Super learner analysis of real-time electronically monitored adherence to antiretroviral therapy under constrained optimization and comparison to non-differentiated care approaches for persons living with HIV in rural Uganda

Introduction Real-time electronic adherence monitoring (EAM) systems could inform on-going risk assessment for HIV viraemia and be used to personalize viral load testing schedules. We evaluated the potential of real-time EAM (transferred via cellular signal) and standard EAM (downloaded via USB cable) in rural Uganda to inform individually differentiated viral load testing strategies by applying machine learning approaches. Methods We evaluated an observational cohort of persons living with HIV and treated with antiretroviral therapy (ART) who were monitored longitudinally with standard EAM from 2005 to 2011 and real-time EAM from 2011 to 2015. Super learner, an ensemble machine learning method, was used to develop a tool for targeting viral load testing to detect viraemia (>1000 copies/ml) based on clinical (CD4 count, ART regimen), viral load and demographic data, together with EAM-based adherence. Using sample-splitting (cross-validation), we evaluated area under the receiver operating characteristic curve (cvAUC), potential for EAM data to selectively defer viral load tests while minimizing delays in viraemia detection, and performance compared to WHO-recommended testing schedules. Results In total, 443 persons (1801 person-years) and 485 persons (930 person-years) contributed to standard and real-time EAM analyses respectively. In the 2011 to 2015 dataset, addition of real-time EAM (cvAUC: 0.88; 95% CI: 0.83, 0.93) significantly improved prediction compared to clinical/demographic data alone (cvAUC: 0.78; 95% CI: 0.72, 0.86; p = 0.03). In the 2005 to 2011 dataset, addition of standard EAM (cvAUC: 0.77; 95% CI: 0.72, 0.81) did not significantly improve prediction compared to clinical/demographic data alone (cvAUC: 0.70; 95% CI: 0.64, 0.76; p = 0.08). A hypothetical testing strategy using real-time EAM to guide deferral of viral load tests would have reduced the number of tests by 32% while detecting 87% of viraemia cases without delay. By comparison, the WHO-recommended testing schedule would have reduced the number of tests by 69%, but resulted in delayed detection of viraemia a mean of 74 days for 84% of individuals with viraemia. Similar rules derived from standard EAM also resulted in potential testing frequency reductions. Conclusions Our machine learning approach demonstrates potential for combining EAM data with other clinical measures to develop a selective testing rule that reduces number of viral load tests ordered, while still identifying those at highest risk for viraemia.