July 9, 2002
The importance of adherence to combination antiretroviral therapy is well established. The ability of many patients to adhere to even simple combination therapy is often poor, particularly among inner city persons of minority descent. This may be because of social problems, substance abuse, or a lack of information about HIV.
One way to improve adherence is to administer medications in a directly observed fashion (directly observed therapy, DOT), where medical professionals witness patients taking their medications. A recent example of success with DOT was presented by Dr. Margaret Fischl from the University of Miami where prison inmates were given their HIV medications in a DOT fashion. In this study, 100 percent of patients receiving DOT achieved undetectable plasma HIV viral loads after one year on study (Fischl M. 8th Conference on Retroviruses and Opportunistic Infections, 2001 abstract 528). Having inmates receive DOT is one thing, giving non-institutionalized outpatients DOT poses additional challenges.
In this series of presentations of an investigation led by Dr. D. Jayaweera from the University of Miami, 22 antiretroviral-naive HIV-1 infected persons at risk for non-adherence (current injection drug use, delayed time of presentation with HIV or poor HIV-specific knowledge, history of missed appointments or frequent emergency room use) were given a combination therapy of ddI (Videx, 400 mg), 3TC (lamivudine, 300 mg, Epivir), ritonavir (Norvir, 200 mg) and amprenavir (Agenerase, 1200 mg) as once-daily DOT.
Studies of the drug levels of amprenavir were performed to confirm that this dosing combination would produce sufficient levels of drug. Drug levels produced by this once-daily boosted protease inhibitor were consistent throughout the study. Significantly, the drug levels were five- to six-fold higher than levels seen in previous studies of twice-daily unboosted amprenavir, and six- to eight-fold higher than the EC90 (effective concentration required to inhibit 90 percent of viral growth).
These data demonstrate that effective drug levels can be achieved with ritonavir-boosted, once-daily amprenavir. Additionally, drug levels were largely the same at the end of 24 weeks of therapy, implying that there was no significant induction or inhibition of the liver metabolism of the protease inhibitors.
There was significant drop out from the study, with five of 22 persons not completing week 24 analyses, illustrating the difficulty of adherence and follow up in this patient population. Indeed, the pill burden (number and volume) of this regimen is quite large, undoubtedly contributing to study discontinuation. Despite this possibility, there were no serious side effects noted in any of the study patients.
Nevertheless, the combination was successful for the majority of persons who completed the 24 weeks of study: 76 percent of subjects had viral loads less than 400 copies/mL, with a viral load decrease that was greater than three log. Very importantly, CD4+ counts increased from a median of 20 cells/mm3 to a remarkable 157 cells/mm3 at week 24.
These data add to the growing literature about once-daily and/or directly observed therapy. Considerable interest in once-daily therapies stem from the simplicity of dosing frequency -- though often compromised by increased pill counts at dosing. Once-daily boosted amprenavir was shown in this study to produce adequate drug levels. The use of once-daily ritonavir/amprenavir has received renewed attention, particularly in light of the development of an amprenavir prodrug, called 908. 908 should improve on the pill count and tolerability of the current formulation of amprenavir (Agenerase).
For the patients who completed the 24 weeks on study, the performance of this entirely once-daily, directly-observed therapy was very good, especially in light of the extremely low initial CD4+ counts. Indeed, the CD4+ count rises were of particular interest, since previous studies of protease inhibitors have suggested that persons with the lowest initial CD4+ counts usually don't have as much CD4+ cell recovery as persons with higher cell levels. These data imply that the novel combination of ddI/3TC/RTV/APV is very potent and well tolerated.
Furthermore, it helps to recall that many earlier studies of combination therapies excluded patients like those studied by Jayaweera because of the likelihood of treatment non-adherence; efforts like this study should be applauded for their attempts to evaluate and improve the care for some of the most difficult-to-treat persons in our communities. Once-daily DOT might be a way to provide the highest degree of drug potency and ensure the highest likelihood of long-term treatment success.
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