The Bill and Melinda Gates Foundation has granted $12.4 million to the University of New South Wales to study whether lower doses of some commonly used antiretroviral drugs are as effective as currently prescribed doses.
The research programme, led by Professors Sean Emery and David Cooper, will begin with a 700-person randomised study comparing two doses of efavirenz – the standard dose of 600mg once daily and a lower dose of 400mg once daily.
There is some evidence from early drug development studies that a range of antiretroviral drugs, including efavirenz, AZT, 3TC, atazanavir and lopinavir/ritonavir might be just as effective at lower doses.
Lower doses might prove just as effective as prescribed doses, but with a lower risk of toxicity and a lower cost. There is already some precedent for adopting a lower dose of a antiretroviral drugs in order to reduce toxicity: in 2006 the World Health Organization recommended that d4T dosing should be reduced to 30mg twice a day in order to reduce the risk of toxicity, after a meta-analysis of studies found no difference in efficacy between the standard dose of 40mg and lower doses.
The research programme will prioritise drugs where reductions in drug dose could result in the biggest savings, although some of the investigations will also look at the rate of toxicities seen with lower doses, such as the central nervous system side-effects associated with efavirenz.
An analysis by Boston University School of Public Health, carried out for the United Kingdom Department for International Development, found that if all doses of first-line antiretroviral drugs could be reduced without compromising effectiveness, cost savings would allow an extra 113,000 to 390,000 patients to be treated in developing countries at 2008 prices.
The University of New South Wales says that dose reductions could lower the cost of individual drugs by between 25% and 50%, depending on the extent of the dose reduction.
The first study in the ENCORE (Evaluation of Novel Concepts in Optimisation of antiRetroviral Efficacy) research programme will begin recruiting patients in Europe, Asia, Australia, Latin America and North America in the second half of 2009 and will follow patients for 96 weeks. Results of the study are expected by 2013.
ENCORE 2 and 3 will evaluate the pharmacokinetic profiles of lower doses of 3TC and lopinavir/ritonavir in HIV-negative volunteers, to determine whether to move forward to larger dose optimisation trials in HIV-positive individuals.