Modified Directly Observed Antiretroviral Therapy (M-DART): An Intensive, Nurse-directed, Home-centered, Treatment Strategy to Reduce Mortality and Loss to Follow-up in High-risk HIV-infected Patients Initiating Antiretroviral Therapy

Mortality and lost to follow-up (LTFU) rates amongst adult African HIV-infected patients on antiretroviral therapy (ART) are high, especially so in the first 12 months of treatment. Although the risk factors for death and LTFU in these patients have been elucidated, specific care interventions to reduce both death and LTFU have not been reported. Therefore, there is an urgent need for evidence-based knowledge of care interventions that reduce early mortality and LTFU in HIV-infected patients on ART in sub-Saharan Africa. By informing decision-making processes on resource allocation, treatment and care emphasis-areas and planned strategies, such knowledge would provide treatment programs a great opportunity to lower HIV-related mortality while increasing the benefits of ART.

The USAID-AMPATH Partnership (AMPATH) has enrolled >118,000 HIV-infected patients across 60 urban and rural care sites in western Kenya, >65,000 of whom have initiated ART. To date, >9,000 patients have been confirmed dead, half of whom were on ART. Many more are LTFU, unknown whether they are still alive or not. AMPATH is uniquely placed to perform care intervention trials targeting reduction in mortality and LTFU because:

1. There are sufficient study subjects;
2. It has a protocol-driven care program that will enable the establishment of a control group that is cared for in a standard fashion;
3. The AMPATH Medical Record System (AMRS), a fully computerized system containing >80 million observations collected prospectively for >3.0 million visits will provide easy data storage and retrieval;
4. Experienced investigators from the Moi and Indiana University Schools of Medicine and the World Bank will ensure that the study is executed within acceptable clinical trial standards and in a timely fashion; and
5. It has effective community outreach programs which will increase the chances of the study's acceptability in the community, hence its success.

We propose to perform a randomized clinical trial that will compare the effectiveness of a home-based modified directly observed ART treatment strategy to clinic-based standard of care in reducing both mortality and LTFU soon after ART is initiated. A similar cadre of clinicians will be used for home-based as for clinic-based care in order to enhance comparability of outcomes. A cost effectiveness analysis of the intervention will be performed. The patients' quality of life and perceived HIV stigma will be assessed at study enrollment, 24 and 48 weeks. We will perform the study in two of the remotest AMPATH care sites that have very high HIV-prevalence in the hope that the study's results, if positive, will impact care in communities that need it the most.

2. Specific Aims High mortality and LTFU rates soon after HIV-infected patients initiate ART are two major challenges facing HIV treatment and care programs in sub-Saharan Africa. In the first year of ART, mortality in African patients is as high as 26% despite appropriate treatment. The majority of these deaths occur in the first six months. This mortality rate is 5 - 8 times higher than for similar patients in the developed world. The risk factors for mortality in African patients initiating ART have been well elucidated. These risk factors include: late patient presentation with severe immune degradation and clinically advanced HIV disease; active or latent infections such as tuberculosis, invasive bacterial and fungal; anaemia; malnutrition; care in lower level and fee-for-service centers; male gender; and poor adherence to ART. Similarly, LTFU rates are high. Some care programs have reported LTFU rates as high as 40% in the first 12 months of ART. The risk factors for LTFU have also been reported and some mirror those for death. Recently published data indicate that unreported deaths might be the biggest reason for LTFU. With such abundant knowledge on risk factors for death and LTFU after ART initiation, what is now required is the development, implementation and evaluation of novel treatment and care strategies that target specific risk factors with the aim of mitigating these twin challenges.