July 13, 2004
One of the fundamental tenets of HIV patient education is that a very high level of adherence to antiretroviral therapy is essential to achieve an optimal treatment outcome. This innovative pilot study of a 5-day-on, 2-day-off (FOTO) therapy approach by Dr. Cal Cohen and colleagues at the Community Research Initiative in Boston challenges this dogma.
They are not the first group to do so. Previous work by Dr. Marc Dybul and collaborators at the National Institutes of Health used a 7-day-on, 7-day-off approach (7/7) to introduce the concept of structured intermittent therapy to the HIV research community.1,2 Despite the favorable clinical results obtained with the 7/7 treatment scheme, this dosing schedule pushed the envelope with regard to the pharmacokinetics of current antiretroviral agents, and other studies have shown higher failure rates.3 In any case, the 7/7 trials set the stage for this study of the FOTO, or 5/2, approach.
But why even consider a study that purposefully has subjects skip medication dosages 2 days a week? Wouldn't this approach be too risky, and what are the potential benefits?
One reason for the interest in intermittent treatment has to do with the financial costs of antiretroviral therapy. If successful, a FOTO treatment scheme would reduce the cost of antiretroviral therapy by 29%. The average yearly discounted cost of a typical non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen in the United States is $12,204,4 so a 5/2 approach would reduce costs to $8,665/year, for a savings of $3,539.
An additional reason to justify the study of this FOTO approach relates to potential antiretroviral toxicity. We have ample evidence of the potential development of metabolic side effects, body habitus changes and mitochondrial toxicity related to long-term therapy. It is thus reasonable to test whether a lower cumulative exposure to these agents would mitigate these adverse outcomes.
Another force driving this research involves patient preference and quality-of-life considerations. Patient surveys have indicated a strong preference for once-daily, simplified therapy.5 It would not be much of a stretch to envision that many patients on long-term therapy would be eager not to take their medications on the weekends if this approach were proven safe and effective.
The FOTO Trial
This trial was designed to test the hypothesis that subjects with viral suppression on a HAART regimen could have therapy simplified to a 5-day-on, 2-day-off schedule while maintaining virologic control.
This prospective pilot study enrolled 3 open-label treatment cohorts consisting of 10 subjects each. The first cohort consisted of subjects on efavirenz (EFV, Sustiva, Stocrin)-based therapy, the second group was anchored by protease inhibitors (PIs) and the third group received nevirapine (NVP, Viramune)-based therapy. Interim data at 24 weeks were available for all 20 of the efavirenz and PI subjects, and for 7 of the 10 subjects from the nevirapine group.
Of the 27 subjects, 23 were male, and the median age for the 3 groups was 41 years (range 28-58 years). The median CD4+ cell count was 542 cells/mm3 (range 221-1,162 cells/mm3). Of the efavirenz-treated subjects, 8 were on 2 nucleoside reverse transcriptase inhibitors (NRTIs), and 2 received 3 NRTIs. For the PI cohort, 5 subjects were on lopinavir/ritonavir (LPV/r, Kaletra) and saquinavir (SQV, Fortovase, Invirase) only; 2 were on lopinavir/ritonavir, saquinavir, and NRTIs; 2 were on nelfinavir (NFV, Viracept) plus NRTIs; and 1 was on dual PIs and an NNRTI. Of the nevirapine group, 6 subjects had 2 NRTIs added, and 1 subject was on 3 NRTIs.
The PI group did not fare well in this study. Two of the 10 subjects developed virologic rebound. Trough levels of lopinavir and saquinavir were below the level of quantification for these 2 subjects. This suggests that failure of the boosted-PI regimen in these subjects was likely to have been caused by pharmacokinetic considerations. Both of these individuals re-suppressed to undetectable levels of HIV RNA after switching back to continuous treatment.
In contrast, the results in the NNRTI arms of this study were impressive: 10 of 10 subjects remained undetectable at 24 weeks on efavirenz, and 7 of 7 were undetectable on nevirapine. There were several instances of transient viral blips, but all subjects re-suppressed and no resistance was detected.
In terms of quality of life and patient preference, the results were as expected. The subjects in this trial expressed an overwhelming preference for the 5/2 schedule and reported improved quality of life. There was also a non-significant trend toward improvement in lipid levels.
The successful outcomes in the NNRTI groups may be related to the favorable pharmacokinetic attributes of these medications. Significant levels of efavirenz and nevirapine have been shown to remain in the blood for more than a week after discontinuation. Of course, this long half-life cuts both ways, and is the reason for the high rate of the development of resistance to nevirapine when it is given as monotherapy to reduce the risk of maternal-fetal HIV transmission in the developing world. But this preliminary study suggests that, when buttressed by NRTIs, an NNRTI-based regimen may pack sufficient punch to allow a 5/2 dosing schedule.
This is an important report on an innovative treatment strategy. If the positive results from this study hold up over time, and if confirmed by similar results from large randomized trials, the impact on HIV management could be enormous. Beyond cost savings, reduced toxicity and patient preference, this approach would also reduce barriers to implementation of directly observed therapy (DOT) programs. One of the current challenges with DOT administration is arranging for weekend staff coverage; a 5/2 schedule would solve this common problem.
One thing that concerns me is the potential for research of this nature to sow confusion in the HIV adherence educational community. This is not to say this line of research is not important; quite the contrary, studies like this must be conducted. However, we have been consistently communicating that one must never miss an antiretroviral dose, and now we have this curveball to contend with. We need to stress to the community that 5/2 is an experimental approach (don't try this at home!), and the message that no dose should be skipped should not be changed.
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