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

Abstract

Background: 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 ART had an important long-term effect on clinical outcomes in Africa.

Methods: In 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 microL 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 microL (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.

Findings: Two 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).

Interpretation: ART 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.

Funding: UK Medical Research Council, the UK Department for International Development, the Rockefeller Foundation, GlaxoSmithKline, Gilead Sciences, Boehringer-Ingelheim, and Abbott Laboratories.

Figure 1

Trial profile CDM=clinically driven monitoring. LCM=laboratory and clinical monitoring. ART=antiretroviral therapy. *Main reason for ineligibility. † 221 (55%) participants subsequently returned and were rescreened. ‡One participant had taken ART before starting the trial, and was not prescribed trial drugs or followed up; one individual without a consent form at monitoring defaulted before 8 weeks.

Figure 2

Substitution in first-line ART and switch to second-line ART Percentages of participants still on first-line antiretroviral therapy (ART) and ever substituted to an alternate first-line regimen were estimated with cumulative incidences (deaths on first-line therapy were treated as competing risks, as was switch to second-line ART for first-line substitutions). Cause-specific hazard models in which deaths (and switch to second-line ART for first-line substitutions) are censored were used to calculate hazard ratios, stratified by randomisation factors. HR=hazard ratio. CDM=clinically driven monitoring. LCM=laboratory and clinical monitoring.

Figure 3

Clinical disease progression (A) and adverse events (B) All hazard ratios were stratified according to randomisation factors, and p values were calculated with the log-rank test. Number needed to monitor for 1 year to avoid one (first) event was 130 (death) and 59 (new WHO stage 4 event of death) participants. Survival p values were 0·95 at 1 year, 0·92 at 3 years, and 0·90 at 5 years for laboratory and clinical monitoring (LCM) group; 0·94, 0·90, and 0·87 for clinically driven monitoring (CDM) group; and 0·55, 0·18, and 0·08 for the Entebbe cohort, respectively. HR=hazard ratio. ART=antiretroviral therapy. *Data from HIV-infected population of similar disease stage between 1996 and 2000.

Figure 4

CD4-cell counts (A) Mean absolute CD4-cell count with time (unadjusted). CD4-cell counts were done every 12 weeks—small decreases at weeks 60, 84, and 108 are a result of the structured treatment interruption randomisation (terminated). Increase in mean CD4 count in the first 12 weeks was 102 cells per μL (95% CI 98–106) in clinically driven monitoring (CDM) group versus 103 cells per μL (99–107) in laboratory and clinical monitoring (LCM) group (p=0·77). Mean increase per year was subsequently 35 cells per μL (33–37) in CDM group and 42 cells per μL (40–44) in LCM group (p<0·0001). (B) Last CD4-cell count on first-line antiretroviral therapy (ART) or at switch to second-line ART. Number of deaths was 82 during the first year on first-line ART and 37 in the second year in LCM group and 97 during the first year on first-line ART and 32 in the second year in CDM group.