DART results show majority of HAART benefits can be achieved even without routine laboratory monitoring

The results from the DART trial, reported this week in The Lancet, provide important evidence for HAART programmes in resource-constrained settings. From commentary by Phillips & Oosterhout published alongside the results:

In much of sub-Saharan Africa, the scale-up of use of antiretroviral therapy has been so far achieved without routine laboratory monitoring of drug toxicity and efficacy. Until now, there has not been substantive evidence about the consequences of delivering antiretrovirals without such routine monitoring.

In The Lancet today, the DART Trial Team present the Development of AntiRetroviral Therapy in Africa (DART) trial. In DART at enrolment, all participants started triple-drug antiretroviral therapy and were randomised to clinically driven monitoring versus laboratory plus clinical monitoring for toxicity (haematology and biochemistry) and efficacy (CD4-cell counts). Over 5 years, the proportions who had one or more serious adverse events were almost identical, while there was a somewhat higher proportion in the group on clinically driven monitoring who had disease progression or death (28%, compared with 21% in the other group; hazard ratio 1·31, 95% CI 1·14—1·51). This benefit of laboratory plus clinical monitoring is probably due to the use of CD4 count rather than presence of clinical symptoms alone to decide on when to switch to a second-line regimen. This criterion for switching on the basis of CD4 count is just one of the CD4-count switch criteria recommended by WHO; the other criteria (on the basis of CD4-count change from baseline and from peak) are problematic to implement without a baseline CD4 count and frequent CD4 counts being available thereafter.

The other particularly striking result from DART is the 5-year survival in both groups: 87% for clinical monitoring and 90% for laboratory plus clinical monitoring. Such rates of survival are for people in whom the initial median CD4-cell count was 86 cells per μL. For comparison, the survival in the Entebbe cohort of untreated HIV-positive people in 5 years was below 10% (data presented in the DART report), which emphasises the huge clinical benefits of antiretroviral therapy. The DART Trial Team concluded from their results that antiretroviral therapy can be delivered safely with good-quality clinical care, which would allow treatment delivery to be decentralised, and that there is a role for CD4 testing from the second year on antiretrovirals to guide the switch to second-line therapy, which should encourage accelerated development of simpler and cheaper point-of-care CD4 tests. The DART investigators should be complimented for exceptional achievement by completing this important trial with such a low loss to follow-up (7%) in challenging circumstances, which shows that excellent trials can be done in Africa.

The results from DART are very important for antiretroviral programmes, no matter what their current level of routine laboratory monitoring. Programmes that currently deliver antiretrovirals without any laboratory monitoring can be reassured that the vast majority (but not all) of the potential survival benefit of such therapy can be realised with the use of such a simple approach (albeit with particularly intensive and high-quality clinical monitoring, which is a substantial challenge to achieve in routine settings throughout sub-Saharan Africa). Similarly, no antiretroviral programme should enhance laboratory monitoring at the expense of putting more people in need on these drugs. Those clinics that do use routine measurement of biochemistry and haematology can reduce their laboratory costs to enable spending on other aspects of the programme (which has already started in some programmes). Programmes that monitor people on antiretrovirals with CD4 counts should consider adopting the switch criterion used in DART of CD4 count below 100 cells per μL (ie, only this one of the WHO-recommended criteria, rather than all three), and apply this criterion to people who have been on therapy for at least 2 years. Such a delay should help to reduce the number of people in whom a switch is made when viral load is actually suppressed.

Read the commentary at The Lancet (open access; registration required)

Details on the main paper below:

The Lancet, Volume 375, Issue 9709, Pages 123 - 131, 9 January 2010

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

DART Trial Team

Summary

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 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.

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.

Read the paper at The Lancet (open access; registration required)