An article published Online First and in an upcoming edition of The Lancet reports that antiretroviral therapy (ART) can be delivered safely without routine laboratory monitoring for toxic effects. However, the 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. The article is the work of the DART Trial Team, led by Dr A Sarah Walker, MRC Clinical Trials Unit, London, UK, and colleagues.

In Africa, ART is often managed without routine laboratory monitoring; but, the effects of this approach are unclear. The authors investigated in this study whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa.

This randomized trial was carried out in three centres in Uganda and one in Zimbabwe. A total of 3,321 took part in the trial. They were all symptomatic, ART-naive, HIV-infected adults with CD4 counts less than 200 cells per μL starting ART. They were randomly assigned to laboratory and clinical monitoring (LCM; n=1659) or clinically driven monitoring (CDM; n=1662). A total of 3,316 of these patients were included in the analysis (three were duplicates and two were ineligible). Haematology, biochemistry, and CD4-cell counts were done every twelve weeks. In the LCM group, all laboratory results were available to clinicians. However in the CDM group, results could be requested if clinically indicated and in the event of serious (grade 4) toxicity events occurring (apart from CD4-cell count).

In both groups participants switched to second-line ART if there were new or recurrent WHO clinical stage 4 events, 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.

The authors found that five-year survival was 87 percent in the CDM group and 90 percent in the LCM group. In both groups, 7 percent of participants were lost during the median follow-up of almost five years. A total of 459 (28 percent) participants receiving CDM compared to 356 (21 percent) LCM had a new WHO stage 4 event or died (6•94 compared to 5•24 per 100 person-years; absolute difference 1•70 per 100 person-years). 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. A total of 283 (17 percent) participants receiving CDM versus 260 (16 percent) LCM had a new serious adverse event. Of these undesirable events, anaemia was the most common (76 compared to 61 cases).

The authors explain: “The results clearly show that first-line ART can be delivered safely without routine biochemistry and haematology monitoring for toxic effects, but that routine CD4-cell count monitoring has a small but significant benefit in terms of disease progression and mortality, probably owing to slightly earlier switching to second-line ART.”

They comment: “DART results have major implications for ART programmes in Africa at a time when there is uncertainty about long-term funding and sustainability and when most people still cannot access treatment. We have shown that routine laboratory monitoring for toxic effects in HIV patients receiving ART has no benefit. ART can be delivered safely with good quality clinical care, allowing treatment delivery to be decentralised.”

They write in conclusion: “Small differences in disease progression suggest a role for CD4-cell testing from the second year on ART to guide the switch to second-line ART and should encourage accelerated development of simpler, cheaper, point-of-care CD4 tests. Laboratories will remain important for assessment of eligibility for ART, in terms of CD4-cell count and contraindications for specific drugs, and for diagnosis and management of opportunistic infections and clinical toxicity. With less need to provide routine monitoring, particularly for toxicity, funding can be focused on drug procurement, strengthening of diagnostic laboratory services, and training and supervision for health-care workers to foster quality clinical monitoring, to support scale-up of ART rollout to rural Africa where 60% of the HIV-infected population live.”

In an associated note, Dr Andrew Phillips, University College London, UK, and Dr Joep van Oosterhout, University of Malawi College of Medicine, Blantyre, Malawi, remark: “The DART trial clearly shows that expansion of antiretroviral therapy to all those in need must be the very highest priority. Such expansion is logistically difficult, but we must not allow other concerns about antiretroviral delivery to detract from meeting that need.”

“Routine versus clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa (DART): a randomised non-inferiority trial”
DART Trial Team (included the MRC Clinical Trials Unit in London the Joint Clinical Research Centre in Kampala, The Infectious Diseases Institute in Kampala, the MRC/UVRI Uganda research Unit on AIDS in Entebbe, the University of Zimbabwe Clinical Trials Centre in Harare and Imperial College London.)
DOI: 10.1016/S0140-6736(09)62067-5
The Lancet

Written by Stephanie Brunner (B.A.)