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Examining critical issues associated with human immunodeficiency virus antiretroviral therapy administration in resource-limited settings:adherence and drug quality


Human Immunodeficiency Virus (HIV) infection remains a global health problem affecting many lives especially in sub-Saharan Africa (SSA). The push by the global community towards universal access to HIV prevention, treatment, care, and support has enabled millions of individuals to start on antiretroviral therapy (ART) in resource-limited settings. However, there is concern that widespread antiretroviral use could lead to widespread drug resistance. Suboptimal adherence leading to incomplete viral suppression is the primary predictor of HIV drug resistance. Concerns have been raised about the ability of patients in resource-limited settings to maintain the high level of adherence required to produce adequate viral suppression and hence prevent the emergence of resistant strains of HIV.

The cost of antiretroviral medications is the most frequently cited barrier to adherence in resource-limited settings. Even with the recent substantial reductions in drug prices, many patients cannot afford to sustain their therapy over time. Generic antiretroviral medications (ARVs) today form the backbone of first-line regimens in developing countries. However, there are limited data on the bioavailability and bioequivalence of generic ARVs with branded pharmaceutical equivalents. While substantial effort has been put into increasing access to ART in resource-limited settings, less attention has been paid to the responsibilities of governments and international agencies to address the threat of substandard and counterfeit ARVs. The prevalence of counterfeit ARVs in resource-limited settings is not known. The Beck Depression Inventory (BDI) is a commonly used instrument to measure depressive symptoms in HIV-infected populations in SSA but it has never be validated in these populations

This dissertation is an attempt to address some of the critical issues associated with administration of ART in resource-limited settings. I explored the issues of adherence to HIV medications and ARV drug quality using data collected from patients participating in three prospective cohort studies and one cross sectional study conducted in two different HIV-infected populations in Uganda between September 2002 and December 2006. Specifically, I assessed i) the effect of source of payment for ARVs (no cost vs. self-pay) on adherence; ii) the impact on adherence of treating all HIV-infected members in a household; iii) the psychometric properties of the Beck Depression Inventory (BDI) when used in an HIV-infected population, and iv) the bioequivalence of a fixed dose combination generic drug (Triomune®) with the brand name pharmaceutical equivalents (Zerit®/Epivir®/Viramune®).

Patients receiving no cost ART had 3.8 percentage points higher adherence than those patients paying for their treatment. Excellent adherence was observed when all household members infected with HIV were treated, however adherence declined over time. Depression was associated with poor adherence. The BDI had good psychometric properties with Cronbach's alpha of 0.79 and the expected a posteriori reliability coefficient (EAP) of 0.86. Comparing generic and brandname ARVs, we found that the generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. Fifty percent of the total variability in maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) was due to between-subject variability.

These results suggest that removing a financial barrier to treatment with ART by providing no cost HIV treatment may significantly improve adherence to ART. Our results also indicate that providing free ART to all eligible members in a household is associated with excellent adherence in both parents and children. Adherence to ART among new parents declines over time, even when patients receive treatment at no cost. Depression should be addressed as a potential adherence barrier. These findings support the use of the BDI-II in assessing depressive symptoms for HIV-infected patients in sub-Saharan Africa, especially women. Finally, these findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of between-subject variability in AUC and Cmax in these populations is critical.

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