UNSW has received a grant of more than $18 million (US $12.42 million) from the Bill & Melinda Gates Foundation to support a research project with the potential to extend drug therapy to millions of HIV-affected people worldwide.
The research team, led by Professor Sean Emery and Professor David Cooper, at UNSW's National Centre in HIV Epidemiology and Clinical Research (NCHECR), will study the effectiveness of optimised doses of HIV drug treatment, known as antiretroviral therapy (ART).
If effective, ENCORE (for Evaluation of Novel Concepts in Optimization of antiRetroviral Efficacy), would allow governments and non-government organisations to purchase more drugs, and ease the pressure on manufacturing capacity to meet the growing global demand for ART. Dose optimisation could allow enhanced funding for further treatment, care and prevention work.
"We hope that our work will see more people with access to therapy for any given level of funding," Professor Emery said.
Drug therapy for HIV not only extends and improves the quality of life of people with HIV, it also may reduce the likelihood of that person infecting others. Consequently the roll-out of HIV drug therapy supports the work of HIV/AIDS prevention.
The focus of care for HIV-infected people is the continued scale-up of access to ART, but the success of the roll-out of ART is putting enormous pressure on both the ability to pay for the drugs and the capacity to manufacture them. Alternative means of reducing the costs, such as changes to the manufacturing process, have been exhausted.
More than three million people in developing countries currently receive drug therapy for HIV infection, and the World Health Organisation estimates that this will rise three-fold to nine million by 2015.
"We are very honoured and excited to receive this support from the Bill & Melinda Gates Foundation to lead this important work," Professor Cooper said.
The ENCORE study: background information
What is the purpose of ENCORE?
The purpose of the ENCORE program is to investigate whether there is sufficient scientific evidence to support changes in international and national ARV dosing guidelines. Specifically, ENCORE has been designed to determine the optimized dose of some antiretroviral drugs (ARVs), while maintaining effectiveness, and possibly improving safety/tolerability. The first trial will examine whether the daily dose of efavirenz can be safely and effectively reduced to 400 mg daily from the current internationally used dose of 600 mg daily.
Why do we need to do the study?
Dose finding during initial drug development often maximizes tolerability without a full exploration of the minimally effective dose. Clinical and pharmacokinetic (PK) data from both product development phases and from post-marketing research suggests that the licensed dose for certain ARVs might be reduced without compromising efficacy (effectiveness).
Why would this information be useful?
Lower ARV doses could improve the sustainability (affordability) of rolling out ARV treatments, making treatment more accessible to the people who need it. The WHO estimates that by 2015, nine million people in resource-limited settings will be treated with combination ART, up from just over three million people today. If the research determines that the dose can be reduced without loss of efficacy, dose reduction could reduce treatment costs by 20% to 50% - potentially improving access to the medication. Lower doses may also enhance the tolerability and durability of ARVs in clinical practice.
Where and when will the study take place?
ENCORE is a 96-week, 700-patient, randomised controlled clinical trial (RCT) that will be conducted through an existing, centrally-co-ordinated international research network. It will take place at sites in high-, middle- and low-income settings, including Australia, North and South America, Europe and Asia. We expect to start enrolling patients by mid-2009 and to publish results by mid-2013.
Conducting research in this range of locations has a number of potential benefits, including producing more generalised (widely applicable) research findings, which could enable more rapid uptake of results in routine clinical care in diverse clinical settings. Conducting the trial in multiple settings can also facilitate patient recruitment.
Can we trust the results?
The ENCORE study will be conducted by a world class research network led by a highly acclaimed academic group - and will comply with the most rigorous scientific research methodology. An independent Scientific Advisory Board has reviewed the proposed trial, and safety and study conduct will be overseen by an independent Data Safety Monitoring Board (DSMB).
The clinical trial will be randomised, double blind and placebo controlled - and the size and duration of the study are designed to ensure high quality data. Additionally, the DSMB will conduct planned interim analyses on several occasions throughout the study.
What will be the long-term benefits of ENCORE?
If successful, ENCORE could help make safe and effective ARV treatment more affordable and accessible to the people who need it.
How will the pharmaceutical companies respond to ENCORE?
We share the goal of ensuring that everyone who needs treatment for HIV is able to access it.
While the pharmaceutical companies are not directly involved in the conduct of the study, we are working with them to ensure that ENCORE builds on the current body of scientific knowledge about antiretrovirals. Study drugs may be provided by the pharmaceutical manufacturers.
Could ENCORE be considered a high-risk study in a vulnerable population, where access to a choice of treatments is limited? How will care be continued for participants at the end of the study period?
The conduct of research in the ENCORE program will comply with the highest national and international ethical standards. Particular care will be taken to ensure that people who participate in the trial do so voluntarily, free from any coercion. In addition, consistent with the International AIDS Society's recommendations, ENCORE will be responsible for study drug distribution to the sites for the two years of study and the third year of post-study drug supply.
Interim trial analyses will be reviewed by an independent DSMB, which will recommend to the Protocol Steering Committee whether the study should continue unchanged or be altered. In addition, the DSMB will be provided with information relating to the conduct and management of the study. If a patient changes study medications as a result of intolerability, toxicity or failure of either randomised regimen, the study will ensure access to an effective, alternative medication for three years following randomisation.
How will the success or failure of the trial be defined?
The measure of the trial's success will be viral suppression. An ideal outcome would be for every participant to sustain very low levels of virus in the blood. However, it is possible that viral markers for HIV will rise in some participants. All participants will be closely monitored throughout the trial for signs of intolerability, toxicity or failure of the drug regimen. If a participant needs to change medication, the study will ensure access to an alternative, effective medication for three years following randomisation.
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