The role of tenofovir in the prevention of HIV infections

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

On the basis of the original observations of Tsai et al.[1] that SIV infections in macaques can be completely prevented by tenofovir [(R)-9-(2-phosphonylmethoxypropyl)adenine], and the safety/efficacy profile that has been established for tenofovir disoproxil fumarate (Viread) in the treatment of AIDS (HIV infection) over the past 5-year period (2001–2006) since tenofovir was approved for clinical use, tenofovir could be strongly endorsed (as a single daily pill) for the pre and postexposure prophylaxis of HIV infections in humans. In the absence of an effective HIV vaccine in the near future, what are the reasonable alternatives to prevent HIV infections? A possible combined chemo and immunoprophylactic approach may be based upon the concept that continuous exposure of HIV particles to gp120-binding agents such as cyanovirin-N or mannose-specific plant lectins (derived from the Amaryllidaceae family) may wipe out glycosylation sites, thus triggering the production of specific neutralizing antibodies to previously hidden gp120 epitopes [2]. Cyanovirin-N gel, when applied as a topical microbicide, has been shown to prevent the rectal transmission of chimeric SIV/HIV-1 in macaques [3]. Mannose-specific plant lectins [4] and virtually all anti-HIV agents that have been shown to block HIV replication by interfering with virus adsorption, viral entry, virus–cell fusion, or even further up in the viral life cycle (nucleoside, nucleotide and non-nucleoside reverse transcriptase inhibitors) [5] could be formulated as topical microbicides to prevent genital HIV transmission. There are, however, a number of pitfalls involved with the use of microbicides. These are related to the stability of the microbicidal formulations, their safety, appearance (i.e. look, smell, taste, etc.), manufacturing costs, and furthermore the preventive effectiveness of microbicides will be restricted to the site where, and the diligence by which, they are applied (i.e. intravaginally). These issues should be weighed against the convenience of having complete protection from HIV achieved with a single, orally administered, pill per day. That complete protection against SIV infection could be achieved was demonstrated more than 10 years ago when Tsai et al.[1] found that (R)-9-(2-phosphonylmethoxypropyl)adenine (a nucleotide reverse transcriptase inhibitor, now known as tenofovir), when administered subcutaneously beginning either 48 h before, or 4 or 24 h after virus inoculation, prevented SIV infection in all macaques without toxicity, whereas all control macaques became infected. Similarly, the combination of the nucleotide reverse transcriptase inhibitor tenofovir with emtricitabine, a nucleoside reverse transcriptase inhibitor, both upon subcutaneous injection, was found to prevent rectal chimeric SIV/HIV-1 transmission completely in macaques [6]. Tenofovir, in its oral prodrug form, tenofovir disoproxil fumarate, has in the meantime become one of the cornerstones for anti-HIV therapy. Tenofovir disoproxil fumarate, whether or not in combination with emtricitabine can be conveniently administered as a single pill a day, and in the meantime, efavirenz, a non-nucleoside reverse transcriptase inhibitor has been added, to this combo pill. Given the prolonged half-life of tenofovir diphosphate, the active metabolite of tenofovir, within the cells (2 days or longer), potentially conferring protection over an extended period [7], and allowing separation of the prevention intervention (taking a pill) from the potential exposure (sex act), the prophylactic use of tenofovir can be viewed as similar to the use of birth control pills for preventing conception. The advantages of using a single daily oral pill, whether based on tenofovir alone or combined with emtricitabine (and efavirenz), in the prophylaxis of HIV infections are considerable. Among the more obvious, a single oral daily administration would avoid the formulation and application problems that are inherent with topical microbicides (as mentioned above), and equally or more importantly it should, in principle, offer protection against all forms of HIV infection, irrespective of the route of transmission (genital, parenteral or perinatal). Studies are currently in progress to assess the role of tenofovir in the prevention of HIV infections in: (i) female sex workers (west Africa: Ghana, Nigeria, Cameroon); (ii) intravenous drug users (Thailand); (iii) young adults (Botswana); and (iv) men who have sex with men (United States). The study in Botswana is based on the combination of tenofovir with emtricitabine; the results from the first prevention study with tenofovir in Ghana, Nigeria and Cameroon are expected to be made public at the AIDS Conference in Toronto in August 2006.