cohen, A Colson, G Pierone, and others. 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. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2009). July 19-22, 2009. Cape Town, South Africa. Abstract MoPeB063.

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