If medical services can identify populations where the risk of acquiring and passing on HIV is extraordinarily high, should they be offering those people medical treatment in order to prevent HIV infection? This question was posed by the senior Canadian AIDS researcher Dr Mark Wainberg in a session on research priorities at the Barcelona conference on AIDS, as he outlined plans to answer it.
At least two clinical trials are now proposed, and one has preliminary ethical approval, to find out whether a daily dose of an antiretroviral, combined with ongoing support for condom use and other prevention methods, can make enough of a difference to the risk of HIV to outweigh any side effects of the treatment. The results could be available as early as 2003. If positive, they would pose a major challenge to services such as sexually transmitted disease clinics throughout the world, including Europe and North America.
What drugs could be used?
It is clear that a single drug can be enough to prevent HIV infection, even though combinations of antivirals are needed to treat it. The remarkable success of nevirapine, given as one dose to a mother during labour and as a single dose to a baby after 72 hours, is clearly because the drug is in the baby’s body before the time when most exposure to HIV occurs, and not because of any effect on the mother’s viral load.
However, there are serious concerns about using nevirapine in this way because a single mutation is enough to make the virus resistant to the drug. This, along with the risk of side effects when nevirapine is used over extended periods, rules out giving it long-term to HIV negative people for preventing sexual transmission in the proposed trials.
To have a chance of preventing infection, it is necessary for any drug used to act early in the virus’s life cycle, before it has put its genes into the nucleus of any cells. In practice, at the moment, this means using nucleoside or nucleotide analogue reverse transcriptase inhibitors.
Dr Wainberg argues that there are two drugs now available which could be tested, in the context of such a clinical trial. These are tenofovir (oral PMPA) and the newer enteric coated form of ddI (didanosine), both of which can be taken once daily and achieve sustained high levels of the drugs in people’s bodies. Drug resistance to these drugs is not common among viruses circulating in the community in most countries, especially not in South Africa where the first trial is likely to be set up, among sex workers at extremely high risk of HIV.
Tenofovir was in fact the first drug shown to prevent infection, when given to monkeys before they were exposed to an HIV-related virus, and would seem on the face of it to be easier to take. Family Health International is set to test this, as reported here. However, Dr Wainberg thought that enteric coated ddI may be the first drug to go into a clinical trial. More is known about the side effects, although these will require careful monitoring (mainly, in the case of ddI, for pancreatitis; see here for further information on ddI).
Designing the trial
Dr Wainberg proposes that a placebo-controlled, double-blind trial should now be carried out, in which the provision of an antiretroviral (or a placebo) would be combined with intensive support and encouragement to use condoms. Exactly how large the trial would need to be will depend on the rate of infection in the community where it is carried out, but given the existence of some populations of sex workers with continuing high rates of HIV infection despite condom promotion efforts and access to treatment for sexually transmitted infections, it need not be very large. Dr Wainberg believes that the trial planned could give clear results on an interim analysis as early as six months into the trial, but should be designed to last no longer than one year in total.
Could a trial of this kind be carried out among gay men in Britain or another western country, or among injecting drug users in any country? Dr Mike Youle at the Royal Free Hospital in London believes that it could. It will be very interesting to see if he is right.
Wainberg M. Science in panel discussion on R&D priorities: who decides? XIV International AIDS Conference, Barcelona, abstract MoOr109, 2002.