There was exciting news on Monday when it was announced at an international AIDS conference in Vienna that microbicide gel had dramatically reduced the transmission of HIV in a Phase 2 clinical trial involving 889 women in South Africa. If confirmed by larger phase 3 trials this gel will offer millions of women a way to protect themselves against this dread disease that blights communities around the world.
Unlike previous microbicide gels that failed to offer significant protection against HIV infection this gel included the anti-retroviral drug tenofovir. Regular readers of this blog may recognize tenofovir, it was discussed in an article on the role of non-human primate research in developing HIV prophylaxis by virologist Dr. Koen Van Rompay that we posted last year. Dr. Van Rompay’s article looked at the use of oral tenofovir in pre- and post-exposure prophylaxis rather than its use in a microbicide gel.
So did the research on preventing SIV transmission in monkeys influence the decision to use tenofovir in this microbicide gel? You betcha! In the first report of a Phase 1 trial of this tenofovir-containing microbicide gel published in 2006 (1) the authors state that the success of tenofovir in preventing SIV infection on monkeys – the same research discussed by Dr. Van Rompay – was a deciding factor when they took this gel into clinical trials.
‘Tenofovir gel, 9-[(R)-9-(2-phosphonylmethoxyprophyl) propyl]adenine monohydrate, a nucleotide reverse transcriptase inhibitor, has demonstrated ability to inhibit retroviral replication in animals and humans, and it has been well tolerated when used orally, as tenofovir disoproxil fumarate, (tenofovir DF; Viread) [16–20]. Tenofovir DF has been approved for treatment of HIV-1 infection and is increasingly used as part of therapeutic regimens for HIV-positive individuals . Tenofovir has been proven to be effective in blocking the transmission of SIV in animal models when given as pre- or postexposure prophylaxis systemically or when applied as an intravaginal gel [22–25]. Tenofovir bisphosphate, the active intracellular moiety, has a very long intracellular half-life (> 72 h), which could allow for more convenient, coitally independent intravaginal use . Given the data showing animal protection with tenofovir gel, and the extensive human safety data with oral tenofovir in HIV-positive patients, the HIV Prevention Trials Network (HPTN) decided to assess the safety and tolerability of tenofovir gel in HIV-negative and HIV-positive women and their male sexual partners (HPTN 050).’
The above passage also mentions that they tested whether the microbicide gel containing tenofovir could prevent vaginal SIV transmission in monkeys*, and the finding that it could drove their subsequent decision to take the gel into clinical trials. This was an important decision, a review of HIV microbicide gels published in the journal Science (2) two years ago pointed out the failure to evaluate other microbicide gels in monkey models of HIV transmission allowed these gels to proceed into clinical trials where they subsequently failed. It is notable that the microbicide PRO 2000, also evaluated in monkeys, is the only other microbicide to demonstrate an ability (albeit less dramatic) to prevent HIV infection in clinical trials.
So what now? Well the tenofovir containing gel will go on into larger phase 3 trials to further evaluate its ability to prevent HIV infection in women. In the meantime following a study showing that it can prevent the transmission of rectal SIV transmission in macaques (3) this gel is now in phase 1 safety trials in men.
This is welcome news after years of disappointment, and further evidence that where HIV is concerned there can be no shortcuts; all therapies whether microbicide gels or vaccines must be thoroughly evaluated in stringent animal models before being taken to human clinical trials. Perhaps now we can start to turn realism into optimism.
In other news this week, Americans for Medical progress have announced the 2010 Michael D. Hayre Fellows in Public Outreach. Neuroscientists Elizabeth Burnett and Scott Dobrin will use the fellowship grant to develop their project “Speaking Honestly – Animal Research Education (SHARE)”, which is designed to guide educators in leading classroom discussions on the humane use of animals in research in an engaging and interactive manner. We wish them the very best as they follow in the footsteps of the first Hayre fellow, Speaking of Research founder Tom Holder.
* Unfortunately this study was never published in the scientific literature, this is something that sometimes happens with pre-clinical studies performed by biotechnology and pharmaceutical companies…usually because they wish to keep the work confidential for commercial reasons…and is a source of great frustration to people like me who write about this work!
1) Mayer K.H. et al. “Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women.” AIDS. volume 20(4), pages 543-551 (2006), DOI:10.1097/01.aids.0000210608.70762.c3.
2) Grant R.M. “Whither or wither microbicides?” Science. Volume 321(5888), pages 532-534 (2008), PubMed Central:PMC2835691.
3) Cranage M. et al. “Prevention of SIV Rectal Transmission and Priming of T Cell Responses in Macaques after Local Pre-exposure Application of Tenofovir Gel” PLoS Med. Volume 5(8):e157(2008) DOI:10.1371/journal.pmed.0050157