DART Trial Team. Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): A randomised non-inferiority trial. Lancet. 2010 Jan 9;375(9709):123-31.
Because of limited resources and poor health infrastructure, antiretroviral therapy (ART) programs in Africa do not include routine laboratory monitoring for efficacy or toxicity of treatment. Studies have not been published that compare efficacy or toxicity with clinical and laboratory monitoring for response to therapy. Information about the effect of monitoring for response to therapy is needed to set policy on standards of care in ART programs and strategies for expansion of care programs.
To compare outcomes among persons who received routine monitoring of CD4 cell counts for treatment efficacy and hematology and biochemistry for safety with outcomes among persons who did not receive laboratory monitoring
HIV treatment centers in Kampala and Mulago, Uganda and Harare, Zimbabwe
Randomized non-inferiority trial
ART-naïve, HIV-infected adults with symptomatic (World Health Organization [WHO] stages 2-4) disease and CD4 cell counts <200 cells/µL
Progression to a new WHO stage 4 event or death or serious adverse event not related solely to HIV, such as fatal or life-threatening events
All participants were given triple-drug ART (zidovudine-lamivudine plus tenofovir, abacavir, or nevirapine) and randomized
to clinically driven monitoring (CDM) or laboratory plus clinical monitoring (LCM). Randomization was stratified by CD4 count (0-99 cells/µL and 100-199 cells/µL) and first-line ART and was done using computer-generated sequential numbers that the clinicians received by telephoning the trials center. All participants saw a physician and had a routine full blood count with white cell differential, lymphocyte subsets (CD4, CD8), and liver and renal function tests (bilirubin, urea, creatinine, and aspartate aminotransferase and alanine transaminase) at screening, weeks 4 and 12, and every 12 weeks thereafter. Test results were provided to clinicians for participants in the LCM group but not for those in the CDM group, unless results indicated severe toxicity or were requested for clinical reasons. Clinicians for all participants could request diagnostic tests other than total and CD4 lymphocytes for the CDM group. Substitution of ART was permitted within classes for adverse events. Changing to second-line ART was based upon clinical criteria for all participants or on laboratory criteria for participants in the LCM group. Participants were followed from enrollment (Jan 15, 2003 through Oct 24 2004) until Dec 31, 2008. Laboratory results then were provided for participants in the CDM group.
A total of 3316 participants were included in the intention-to-treat analysis. Baseline characteristics were similar in the
two groups. Median follow-up was 4.9 years in both groups. Seven percent of participants were lost to follow-up. At the end of the study, 1346 (81%) participants in the CDM group and 1295 (78%) participants in the LCM group were on first-line ART, including 17% of people in the CDM and LCM groups who changed drugs within the same class. Self-reported adherence was similar in the two groups: 3.5% and 3.3% of participants in the CDM and LCM groups, respectively, reported missed pills. Changes to second-line ART occurred in 19% of CDM participants and 22% of LCM participants.
New WHO stage 4 condition or death occurred in 28% of CDM and 21% of LCM participants (hazard ratio [HR] 6.94, 95% confidence interval [CI]: 6.33-7.60 and HR 5.24, 95% CI: 4.72-5.81 per 100 person-years, respectively, and a relative hazard ratio of 1.31 (95% CI: 1.14-1.51, P=0.001). New WHO stage 4 event-free survival at five years was 72% (95% CI: 70%-74%) in the CDM group and 78% (95% CI: 76%-80%) in the LCM group. There were 218 (13%) deaths in the CDM group and 164 (10%) deaths in the LCM group (HR 2.9, 95% CI: 2.6-3.4 vs. HR 2.2, 95% CI: 1.9-2.5 per 100 person-years, respectively) and absolute difference was 0.77 per 100 person-years. Five-year survival was 87% (95% CI: 85%-88%) in the CDM group compared to 90% (95% CI: 88%-91%) in the LCM group.
CD4 counts increased over the duration of the trial: 82% of CDM and 86% of LCM had CD4 counts >200 cells/µL at 5.1 years. Median CD4 counts for the 2337 participants last seen alive on first-line ART was 339 cells/µL (interquartile range [IQR] 225-467 cells/µL) in the CDM group and 372 cells/µL (IQR 251-499 cells/µL) in the LCM group, with 81 of 1178 (7%) versus 22 of 1159 (2%), respectively, having CD4 counts of <100 cells/µL. Serious adverse events occurred in 17% of the CDM participants and 16% of the LCM participants. Differences in disease progression occurred from the third year on ART, whereas higher rates of switching to second-line treatment occurred in LCM participants from the second year. Two hundred eighty-three (17%) participants receiving CDM versus 260 (16%) receiving LCM had a new serious adverse event (HR 1.12, 95% CI: 0.94-1.32; P=0.19), with anemia being the most common (76 vs. 61 cases).
These findings indicate that ART can be provided safely and effectively without routine laboratory monitoring, but CD4 cell count monitoring from the second year may be advantageous for changes in ART.
This was a high-quality randomized trial: the methods for group allocation were appropriate, loss to follow-up was accounted for and relatively small, and the authors used an intention-to-treat analysis. Blinding of the outcome assessor was not possible.
The findings from this study have very important implications for current ART programs and for the expansion of such programs. Because the outcomes in the two groups were similar, treatment can be managed without routine laboratory monitoring of toxicity and efficacy of treatment. Thus, delivery of ART can be expanded into areas where laboratory tests are difficult to include as part of routine care. There does appear to be a small benefit to CD4 monitoring in the second year of treatment to determine the need for changing to second-line ART. Avoiding routine laboratory tests will allow more funds to be directed toward procuring and providing ART and clinical care.
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