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CDC Animal Studies Explore the Next Generation of Questions Related to the Use of Antiretrovirals for HIV Prevention
CDC Analyses Presented at the 18th Conference on Retroviruses and Opportunistic Infections:
- Oral Presentation 30: Dobard, et al., High protection against vaginal infection in macaques by post-exposure prophylaxis with gel containing raltegravir
- Oral Presentation 31: Cong, et al., Complete protection against rectal transmission of an Emtricitabine (FTC)-resistant SHIV 162p3-M184V mutant by intermittent prophylaxis with Truvada
In 2010, two landmark clinical trials demonstrated for the first time that antiretroviral drugs used to treat HIV infection could also help prevent HIV infection in some high risk populations. The first study showed promise that a new prevention tool may be on the horizon when it found that a vaginal microbicide gel containing the drug tenofovir (not yet commercially available) reduced HIV risk among women if used 12 hours before sex and soon after sex. Results of another large clinical trial found that a once-daily pill containing tenofovir plus emtricitabine (brand name Truvada) reduced HIV risk among gay and bisexual men, when used in combination with other prevention methods, including condoms. This approach is called pre-exposure prophylaxis, or PrEP. Additional human trials are underway to determine if PrEP is safe and effective among heterosexuals and injection drug users and to further confirm and build upon the initial findings on the ARV-based vaginal gels.
At the same time, CDC animal studies are exploring the next generation of questions that may ultimately help inform future research and practice. While human trials are always necessary to confirm findings from animal research, a combination of human and animal studies ultimately allows the search for new prevention methods to move forward as quickly as possible.
New CDC animal studies presented at the 18th Conference on Retroviruses and Opportunistic Infections (CROI) explore for the first time whether the use of an ARV-based gel soon after viral exposure can interrupt vaginal transmission in macaques, as well as the efficacy of Truvada-based PrEP when challenged by drug-resistant strains of virus.
First evidence that post-exposure use of a vaginal gel may prevent infection
An animal study led by CDC’s Drs. Charles Dobard and Walid Heneine evaluated the effectiveness of a vaginal gel containing the anti-HIV drug raltegravir when applied soon after exposure to a monkey virus similar to HIV. The study provides the first evidence that post-exposure use of a gel may be effective. Raltegravir is in a class of drugs known as integrase inhibitors, which is just now beginning to be considered for prevention.
In the study, macaques were exposed to simian human immunodeficiency virus (SHIV, a combination of HIV and a related monkey virus) twice a week for up to 10 weeks. Six animals received an application of a raltegravir vaginal gel three hours after each exposure, and five of these six macaques remained uninfected after 20 exposures. In comparison, all four animals that received a placebo gel became infected after an average of 10 exposures.
While this approach has not yet been evaluated in human trials, researchers believe the use of post-exposure gels could potentially provide women with more opportunities to protect themselves from infection, if this strategy is ultimately proven safe and effective in women.
Animal study finds PrEP with Truvada effective even against emtricitabine-resistant virus
Because Truvada, a combination of tenofovir and emtricitabine, is the drug that has proven to be safe and effective in reducing HIV risk among gay and bisexual men and is also being evaluated for use in other populations, it is critical to better understand whether it is likely to be effective against strains of HIV that have documented resistance to each of Truvada’s component drugs. This is an issue that is difficult to fully evaluate in the human trials, given the small number of infections and the inability to measure all of the strains of HIV to which individuals are exposed.
In this animal study led by CDC’s Drs. Mian-er Cong and Gerardo Garcia-Lerma, 10 macaques were exposed to a strain of SHIV with the emtricitabine resistance mutation known as M184V once a week for 14 weeks. Five of the macaques received intermittent PrEP with oral tenofovir and emtricitabine three days before exposure to the virus and two hours afterwards. None of these animals became infected, while all five animals that did not receive the drugs were infected after an average of three exposures. This encouraging result may reflect the fact that the M184V mutation is also known to increase the sensitivity of HIV to tenofovir.
Researchers are now working to assess whether PrEP with Truvada will protect against strains of SHIV that have the mutation associated with tenofovir resistance, known as K65R. This mutation decreases susceptibility to both tenofovir and emtricitabine. These studies, along with available data from human trials, will help provide a better understanding of the potential impact of resistance on PrEP efficacy.
Additional CDC animal studies at CROI
CDC researchers are presenting a number of additional animal studies at the conference which provide insight into other issues that may play a role in the effectiveness of PrEP, if they prove to be predictive of human experience. These include research to better understand how the absorption of antiretroviral drugs may differ during the menstrual cycle, studies exploring the pharmacodynamics of tenofovir in rectal tissues, as well as additional research on the impact of PrEP on the early course of infection among animals that are infected despite using PrEP.
Additional related CDC animal studies presented at CROI include:*
- Poster Presentation 511: Zheng et al., Reduced viral replication and limited env diversification in macaques failing oral antiretroviral pre-exposure prophylaxis
- Poster Presentation 986: Dobard et al., Substantial changes in vaginal absorption of antiretroviral drugs from gels during the menstrual cycles in macaques
- Poster Presentation 987: Aung et al., Natural substrate concentrations can modulate the prophylactic efficacy of TFV
- Poster Presentation 988: Kersh et al., Potent T cell immunity during breakthrough SHIV infection following oral PrEP
* All related studies are embargoed until Monday afternoon (February 28) at 4:00 pm EST.
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