Antiretroviral therapy (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. These are the conclusions of an Article published Online First and in an upcoming edition of The Lancet, written by the DART Trial Team, led by Dr A Sarah Walker, MRC Clinical Trials Unit, London, UK, and colleagues*.
ART is often managed without routine laboratory monitoring in Africa; however, the effect of this approach is unknown. In this study, the authors investigated whether routine toxicity and efficacy monitoring of HIV-infected patients receiving ART had an important long-term effect on clinical outcomes in Africa.
This randomised trial took place in three centres in Uganda and one in Zimbabwe. A total of 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). 3316 of these patients were included in the analysis (3 were duplicates and 2 were ineligible). Haematology, biochemistry, and CD4-cell counts were done every 12 weeks. In the LCM group, all laboratory results were available to clinicians; in the CDM group, results (apart from CD4-cell count) could be requested if clinically indicated and in the event of serious (grade 4) toxicity events occurring.
Participants switched to second-line ART after new or recurrent WHO clinical 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. The authors found that 5-year survival was 87% in the CDM group and 90% in the LCM group, and 7% of participants in both groups were lost during the median follow-up of almost five years. 459 (28%) participants receiving CDM versus 356 (21%) LCM had a new WHO stage 4 event or died (6•94 vs 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. 283 (17%) participants receiving CDM versus 260 (16%) LCM had a new serious adverse event, with anaemia being the most common (76 vs 61 cases).
The authors say: "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 add: "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 conclude: "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 accompanying Comment, Dr Andrew Phillips, University College London, UK, and Dr Joep van Oosterhout, University of Malawi College of Medicine, Blantyre, Malawi, say: "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."
For Caroline Grundy in the DART trial team, please contact Lucy Goodchild, Imperial College London Press Office T) +44 (0) 20 7594 6702 / +44(0) 7803 886 248 E) l.goodchild@imperial.ac.uk
Medical Research Council Press Office T) +44 (0) 20 7637 6011 E) press.office@headoffice.mrc.ac.uk
Dr Andrew Phillips, University College London, UK. T) +44 (0) 7738 181457 E) a.phillips@pcps.ucl.ac.uk
For full Article and Comment, see: http://press.thelancet.com/dart.pdf
Notes to editors: *The DART research 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.
Journal
The Lancet