Routine versus clinically driven laboratory monitoring of HIV antiretroviral A

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

HIV 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 antiretroviral therapy had an important long-term effect on clinical outcomes in Africa. In this open, non-inferiority trial in three centres in Uganda and one in Zimbabwe, 3321 symptomatic, antiretroviral therapy-naive, HIV-infected adults with CD4 counts less than 200 cells per muL starting antiretroviral therapy 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 laboratory and clinical monitoring group, results were available to clinicians; in the clinically driven monitoring group, results (apart from CD4-cell count) could be requested if clinically indicated and grade 4 toxicities were available. Participants switched to second-line antiretroviral therapy after new or recurrent WHO stage 4 events in both groups, or CD4 count less than 100 cells per muL (laboratory and clinical monitoring 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. Two participants assigned to clinically driven monitoring and three to laboratory and clinical monitoring 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 clinically driven monitoring versus 356 (21%) laboratory and clinical monitoring 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 antiretroviral therapy, whereas higher rates of switch to second-line treatment occurred in LCM from the second year. 283 (17%) participants receiving clinically driven monitoring 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). Antiretroviral therapy 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 antiretroviral therapy to guide the switch to second-line treatment.

These findings, presented at the International AIDS Society conference in Cape Town in July 2009 are fully described here, complementing the excellent film produced by Tom Gibb (http://www.youtube.com/MRCcomms#p/u/1/MSyFmbiR-Hc). The results of this trial, designed to determine whether clinician monitoring of signs and symptoms without knowledge of CD4 count was not inferior to similar monitoring with knowledge of CD4 test results, suggest that once eligibility for antiretroviral treatment is determined, clinically driven monitoring holds the fort well for the first 2 years of treatment, freeing up resources and allowing extension of treatment access to more remote areas with no laboratory infrastructure.