Could chemoprophylaxis be used as an HIV prevention strategy while we wait for an effective vaccine? (2003)

A recent presentation by Jackson and co-workers [1] at the XVth World AIDS Conference ushered in a new era of HIV prevention. Their study examined the safety and pharmacokinetics of nevirapine in HIV-uninfected high-risk individuals, showing for the first time that a drug used to treat HIV might have the potential to prevent HIV infection. There is little evidence that there has been a significant reduction in the global rate of infection over time. HIV still spreads like wild-fire in susceptible communities [2], and is increasingly of multidrug-resistant strains of the virus [3]. The quest for an effective preventative vaccine for the uninfected has been, to date, unfruitful [4]. Indeed, there are some concerns that elicited anti-HIV immune responses may be too narrow for complete protection, severely limiting vaccine efficacy [5]. Significant populations are at high risk of imminent HIV infection, such as HIV-discordant sexual partners or those who chose not to use condoms. For these individuals a current vaccine strategy may be too far in the future. One response to other infectious agents for which an effective preventative vaccine does not exist is that of combining avoidance of the pathogen with chemoprophylaxis. Chemoprophylaxis of malaria allows non-immune individuals to visit or live in endemic areas with greater safety [6]. These drugs are used in association with avoidance strategies, such as mosquito nets, topical agents and bio-control methods. Although not devoid of problems, including user variability, toxicity, and the evolution of resistance, this preventative strategy is successful in limiting infection in a non-immune population. In the same way as infection with malaria is usually infrequent, one can argue that the risk of HIV seroconversion is relatively low, because it represents intermittent rather than continuous exposure to the pathogen. Condoms are known to be extremely successful at preventing the sexual transmission of HIV, but breakage does occur, resulting in exposure risk, and even more frequent now is the non-use of condoms, representing a much greater risk of seroconversion. Those who do not use condoms for whatever reason might find taking a prophylactic drug more acceptable. Little discussion has occurred regarding the possibility of pre-exposure prophylaxis as an HIV prevention strategy. The ideal agent should prevent the infection of cells, or at least nuclear integration when exposed to HIV. It should be an agent taken once a day or less frequently, non-toxic, well tolerated, and easily administered. Such a drug, of course, does not exist for the prevention of malaria, and yet we believe that chemoprophylaxis is an appropriate response for visitors to endemic areas who are at high risk of exposure to this pathogen. The availability of putative agents, such as tenofovir, a nucleotide reverse transcriptase inhibitor, with low toxicity and impressive post-exposure activity against HIV in simian studies [7–9] should perhaps alter our approach to HIV prevention. Studies of postexposure treatment in animals have yielded the suggestion that HIV infection can be prevented in this manner and even that antiretroviral agents may have a persistent protective antiviral effect after drug withdrawal [10,11]. There are well-established high-risk populations for HIV seroconversion that would be suitable for the evaluation of this intervention strategy. These include seronegative migrant male workers in developing country settings who routinely visit female sex workers, sex workers and sexually active uninfected high-risk gay men. Although barrier methods remain the gold standard for HIV prevention, the use of a therapeutic inhibitor of HIV infection could benefit those who may be less empowered to insist on condom usage, such as women, or those, such as well informed gay men, who choose not to use them [12]. Although not reducing our striving for a vaccine, it is also vital that we do not overlook an adjunctive method of protection against HIV infection. Few believe the vaccines that we develop will be completely protective, and may need to be developed on a regular basis as is done with influenza to deal with the high mutability of HIV [13]. Studies are urgently needed to establish if pre-exposure chemoprophylaxis, alone or in combination with barrier protection, is an appropriate response to an epidemic for which a completely effective vaccine remains highly elusive and may be unattainable. This will not be simple and will take time. However, for the populations at greatest risk of HIV infection the benefits of chemoprophylaxis may weigh positively against the risk of drug toxicity. Attempts at curbing new infections in at-risk groups have not been wholly successful to date. Perhaps it is time to think laterally and learn from history.