A cluster randomized trial of routine HIV-1 viral load monitoring in Zambia: study design, implementation, and baseline cohort characteristics

Abstract

Background: The benefit of routine HIV-1 viral load (VL) monitoring of patients on antiretroviral therapy (ART) in resource-constrained settings is uncertain because of the high costs associated with the test and the limited treatment options. We designed a cluster randomized controlled trial to compare the use of routine VL testing at ART-initiation and at 3, 6, 12, and 18 months, versus our local standard of care (which uses immunological and clinical criteria to diagnose treatment failure, with discretionary VL testing when the two do not agree).

Methodology: Dedicated study personnel were integrated into public-sector ART clinics. We collected participant information in a dedicated research database. Twelve ART clinics in Lusaka, Zambia constituted the units of randomization. Study clinics were stratified into pairs according to matching criteria (historical mortality rate, size, and duration of operation) to limit the effect of clustering, and independently randomized to the intervention and control arms. The study was powered to detect a 36% reduction in mortality at 18 months.

Principal findings: From December 2006 to May 2008, we completed enrollment of 1973 participants. Measured baseline characteristics did not differ significantly between the study arms. Enrollment was staggered by clinic pair and truncated at two matched sites.

Conclusions: A large clinical trial of routing VL monitoring was successfully implemented in a dynamic and rapidly growing national ART program. Close collaboration with local health authorities and adequate reserve staff were critical to success. Randomized controlled trials such as this will likely prove valuable in determining long-term outcomes in resource-constrained settings.

Trial registration: Clinicaltrials.gov NCT00929604.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Design of the Viral Load Study.

* Immune Reconstitution Syndrome (IRIS) is not considered evidence of clinical treatment failure. The assessment of whether a clinical event represents IRIS or a genuine incident opportunistic infection is determined locally by the clinician. Note: when clinical or immunologic criteria for therapeutic failure are met, a procedure for allocating ‘discretionary’ viral load testing is utilized. Any evident infections are investigated and treated. In cases of suspected immunologic treatment failure, the CD4+ lymphocyte count is repeated one month after treatment of infection and/or intensive adherence counseling. If the patient still meets criteria for therapeutic failure after adherence is judged to be excellent and (in cases of immunologic failure) after a repeat CD4+ lymphocyte count, HIV-1 viral load testing is performed for those patients meeting either clinical or immunologic criteria, but not both. Patients meeting both clinical and immunologic criteria for therapeutic failure are assumed to have virologic failure and the decision to change to ART regimen is made without viral load testing.

Figure 2. Detectable hazard ratio as a consequence of utilizing routine HIV-1 viral load monitoring at varying between-clinic coefficients of variation.

Calculation assumes a historical 18 month post-ART mortality rate of 15.6 per 100 years (140 patients remaining per clinic).

Figure 3. Participant screening and enrollment.

Figure 4. Participant accrual by clinic.

Superscript denotes matched clinic pairs. ‘Matero Ref.’ refers to Matero Reference clinic.