Opportunities to reduce early antiretroviral therapy mortality in sub-Saharan Africa through improved tuberculosis case-finding and retention in HIV-TB care

Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality, including among people living with HIV (PLHIV) starting antiretroviral therapy (ART). This thesis explores opportunities for reducing PLHIV mortality in sub-Saharan Africa. Firstly, a systematic review of eight Xpert MTB/RIF (Xpert) impact trials found that lack of Xpert impact on mortality was mainly due to higher empiric TB treatment rates in microscopy versus Xpert arms. Secondly, the Botswana XPRES trial evaluated the effect of an intervention package comprising (1) support for intensified TB case finding (ICF), (2) strengthened tracing to support retention, and (3) Xpert replacing sputum-smear microscopy on early (6-month) ART mortality. Strengthened ICF and retention were associated with about 23% lower 6- month mortality. No mortality benefit of Xpert replacing microscopy was observed. Thirdly, to identify PLHIV at highest risk of early ART mortality, CD4-independent and - dependent scores were derived from XPRES data and externally validated. Sensitivity of CD4-independent score ≥4 in predicting mortality (86%) was twice that of WHO stage alone (48%). Both CD4-independent score ≥4 and CD4-dependent score ≥5 had similar sensitivity but higher specificity than WHO-recommended advanced HIV disease criteria (i.e., CD4 <200/μL or WHO stage III/IV). Finally, a TB risk score for PLHIV was derived from XPRES data and validated on three external datasets, with the aim of increasing (1) detection of asymptomatic TB, and (2) sensitivity to exclude TB prior to TB preventive therapy. In the external datasets, TB risk score ≥2 had higher sensitivity (87-97%) than the WHO four-symptom screening rule (80- 94%) but lower specificity (12-58% versus 16-70%). In conclusion, strengthening TB screening and retention in care could reduce early ART mortality in sub-Saharan Africa. In addition, early mortality and TB risk scores could help clinicians better detect and differentiate risk and should be further evaluated.