A randomised trial of monitoring practice and treatment interruptions in the management of antiretroviral therapy in HIV
Lead Research Organisation:
Medical Research Council
Department Name: UNLISTED
Abstract
Most poor countries with many HIV-infected people, such as those in sub-Saharan Africa, are adopting the WHO ?public health approach? for providing anti-HIV (antiretroviral) drugs. This uses simple approaches to treatment that can be delivered by health care workers under supervision of non-specialist clinicians, supported by basic laboratory tests, available. Doctors in specialist hospitals support clinical teams and problem cases are referred to them for expert management. Without this simplified approach, with the severe shortage of doctors and HIV specialists, scaling up anti-HIV drugs provision to meet the needs of HIV-infected people would be impossible.
However, even simple laboratory tests need significant infrastructure (laboratories, reagents, electricity) and trained personnel. Costs of laboratory tests can be as high as costs of the drugs, and are not feasible in large areas of Africa. Finding out whether or not anti-HIV drugs can be given safely and effectively without the intensive routine laboratory testing provided in industrialised countries is of significant relevance to clinical management of HIV-infected people in the developing world. Many anti-HIV drug treatment programmes are struggling to staff and develop laboratory services - if clinical monitoring only (i.e. with no tests) and laboratory monitoring (with tests) have similar clinical outcomes, then emphasis should be given to support and training for quality clinical services, rather than providing laboratory tests. If HIV disease progresses significantly faster when patients receive anti-HIV drugs without regular tests, then provision of anti-HIV drugs must be accompanied by new resources to strengthen and deliver a basic laboratory service.
This proposal describes an extension to an ongoing clinical trial addressing this and other key issues surrounding management of anti-HIV drugs in resource-limited settings. The reason the trial needs an extension is because disease progression is occurring much less frequently than originally anticipated when the trial was started. This is surprising - but is very good news for anti-HIV programmes in Africa and other resource-limited settings, and for trial participants. However, it also means that longer follow-up is needed to meet the trial?s primary objective of evaluating the relative risks and benefits of giving anti-HIV drugs with and without regular laboratory monitoring tests. Given the potentially huge numbers of HIV-infected people in developing countries, for whom the results of this trial will have a direct impact, we believe it is critical to have longer follow-up of DART patients in order to address these questions as originally planned.
However, even simple laboratory tests need significant infrastructure (laboratories, reagents, electricity) and trained personnel. Costs of laboratory tests can be as high as costs of the drugs, and are not feasible in large areas of Africa. Finding out whether or not anti-HIV drugs can be given safely and effectively without the intensive routine laboratory testing provided in industrialised countries is of significant relevance to clinical management of HIV-infected people in the developing world. Many anti-HIV drug treatment programmes are struggling to staff and develop laboratory services - if clinical monitoring only (i.e. with no tests) and laboratory monitoring (with tests) have similar clinical outcomes, then emphasis should be given to support and training for quality clinical services, rather than providing laboratory tests. If HIV disease progresses significantly faster when patients receive anti-HIV drugs without regular tests, then provision of anti-HIV drugs must be accompanied by new resources to strengthen and deliver a basic laboratory service.
This proposal describes an extension to an ongoing clinical trial addressing this and other key issues surrounding management of anti-HIV drugs in resource-limited settings. The reason the trial needs an extension is because disease progression is occurring much less frequently than originally anticipated when the trial was started. This is surprising - but is very good news for anti-HIV programmes in Africa and other resource-limited settings, and for trial participants. However, it also means that longer follow-up is needed to meet the trial?s primary objective of evaluating the relative risks and benefits of giving anti-HIV drugs with and without regular laboratory monitoring tests. Given the potentially huge numbers of HIV-infected people in developing countries, for whom the results of this trial will have a direct impact, we believe it is critical to have longer follow-up of DART patients in order to address these questions as originally planned.
Technical Summary
DART is an open randomised trial evaluating two strategic approaches for ART management in previously untreated symptomatic HIV-infected adults with CD4 cell counts under 200 cells/mm3 initiating ART in three clinical centres in Africa (2 in Uganda and 1 in Zimbabwe). The first strategy compares clinical monitoring only (CMO) with laboratory plus clinical monitoring (LCM) for efficacy (CD4 cell counts) and toxicity (haematology and biochemistry). The second approach compares structured treatment interruptions (STI) (12 weeks on, 12 weeks off ART) with continuous ART in patients who achieve CD4 cell counts over 300 cells/mm3 after 48 weeks on continuous ART. All patients receive triple-drug antiretroviral therapy, with three different regimens being used first-line, one being the standard WHO recommended 2NRTI+NNRTI. The primary endpoint for both comparisons is development of a new WHO stage 4 event (like AIDS) or death, and the trial is designed to demonstrate equivalence between each pair of randomised strategies. 3300 patients were enrolled into the CMO/LCM comparison, and 800 into the STI comparison. Retention and follow-up have been excellent. Substudies including the blinded NORA (Nevirapine OR Abacavir) randomised substudy trial, and a virology substudy are included; high quality DART data are also extremely valuable for addressing numerous epidemiological questions surrounding the optimal use of ART in resource-limited settings.
Although the approved DART protocol was a 5 calendar year trial (2003-2007), initial MRC funding was for four years in the first instance (because of the application process at the time). Further, over the last year it has become apparent that the rate for the primary endpoint - progression to new WHO stage 4 event or death - is considerably lower than predicted (approx 10% rather than 15% annually). This is surprising - but is very good news for ART programmes in Africa and other resource-limited settings, and for DART participants. However, this lower progression rate reduces the power of the trial. Therefore this proposal describes an extension requested for the DART sites supported by the MRC (MRC Entebbe, MRC CTU and Imperial College) in order to close the funding gap for DART for 2006/2007 and extend the trial for one additional calendar year (2008) to maintain power according to the original trial design. Similar proposals are being developed for partner funders of DART.
Although the approved DART protocol was a 5 calendar year trial (2003-2007), initial MRC funding was for four years in the first instance (because of the application process at the time). Further, over the last year it has become apparent that the rate for the primary endpoint - progression to new WHO stage 4 event or death - is considerably lower than predicted (approx 10% rather than 15% annually). This is surprising - but is very good news for ART programmes in Africa and other resource-limited settings, and for DART participants. However, this lower progression rate reduces the power of the trial. Therefore this proposal describes an extension requested for the DART sites supported by the MRC (MRC Entebbe, MRC CTU and Imperial College) in order to close the funding gap for DART for 2006/2007 and extend the trial for one additional calendar year (2008) to maintain power according to the original trial design. Similar proposals are being developed for partner funders of DART.
