Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial

Abstract

SummaryBackgroundHIV antiretroviral therapy (ART) is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. This trial investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa.MethodsIn this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per μL starting ART were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662) by a computer-generated list. Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line ART after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per μL (LCM only). Co-primary endpoints were new WHO stage 4 HIV events or death, and serious adverse events. Non-inferiority was defined as the upper 95% confidence limit for the hazard ratio (HR) for new WHO stage 4 events or death being no greater than 1·18. Analyses were by intention to treat. This study is registered, number ISRCTN13968779.FindingsTwo participants assigned to CDM and three to LCM were excluded from analyses. 5-year survival was 87% (95% CI 85–88) in the CDM group and 90% (88–91) in the LCM group, and 122 (7%) and 112 (7%) participants, respectively, were lost to follow-up over median 4·9 years' follow-up. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6·94 [95% CI 6·33–7·60] vs 5·24 [4·72–5·81] per 100 person-years; absolute difference 1·70 per 100 person-years [0·87–2·54]; HR 1·31 [1·14–1·51]; p=0·0001). Differences in disease progression occurred from the third year on ART, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event (HR 1·12 [0·94–1·32]; p=0·19), with anaemia the most common (76 vs 61 cases).InterpretationART can be delivered safely without routine laboratory monitoring for toxic effects, but differences in disease progression suggest a role for monitoring of CD4-cell count from the second year of ART to guide the switch to second-line treatment.FundingUK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Monitoring and switching of first-line antiretroviral therapy in adult treatment cohorts in sub-Saharan Africa: collaborative analysis

“…26 The DART trial in Uganda and Zimbabwe compared three-monthly CD4 count monitoring and clinical monitoring and found higher switching rates in the CD4 monitoring arm. 27 Similarly, the ANRS 12110 trial in Cameroon reported that patients in whom VL and CD4 cell counts were measured every 6 months had higher rates of switching than patients assigned to clinical monitoring. 22 In contrast, a trial from Thailand, which compared CD4 monitoring with VL monitoring, found similar rates of switching.…”

CYP2B6 c.983T>C polymorphism is associated with nevirapine hypersensitivity in Malawian and Ugandan HIV populations

“…29 Cases were defined according to available patient records and subsequently categorized into the sub-phenotypes previously described.…”

CD4+ gain percentile curves for monitoring response to antiretroviral therapy in HIV-infected adults

“…Although virologic monitoring is the gold standard for ART monitoring, randomized control trials [5, 26, 27] found routine monitoring of CD4 count to perform similar to virologic monitoring in term of prediction of disease progression and mortality. The WHO based the preference of viral load over CD4 count monitoring on the poor accuracy of routine CD4 count monitoring for early detection of treatment failure when using the WHO definition for immunological failure [28].…”

“…Clinical trials have shown that viral load monitoring is a more sensitive and early indicator of treatment failure than CD4 monitoring [3–5]. In the United States [6], monitoring viral load is therefore recommended every 4–8 weeks until viral suppression is achieved and every 3 to 4 months thereafter during the first 2 years of ART.…”