Free HIV Antiretroviral Therapy Enhances Adherence among Individuals on Stable Treatment: Implications for Potential Shortfalls in Free Antiretroviral Therapy

Objective: To estimate the population-level causal effect of source of payment for HIV medication on treatment adherence using Marginal Structural Models. Methods: Data were obtained from an observational cohort of 76 HIV-infected individuals with at least 24 weeks of antiretroviral therapy treatment from 2002 to 2007 in Kampala, Uganda. Adherence was the primary outcome and it was measured using the 30-day visual analogue scale. Marginal structural models (MSM) were used to estimate the effect of source of payment for HIV medication on adherence, adjusting for confounding by income, duration on antiretroviral therapy (ART), timing of visit, prior adherence, prior CD4+ T cell count and prior plasma HIV RNA. Traditional association models were also examined and the results compared. Results: Free HIV treatment was associated with a 3.8% improvement in adherence in the marginal structural model, while the traditional statistical models showed a 3.1–3.3% improvement in adherence associated with free HIV treatment. Conclusion: Removing a financial barrier to treatment with ART by providing free HIV treatment appears to significantly improve adherence to antiretroviral therapy. With sufficient information on confounders, MSMs can be used to make robust inferences about causal effects in epidemiologic research

Steady state bioequivalence of generic and innovator formulations of stavudine, lamivudine, and nevirapine in HIV-infected Ugandan adults

Background: Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune®) or the corresponding brand formulations (Epivir®, Zerit®, and Viramune®). Methodology/Principal Findings: An open-label, randomized, crossover study was carried out in 18 HIV-infected Ugandan subjects stabilized on Triomune-40. Subjects received lamivudine (150 mg), stavudine (40 mg), and nevirapine (200 mg) in either the generic or brand formulation twice a day for 30 days, before switching to the other formulation. At the end of each treatment period, blood samples were collected over 12 h for pharmacokinetic analysis. The main outcome measures were the mean AUC0–12h and Cmax. Bioequivalence was defined as a geometric mean ratio between the generic and brand name within the 90% confidence interval of 0.8–1.25. The geometric mean ratios and the 90% confidence intervals were: stavudine Cmax, 1.3 (0.99–1.71) and AUC0–12h, 1.1 (0.87–1.38); lamivudine Cmax, 0.8 (0.63–0.98) and AUC0–12h, 0.8 (0.65–0.99); and nevirapine Cmax, 1.1 (0.95–1.23) and AUC0–12h, 1.1 (0.95–1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters. Conclusions/Significant Findings: These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical

Steady State Bioequivalence of Generic and Innovator Formulations of Stavudine, Lamivudine, and Nevirapine in HIV-Infected Ugandan Adults

Generic antiretroviral therapy is the mainstay of HIV treatment in resource-limited settings, yet there is little evidence confirming the bioequivalence of generic and brand name formulations. We compared the steady-state pharmacokinetics of lamivudine, stavudine and nevirapine in HIV-infected subjects who were receiving a generic formulation (Triomune®) or the corresponding brand formulations (Epivir®, Zerit®, and Viramune®)., 1.1 (0.95–1.31). The generic formulation was not statistically bioequivalent to the brand formulations during steady state, although exposures were comparable. A mixed random effects model identified about 50% intersubject variability in the pharmacokinetic parameters.These findings provide support for the use of Triomune in resource-limited settings, although identification of the sources of intersubject variability in these populations is critical

Transitioning the COVID-19 response in the WHO African region: a proposed framework for rethinking and rebuilding health systems

The onset of the pandemic revealed the health system inequities and inadequate preparedness, especially in the African continent. Over the past months, African countries have ensured optimum pandemic response. However, there is still a need to build further resilient health systems that enhance response and transition from the acute phase of the pandemic to the recovery interpandemic/preparedness phase. Guided by the lessons learnt in the response and plausible pandemic scenarios, the WHO Regional Office for Africa has envisioned a transition framework that will optimise the response and enhance preparedness for future public health emergencies. The framework encompasses maintaining and consolidating the current response capacity but with a view to learning and reshaping them by harnessing the power of science, data and digital technologies, and research innovations. In addition, the framework reorients the health system towards primary healthcare and integrates response into routine care based on best practices/health system interventions. These elements are significant in building a resilient health system capable of addressing more effectively and more effectively future public health crises, all while maintaining an optimal level of essential public health functions. The key elements of the framework are possible with countries following three principles: equity (the protection of all vulnerable populations with no one left behind), inclusiveness (full engagement, equal participation, leadership, decision-making and ownership of all stakeholders using a multisectoral and transdisciplinary, One Health approach), and coherence (to reduce the fragmentation, competition and duplication and promote logical, consistent programmes aligned with international instruments)

Longitudinal Antiretroviral Adherence in HIV+ Ugandan Parents and Their Children Initiating HAART in the MTCT-Plus Family Treatment Model: Role of Depression in Declining Adherence Over Time

We conducted a study to assess the effect of family-based treatment on adherence amongst HIV-infected parents and their HIV-infected children attending the Mother-To-Child-Transmission Plus program in Kampala, Uganda. Adherence was assessed using home-based pill counts and self-report. Mean adherence was over 94%. Depression was associated with incomplete adherence on multivariable analysis. Adherence declined over time. Qualitative interviews revealed lack of transportation money, stigma, clinical response to therapy, drug packaging, and cost of therapy may impact adherence. Our results indicate that providing ART to all eligible HIV-infected 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 barrier to adherence. Further study is necessary to assess the long-term impact of this family treatment model on adherence to ART in resource-limited settings

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 populationsThis 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

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

Marginal structural model estimates vs. Traditional model estimates of the effect of source of payment for HIV medication on adherence.

*<p>adjusted for income, duration on ART, prior adherence, prior CD4+ T cell count, prior HIV RNA.</p

Multivariable regression model of source of payment for HIV medication on confounders.

<p>NOTE: Model was selected using cross-validated deletion/substitution/addition algorithm.</p>a<p>log transformed.</p