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Risks and Benefits of 5 Days On/2 Days Off in the FOTO Study
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
People who took a weekend break from their regimen of efavirenz, tenofovir (TDF), and emtricitabine (FTC) made it through a 24-week study with the same viral control rate as people who took those antiretrovirals 7 days a week [1]. This small, intriguing trial took a novel slant on the goals of planned treatment interruptions.
The idea behind FOTO is that all three drugs in the regimen have long half-lives--perhaps long enough to sustain viral suppression over a 2-day drug break. That makes FOTO distinct from other treatment interruption strategies that expect--sometimes even invite--a viral rebound when people stop taking their antiretrovirals. The investigators, a group of US clinicians, suggested that "short interruptions, intended to prevent rebound viremia, may allow flexibility in dosing while preserving the benefits of virus suppression."
To test that hypothesis, they enrolled 60 people who already had a viral load below 50 copies while taking efavirenz plus TDF/FTC. They randomized them to steady therapy or to 5 days on and 2 days off. Statisticians figured that 60 study participants would provide 80% power to test whether the upper limit of a one-side 95% confidence interval for the difference in viral suppression between the two strategies exceeds 15%. If the upper limit of the confidence interval stays within 15%, the strategies are equivalent.
Twenty-five people in each 30-person group were men and 70% were white. Age averaged 42 years in the FOTO arm and 47 in the continuous-therapy control arm. CD4 counts were in the 600s. Five people in the FOTO group decided to pull out of the study early, one because of anxiety. The control group lost one member because of pregnancy and another who stopped keeping clinic appointments.
At week 24 a missing-data-equal-failure analysis figured an 83% sub-50 response rate in the FOTO group and an 80% rate in the control group, a result establishing that the FOTO strategy is not inferior to steady therapy through 24 weeks. At that point no one in either group met the study definition of failure, a confirmed viral load above 400 copies. There were 10 viral blips between 50 and 500 copies in the control group and 8 in the FOTO group. The only blip above 400 came in the control group. CD4 counts remained stable in both groups.
The researchers recorded two serious adverse events, one in each study arm. There were two adverse events considered possibly related to treatment, both of them grade 1 central nervous system side effects, insomnia and dizziness. This result hints that stopping and restarting efavirenz may predispose some people to recurrence of that drug's hallmark toxicities.
Adherence in the FOTO arm was imperfect. Eight people, or 27% of the 30 enrollees, took more than 2 days off at some point in the trial. Although that did not result in rebounding viremia, the finding may spur some worries about maintaining strict adherence with this strategy, especially in people who may be less motivated than randomized trial participants. That motivation is reflected in results of a patient survey that found a median 9.5 rating on a scale with 0 as "prefer continuous therapy" and 10 as "prefer FOTO." Three of the 30 people in the FOTO arm took more than 5 doses per week at some point.
A study as small and brief as this cannot establish FOTO as a strategy ready for rollout in the clinic. Taking Atripla 5 days a week instead of 7 will yield a measurable dollar savings, though perhaps at the expense of placing greater demands on the patient's ability to take the drugs on schedule. Remembering to do something every day of the week is probably easier for more people than remembering to do something for 5 days, then not for 2, then for the next 5, in a cycle that could last years.
Reference
1. Cohen C, Colson A, Pierone G, et al. The FOTO study: 24-week results support the safety of a 2-day break on efavirenz-based antiretroviral therapy. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract O214.
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