A randomised trial of monitoring practice and pulse antiretroviral therapy in African children with HIV infection

In industrialised countries, triple-drug Anti-Retroviral Therapy (ART) has transformed AIDS from a fatal to a chronic disease where the main issues are the effects of long-term side-effects to these drugs. ART is becoming increasingly available in resource-poor countries, following dramatic price reductions and donor commitments to provide drugs, such as the global fund for Malaria, TB and AIDS. However, ART remains out of reach for many patients in the African countries worst affected by AIDS. This is also because of the additional need for infrastructure to do blood tests for monitoring immunity levels and side-effects of drugs. These test are routinely done in industrialised countries but are expensive, require special machines and trained personnel and may not always be necessary. The DART trial is finding out whether ART can be given safely and effectively to adults with HIV by health agencies with limited ability to do monitoring. DART is also investigating whether intermittent therapy (in regular on-off cycles), which might reduce long-term side-effects as well as drug costs, is as safe and effective as continuous ART at fighting HIV/AIDS. The results are expected in 2008. So far 2000 of the 3000 adults needed for the trial have been enrolled during 2003. In an anonymous survey, we found out that around 40% DART trial participants are caring for a sick child with symptoms suggestive of HIV in the same household. Therefore for ethical as well as scientific and practical reasons (to avoid pill-sharing), we are planning a similar trial to DART for children. Junior DART will enrol 1200 children and adolescents of DART families and address similar questions as adult DART. Growth could be an important additional way to monitor how well children are responding to ART, making clinical monitoring even more viable than in adults. In addition, children have more active immune systems, which may recover better and more quickly when ART is restarted after a period off therapy. Therefore it is quite possible that the results from the adult DART trial cannot just be assumed to be the same for children DART and Junior DART will be done in the same centres in Uganda and Zimbabwe and will form the basis of developing family-based care for HIV infection in Africa.

Junior DART is a randomised open-label trial enrolling 1200 African HIV-infected children, aged 6 months to 18 years, with an adult carer in the DART (Development of AntiRetroviral Therapy) trial which has enrolled 2000 of 3000 adults in Uganda (2 sites) and Zimbabwe (1 site). Junior DART will take place in the same sites and the 2 trial teams will work closely together. Junior DART will have two major randomisations: to clinical monitoring only (CMO) versus laboratory and clinical monitoring (LCM); and to intermittent (planned treatment interruptions, PTI) versus continuous ART. In a further randomised substudy, 3 regimen strategies for initiating ART will be compared in terms of HIV RNA viral load response.
Eligible children should have paediatric WHO Stage 2 or 3 disease, and CD4 percent 20% for children 2 years, 15% for children 2-11 years, or CD4 count 200 cells/mm3 for those aged 12-18 years. It is expected that at least 750 children randomised to CMO versus LCM will be 2 years and have achieved a sufficient increase in CD4 (CD4 ?20% for 2-11 years and CD4 250 cells/mm3 for 12-18 years) by 48 or 72 weeks to be eligible for the second randomisation to PTI versus continuous ART. This will only open after a non-randomised pilot study of PTIs in 100 children satisfying these threshold criteria has been completed (with all children having monthly CD4 measurements) and the DSMC and Trial Steering Committee have assessed the safety of the proposed PTI strategy.
Recruitment into the trial will take place over one year with minimum follow-up of 4 years. First and second-line ART will be available for all children (for up to five years). The decision to change to second-line ART will be based on clinical criteria alone for the CMO arm and on clinical plus laboratory criteria for the LCM arm. Issues of after-trial ART are being negotiated with governments in the same way as for adult DART.
The primary efficacy endpoint will be progression to a new paediatric WHO stage 3 (AIDS) event or death in children under 13 years, or adult WHO stage 4 disease for those 13 years and older. The primary outcome for the randomised substudy will be change in HIV RNA from baseline to 48 weeks, performed retrospectively on stored plasma samples.