Preventing HIV infection

In 2002, the prevailing view was that preventive strategies, rather than the provision of highly active antiretroviral therapy (HAART), were the only feasible way to control the spread of HIV infection.1 Antiretroviral treatment is now cheaper, thanks to initiatives from the pharmaceutical industry and generic manufacture, and its wider availability encourages more people to seek HIV testing. In line with the “3 by 5”strategy, the World Health Organization aims to provide HAART for three million people by the end of 2005 while continuing to promote prevention. Provision of treatment may be hindered by availability or infrastructural capacity. To make a sustainable impact on the global epidemic of HIV infection, investment in prevention research, including biomedical prophylaxis, remains paramount. Various government campaigns aimed at increasing knowledge and modifying high risk behaviour have been temporally associated with reduced incidence and prevalence of HIV infection in a few countries, notably Thailand and Uganda.2 It remains unclear, however, whether these events are causally related. Phase III studies of potential vaccines against HIV have proved unsuccessful, but there is still hope for other preventive measures. For example, considerable research activity continues to investigate microbicides, with several compounds in development showing promise.3 The necessary phase III trials will not, however, yield results in the near future.

Male circumcision has also been studied widely as a possible preventive measure. Observational studies have suggested that circumcision reduces the risk of acquiring and transmitting HIV infection, although previous meta-analyses did not confirm this.4 A recent prospective randomised trial of early circumcision compared with delayed circumcision among more than 3000 uncircumcised young men was stopped prematurely because of the considerable benefit of early circumcision. Circumcision was offered to men in the intervention group immediately after randomisation and would be offered to those in the control group at the end of follow up. The trial was stopped at the interim analysis after a mean of 18.1 months. Twenty HIV infections occurred in the intervention group and 49 in the control group, corresponding to a rate ratio of 0.40 (95% confidence interval 0.24 to 0.68; P < 0.001). When controlling for behavioural factors, including sexual behaviour, condom use, and health seeking behaviour, this ratio corresponded to a protective effect of 61% (34% to 77%).5 These data are encouraging but should not elicit a false sense of security and neglect of further preventive measures.

Credit: RAJESH JANTILAC/AFP/GETTY IMAGES

The possibility of chemoprophylaxis before exposure to HIV has caused both interest and marked controversy. Research on monkeys has shown that the antiretroviral drug tenofovir, given up to 48 hours before and after intravenous exposure to HIV, prevents infection.6 More recent data show that oral tenofovir reduces, but does not obviate, the risk from subsequent mucosal exposure to the virus.7 Researchers gave tenofovir to 12 macaques daily, weekly, or not at all, followed by multiple rectal challenges with simian immunodeficiency virus (SIV). Although tenofovir seemed to protect the macaques initially, eventually all the animals became infected with repeated exposure to the virus.

Randomised controlled trials investigating the use of pre-exposure tenofovir in the prevention of HIV acquisition have recently begun in several countries in both less developed and resource rich settings. Many of these trials have proved extremely contentious,8 despite sponsorship or funding from the US National Institute of Allergy and Infectious Diseases, the University of New South Wales, the US Centers for Disease Control and Prevention, and the Bill and Melinda Gates Foundation, rather than the drug company that manufactures tenofovir.

In these ongoing double blinded trials, HIV negative participants were randomised to receive placebo or tenofovir. They were counselled about safer sex and methods of accessing care should they become infected with HIV. Activists have opposed the trials, citing inadequacies in the overall care of participants, the delivery of proved methods for HIV prevention, the provision of antiretroviral therapy to participants who became infected with HIV during the trial, and the mechanisms for community engagement. These difficulties have led to the closure of the pre-exposure studies in several countries.9

Preventing the transmission of HIV infection from mother to child remains a primary goal in the developing world, to emulate successes in Western countries where this risk is kept low through judicious use of HAART and caesarean section. Simply giving a single dose of the non-nucleoside reverse transcriptase inhibitor nevirapine has proved suboptimal in Africa, reducing sensitivity to the drug in a high proportion of mothers as well as offspring and compromising the future effectiveness of this treatment.10 However, short term combination therapy that includes nevirapine reduces the risk of such drug resistance.11 Given that HIV can be transmitted through breast feeding, strategies such as exclusive breast feeding, which is thought to reduce the risk of diarrhoea and infection in infants, treating mothers with HAART, or chemoprophylaxis for the baby may all reduce transmission rates.11^–13