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FAQ - Frequently Asked Questions QUESTIONS Q.1 Why were clinical trials for HIV treatment carried out in Africa?Q.2 What is DART? Q.3 How long did DART last for? Q.4 What were the criteria to be included in DART? Q.5 What were the objectives of DART? Q.6 Why test a clinical monitoring strategy in an African trial? Q.7 How was the safety of the patients on antiretroviral drugs monitored? Q.8 What Drugs were given to patients on DART? Q.9 What were the options for patients who want to leave DART and continue to receive antiretroviral drugs? Q.10 Is there any assurance of provision of antiretrviral drugs after DART? Q.11 Why did DART look at structured treatment interruptions (STIs)? Q.12 Were the benefits and risks of participating in DART explained to trial participants? Q.13 Why did clinic visits take place once a month? Q.14 Why was the doctor only seen once in three months? Q.15 Could other tests be requested outside of the routine DART tests? Q.16 How could participants or their community representatives interact with trial investigators in DART? Q.17 Are there any other new studies coming up? Q.18 Who can be contacted by for further queries about DART? ANSWERS Q.1 Why were clinical trials for HIV treatment carried out in Africa?In Africa, most countries rely on World Health Organisation (WHO) guidelines for a public health approach to ‘scaling up antiretroviral therapy (ART) in resource-limited settings’. These WHO guidelines were highly challenging to produce, because of inadequate evidence for the delivery and use of antiretroviral (ARV) drugs in countries with a high HIV prevalence and with limited capacity and health infrastructure. Guidelines had to be based on the results of trials and clinical experience gained in the USA and Europe, where the standard of care is individual patient management by skilled physician-led health care teams, supported by frequent high-technology laboratory monitoring. While it was urgent that national treatment programmes began to provide access to ARV drugs to the hundreds of thousands of HIV-infected Africans at high risk of dying, a local research agenda was needed in parallel so that the guidelines on treatment could be updated based on lessons learned in Africa. Some questions can be resolved by ‘observational research’ and by evaluating programmes as they are implemented. However other questions require more formal trials where patients are randomly allocated to one intervention and compared in outcome to another. This is because differences in who chooses what intervention can hide important effects of the interventions themselves. Q.2 What is DART? DART is short for ‘Development of Antiretroviral Therapy in Africa’. DART was a randomised trial to monitor approaches to managing antiretroviral therapy (ART) in adults with HIV in Africa. The trial was carried out in three locations; with sites in Uganda in Entebbe and Kampala, and a site in Harare, Zimbabwe. Q.3 How long did DART last for? The DART trial began in 2003 and finished in late 2008. Participants will be moved into national and other ART programs throughout 2009 (See ‘Trial closure’ page for further information). Q.4 What were the criteria to be included in DART? Trial participants had to fulfil a number of criteria in order to take part in the trial: 1. Documentation of HIV-1 infection 2. Over 18 years of age at the beginning of the trial 3. Symptomatic World Health Organisation stage 2, 3 or 4 HIV disease and a CD4 count of less than 200 cells/mm3 (CD4 cells are a type of white blood cell with an important role in fighting infection. HIV infects CD4 cells and the number of these cells present in the body generally decreases as the disease progresses). 4. No prior use of antiretroviral therapy (ART) (except during pregnancy for preventing mother to child transmission (PMTCT)). 5. Agreement and documented informed consent to be randomised to clinically driven monitoring (CDM) or laboratory plus clinical monitoring (LCM); and to structured treatment interruptions (STIs) or continuous ART, if eligible. 6. Life expectancy of at least 3 months. Q.5 What were the objectives of DART? DART was a six year clinical trial of anti-HIV therapy in 3300 patients with advanced HIV disease or AIDS in Uganda and Zimbabwe. The trial aimed to investigate two main questions: can anti-HIV drugs be given in the absence of routine laboratory tests, relying on clinical assessments instead; and can anti-HIV drugs be given intermittently rather than continuously to provide a similar level of benefit to patients but with less associated toxicity. To address the first question all patients underwent laboratory tests to monitor drug toxicity but half of them, selected at random, did not have their results returned to their doctors throughout the trial. This meant that clinical examination alone was used to make health management decisions. For all patients however, doctors were able to request the results of laboratory tests for drug side effects if there was a concern that clinical assessment alone was not sufficient to make a decision. In addition, all laboratory test results that were considered to show severe drug toxicity (grade 4) were always returned to doctors. For the second question, patients who responded well to initial therapy were randomly assigned to either stay on continuous therapy or move on to structured treatment interruptions (STIs): cycles of 12 weeks on and 12 weeks off drugs. The outcome of the trial was assessed in terms of the development of new AIDS-defining illnesses or death. These events were compared across the different groups. Q.6 Why test a clinical monitoring strategy in an African trial? Access to antiretroviral drugs is becoming increasingly possible across Africa but it is not clear how we can safely provide antiretroviral therapy (ART) outside a few centres of excellence in large cities where substantial resources are available. One issue in African countries is how ART can be delivered safely and effectively by health centres with limited laboratory facilities for monitoring drug toxicity and clinical response to drugs, in up-country and rural settings for example. In resource-rich countries standard practice is to use regular, extensive and expensive laboratory tests, yet there is little evidence of how much benefit this is to patients in the long term. In many research-rich countries the costs of such routine testing is much higher than the cost of the provision of ARVs and it also requires expensive equipment and skilled technicians. There is reason to believe that with good clinical care, many laboratory tests for possible drug toxicity would only need to be carried out if clinical symptoms are present. However, it is also possible that toxicity may be detected too late using such an approach. DART evaluated how many laboratory tests were ordered if this was only done when there was clinical concern about a participant. However by continuing to carry out laboratory tests in all patients, the team could also monitor how many serious toxicities were missed. In DART, only participants in the LCM arm of the study had test results returned to doctors. It is only by doing such a randomised study that we can determine which, if any, routine tests are needed to ensure safety and when it is best to test and how often. The results will inform how healthcare spending should be divided between laboratory facilities, tests, equipment and staff compared to doctors, nurses, pharmacists and drugs. With billions of US$ being spent on HIV and AIDS each year across Africa, it is vital that we know how to spend this money in the most effective way possible. In resource-rich countries there is also extensive reliance on laboratory tests for monitoring the effectiveness of ARVs. These include CD4 monitoring, viral load and drug resistance testing. However there is again little real evidence to show how useful these tests are. Viral load and resistance testing are likely to be rare in Africa for several more years due to the high cost and the technical skills needed; they are currently recognised as unfeasible by the WHO in most resource-limited countries for the near to medium future and are not being evaluated in DART. CD4 monitoring is considered feasible and is becoming cheaper and more available. Again, there is no real information about how often to test CD4 count and whether this tells you more than clinically evaluating if a person is well. DART assessed if using CD4 counts to guide when to change failing drugs for new ones added any benefit to changing them when a person became ill. This was an important question as the ultimate aim of ART was to keep people alive and well for as long as possible, given the number of drugs available. In resource-limited settings, there are relatively few options for second-line HIV therapy unlike resource-rich countries with more expensive drugs available. Q.7 How was the safety of the patients on antiretroviral drugs monitored? All participants in DART were monitored in the same way. They routinely visited the clinic once a month but could visit the clinic more often if the need arose. On a scheduled visit they were seen by the counsellors and nurses, who evaluated them and recommend for them to see a doctor if necessary. Otherwise they routinely saw a doctor every three months. On a routine visit, they had blood taken for CD4 count analysis and other tests including tests to monitor kidney and liver function. Results were available to the clinicians for participants in the laboratory plus clinical monitoring (LCM) arm but results for participants in the clinically driven monitoring (CDM) arm were not returned to the clinicians unless they showed severe drug toxicity. A small group of independent experts regularly monitored the results of the LCM and CDM groups. Each time they recommended that the study should continue. If either group were clearly doing worse than the other, they would have recommended closing the trial. This happened with the structured treatment interruptions (STI) study within DART. See the ‘Structured Treatment Interruptions (STIs) in DART’ page for further information. Q.8 What Drugs were given to patients on DART? As first-line treatment, all patients received a triple combination of antiretroviral therapy (ART). Patients were prescribed zidovudine (ZDV) and lamivudine (3TC) in combination (Combivir) as the backbone of their treatment. For their third drug, 2,469 patients received tenofovir (TDF) and 247 patients received nevirapine (NVP). In addition, 600 patients were co-enrolled with additional, separate consent to a double blind 24-week comparison of the safety of abacavir (ABC) versus nevirapine (NVP) as the third drug for first-line therapy. These patients continued to receive ABC or NVP, respectively, after the blinded period finished. For intolerance or toxicity of any individual drug, another ART drug from the same class was substituted. Q.9 What were the options for patients who want to leave DART and continue to receive antiretroviral drugs? In both Uganda and Zimbabwe there are now national programmes for the provision of free antiretroviral (ARV) drugs. If a person should choose to leave DART they would have the same priority for acceptance onto such programmes as other people living with HIV and AIDS that have already had ARV treatment. There is also the option to purchase ARVs but this would not be realistic for many DART participants. Q.10 Is there any assurance of provision of antiretrviral drugs after DART? The governments of both Uganda and Zimbabwe pledged to provide access to antiretroviral (ARV) drugs for DART participants after the trial finished. Around 2,000 participants were based in Uganda, the majority at clinics that had other free treatment programmes available. Around 800 participants were based in Zimbabwe where the existing DART clinic has been developed into a national HIV treatment centre. See the ‘Responsible DART Trial closure’ page for further information. Q.11 Why did DART look at structured treatment interruptions (STIs)? Antiretroviral (ARV) drugs transform the outlook for people living with HIV. However taking ARVs is not always easy. Many people wonder whether they need to take ARVs for the rest of their life or if they could safely go on a ‘drug holiday’. The answer to these questions is not yet known, but the DART structured treatment interruptions (STIs) study has clarified some of the risks of interrupting ARVs. br /> The same groups of experts who managed the CDM and LCM study also monitored the STI study. However in this case they decided it wasn't safe for participants to continue with STIs. All participants on STIs moved back to continuous ARVs after the STI study closed in March 2006. There were a similar number of deaths among those who interrupted treatment (5 deaths) and those who continued treatment at all times (4 deaths) but in total for every 100 participants on STIs for a year, 9 would become seriously ill or die; compared to only 3 participants on continuous ARV therapy. Although the absolute number of participants who became very ill was small, the investigators considered the increase in risk was not acceptable. A questionnaire completed by STI participants after the study closed showed that about a third of participants preferred STI to continuous therapy, one third had problems with STIs including feeling ill and experiencing side effects when back on drugs, and one third had no preference. In Africa questions about STIs are especially relevant as there are currently limited resources for provision of ART and laboratory monitoring. If STIs were feasible, even in some cases, without risking harm to an individual, then those resources could be stretched further and enable more people to be treated successfully. When DART started there was no information available about STIs in Africa and it was agreed that this was an important question that could be addressed within the study. Q.12 Were the benefits and risks of participating in DART explained to trial participants? Patients who enrolled in DART were first given information on the study objectives and procedures, this was generally carried out by a team of trained counsellors. Participants were then provided with a detailed information sheet, approved by independent local ethics committees, to take home with them. They were asked to return around two weeks later to enrol in the study to give them ample time to consider and discuss DART with family or friends if they wished. During trial enrolment there was further counselling and opportunities to ask any questions. The formal signing of the Trial Consent Form only took place after all concerns had been addressed. Of those initially screened for DART, only around 50 per cent actually enrolled. Of those that did not enrol, the majority were found to be ineligible (e.g. CD4 count was too high) but there were also a number of people that simply decided that the study was not for them. It is clearly not in the interests of a long term study like DART to coerce or mislead people to join. In a six year trial it would be almost inevitable that any concealed risks would become apparent and could cause many participants to leave the trial and so destroy the validity of the data. In DART loss-to-follow-up was low (4 per cent) after four years of the study and most of these cases were due to migration to outside the study areas once people felt much better. Q.13 Why did clinic visits take place once a month? Patients were routinely scheduled to visit the clinic once a month, but if they felt sick, they were seen promptly at the clinic or if they were unable to travel, a home visitor assessed them at home. This allowed for more effective monitoring of adherence, side effects and any disease progression. Q.14 Why was the doctor only seen once in three months? The number of doctors versus patients in many African countries is very low, leaving only nurses to look after patients in most health care centres. DART aimed to see if patients could be managed without having to see a doctor every month. During the study, if a participant wanted to see a doctor, or if the nurses deemed it necessary, the patient was seen by a doctor. In the USA and Europe, HIV positive people usually only see a doctor every 3 months. Q.15 Could other tests be requested outside of the routine DART tests? In both the CDM and LCM arm of DART, the doctors could request for non-routine tests to be carried out. These included imaging tests like X-rays, ultrasound scans, CT scans, and any other tests deemed necessary for the management of the patient. The only tests not available for clinical management were HIV viral load tests for all patients and CD4 count tests for CDM patients. See ‘Q.6 Why test a clinical monitoring strategy in an African trial?’ for more information. Q.16 How could participants or their community representatives interact with trial investigators in DART? DART participants visited the DART clinic every four weeks and they always saw a nurse at least. They also had access to counsellors and doctors whenever they needed. Participants were free to raise any concerns they had or to ask any questions. Queries could be escalated to DART Principal Investigators if needed. The DART sites also ran occasional events where participants were informed of any new developments and were able to ask any questions. TASO (The AIDS Support Organisation, Uganda) had a seat on the DART International Coordinating Group and two community representatives acted as independent members on the Trial Steering Committee. This all helped to ensure that participants and the wider community had a voice during the study. Q.17 Are there any other new studies coming up? ARROW (AntiRetroviral Research fOr Watoto) study ARROW is a parallel trial to DART, looking at antiretroviral therapy (ART) management in children. From early 2007 ARROW will be recruiting at all DART sites. 1200 children will be enrolled, will receive ARVs and will be followed up for four to five years. Any HIV positive children being looked after by DART participants will have priority for this trial Q.18 Who can be contacted by for further queries about DART? Please send any queries to dart@ctu.mrc.ac.uk |