This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. While adherence studies in HIV and other settings have focused on the importance of patient-related factors and attitudes as well as treatment-related factors, including ease of administration, dosing frequency, and especially pill burden as key contributors to adherence outcomes, it has yet to be determined whether adherence increases with once, compared to twice, daily dosing. In fact, it is not clear whether once daily dosing is preferable to twice daily dosing since the consequences of a missed dose might be considerably greater in a once daily compared with a potentially more 'forgiving' twice daily regimen. On the other hand, once daily dosing might allow widespread implementation of DOT to facilitate adherence, a strategy that would otherwise not be feasible, or might require 'modification,' such that only one of two daily doses is observed. It is also possible, however, that the advantages of DOT, clearly established for HIV in the prison setting and for tuberculosis treatment given twice or thrice weekly for a finite period, may be transient in HIV infection, which requires life-long treatment or may be offset by the inconvenience and burden of daily DOT if administered outside of an institutional setting for an indefinite treatment duration. This study will evaluate the relative contribution of reduced frequency dosing (twice versus once daily, BID versus QD) and for once-daily dosing, 24 weeks of direct observation (DOT- versus DOT+) of a potent antiretroviral regimen on the magnitude and durability of virologic suppression. It will also examine the possibility of a training effect of 24 weeks of DOT on virologic outcomes through week 48. Additional evaluations will assess early virologic outcomes in the two dosing schedules and treatment strategies and the ability of these outcomes to predict subsequent antiretroviral efficacy through week 48. The impact of reduced dosing frequency and DOT on quality of life and multiple adherence indicators, including electronic monitoring devices, will also be evaluated, together with safety, tolerance, and immunologic responses. Exploratory analyses will evaluate the feasibility of DOT, the success of which may rely on multiple factors, in a multicenter AACTG trial. The targeted population will be antiretroviral na ve. The antiretroviral agents proposed for study, stavudine extended release (d4T XR) (an investigational extended release formulation of d4T), emtricitabine (FTC) (an investigational nucleoside), and lopinavir/ritonavir (LPV/r) (a licensed protease inhibitor), were selected because of favorable pharmacokinetics (e.g., long intracellular or plasma half-life), pill burden, and the potential for once daily dosing as an alternative to conventional twice daily dosing. Drug-drug interaction data are pending or unknown at present for these agents, although there are no theoretical issues which would preclude study of these agents in combination. This study hypothesizes that once-daily treatments of a potent antiretroviral regimen may be able to improve the quality of life of persons with HIV by allowing less complicated drug regimens, without mitigating the magnitude and durability of virologic suppression. It also hypothesizes that DOT administration of a once-a-day regimen is more likely to result in viral suppression at 24 weeks than self administration of the same regimen.
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