Anti-HIV agent - capravirine
The huge strides that have been made in antiretroviral therapy over the past decade have vastly reduced the death rate from AIDS in the developed world.
The huge strides that have been made in antiretroviral therapy over the past decade have vastly reduced the death rate from AIDS in the developed world.
The amount of HIV circulating in the body can now be reduced to negligible levels by regular dosing with a cocktail of antiretroviral drugs, which work by different mechanisms. However, the emergence of drug-resistant mutations means that the current drugs do not - and cannot - remain successful in the long term. So there is a great need for further antiretroviral medicines that are still able to attack the mutated virus.
The earliest anti-HIV drugs were the reverse transcriptase inhibitors, first the nucleoside analogues such as AZT, then non-nucleoside molecules like nevirapine. However, the early non-nucleosides are susceptible to the effects of single point mutations within reverse transcriptase, which can give resistance and cross-resistance to other non-nucleoside reverse transcriptase inhibitors.
A new, promising non-nucleoside drug, capravirine, has been discovered by Shionogi, which has licensed it to Pfizer.1 In vitro studies showed it retains efficacy against a number of otherwise drug-resistant HIV mutants, with at least two mutations needed before reverse transcriptase becomes resistant.
In a Phase I dose escalation study, 55 HIV infected patients who were also receiving antiretroviral therapy other than protease inhibitors or non-nucleoside RTIs were given 1.7, 3.3, 5.0 or 6.7mg/kg three times a day for 14 days, or 8.3mg/kg three times a day or 12.5mg/kg twice a day for 28 days.2 It was well tolerated, and 14 of the patients experienced a mean reduction in viral load in excess of 1.64 log10 over 15 days.
After a 10-month hiatus in development resulting from the discovery that high doses of capravirine caused vasculitis in dogs, a monitoring plan was put into effect to establish its safety in humans. A total of 1009 healthy and HIV infected patients involved in trials were monitored, and no significant difference between adverse event onset, including vasculitis, was seen between those patients given placebo and those given the active.3 Further trials are under way, with active monitoring for vasculitis being carried out, including studies using capravirine with a variety of other antiretroviral drugs in combination.