Tenofovir (Viread) Administered Orally, by Injection, or as a Rectal Microbicide Protects Monkeys from Infection with HIV-like Virus

By Liz Highleyman

In addition to behavioral strategies such as condom use, investigators are exploring several biomedical approaches to HIV prevention. One of the most promising is pre-exposure prophylaxis (PrEP), which involves using antiretroviral drugs prior to exposure in an attempt to prevent the virus from taking hold in the body.

PrEP using tenofovir (Viread), with or without emtricitabine (Emtriva; combined with tenofovir in the Truvada fixed-dose coformulation pill) is currently undergoing clinical trials in humans, but extensive efficacy results are not yet available. Researchers do have relevant data, however, from studies in animals. Reports from 2 such studies were recently published online in the open-access journal PLoS Medicine.

Injected and Oral PrEP

In the first study, J. Gerardo García-Lerma and colleagues evaluated daily and intermittent PrEP in macaque monkeys. The animals (6 per group) were treated with various regimens of emtricitabine and tenofovir:

• Group 1 received once-daily subcutaneous injections of a human-equivalent dose of emtricitabine alone;

• Group 2 received once-daily oral doses (applied to fruit), equivalent to human dosing, of both emtricitabine and tenofovir;

• Group 3 received a once-daily subcutaneous dose of emtricitabine similar to human dosing plus a higher dose of tenofovir;

• Group 4 received an intermittent PrEP regimen similar to that of

• Group 3, but administered only 2 hours before and 24 hours after each weekly virus challenge;

• A control group of 16 macaques did not receive any drug treatment.

All animals were given once-weekly challenges for 14 weeks with a rectally administered recombinant simian/human immunodeficiency virus (SHIV) similar to HIV.

Results

• The risk of infection among macaques in Group 1 was 3.8-fold lower than that of untreated animals (P = 0.02).

• The risk in Group 2 was 7.8-fold lower than of the untreated group (P = 0.008).

• All 6 macaques in Group 3 were protected.

• All 6 animals that received intermittent PrEP (Group 4) were also protected.

• Animals that experienced breakthrough infection despite PrEP had blunted acute viremia (lower viral load).

• The M184V emtricitabine resistance mutation was observed in 2 of 6 treated animals that became infected.

"This model suggests that single drugs for daily PrEP can be protective, but a combination of antiretroviral drugs may be required to increase the level of protection," the study authors concluded.

"Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model," they continued. "These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities."

Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA; Division of Scientific Resources, National Center for Preparedness, Detection, and Control of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA; Emory University School of Medicine/Veterans Affairs Medical Center, Decatur, GA.

Tenofovir Microbicide

Microbicide Applicator

Human trials of various microbicides for the HIV prevention have produced mixed results. So far, however, there have not been full-scale clinical trials of products that contain antiretroviral drugs or microbicides for rectal use during unprotected anal intercourse.

In the second recent study, Martin Cranage and colleagues evaluated whether a topical gel containing tenofovir would protect macaques against rectal challenge with simian immunodeficiency virus (SIV), a relative of HIV that infects monkeys.

Here, 9 monkeys received 1% tenofovir gel rectally up to 2 hours prior to virus challenge, 4 animals received placebo gel, and 4 received no treatment. In addition, 3 macaques were given tenofovir gel 2 hours after a virus challenge. After 20 rectal virus challenges, the monkeys were tested for viral genetic material in plasma and peripheral blood mononuclear cells.

Results

• The researchers observed "a significant protective effect" in the monkeys that received tenofovir gel (P = 0.003).

• 8 of 9 macaques given tenofovir rectally up to 2 hours prior to virus challenge either were protected from infection (6 animals) or had lower viral loads (2 animals).

• All untreated macaques, and 3 of 4 that received placebo gel, became infected.

• 2 of 3 monkeys that received tenofovir gel after a virus challenge also were infected.

• Post mortem analysis of lymphoid tissue did not reveal sequestration of SIV in the protected animals.

• There was a strong positive association between the plasma concentration of tenofovir 15 minutes after rectal application and the degree of protection in the 6 animals challenged with virus at this time point.

• In a laboratory study, colorectal tissue samples from non-SIV challenged tenofovir-treated macaques contained measurable amounts of the drug and were resistant to infection.

• No inhibition of infection was observed, however, in tissue samples from the small intestine.

• Tissue-specific inhibition of infection was associated with the intracellular detection of tenofovir.

• In the absence of seroconversion, Gag-specific interferon-gamma secreting T-cells (immune cells that recognize the virus) were detected in the blood of 4 of 7 protected animals tested.

In conclusion, the investigators wrote, "These results indicate that colorectal pretreatment with antiretroviral drugs, such as tenofovir, has potential as a clinically relevant strategy for the prevention of HIV transmission."

"We conclude that plasma tenofovir concentration measured 15 minutes after rectal administration may serve as a surrogate indicator of protective efficacy," they continued. "This may prove to be useful in the design of clinical studies."

"The finding of T-cell priming following exposure to virus in the absence of overt infection is provocative," they added. "Further studies would reveal if a combined modality microbicide and vaccination strategy is feasible by determining the full extent of local immune responses induced and their protective potential."

Centre for Infection, Division of Cellular & Molecular Medicine, St George's University of London, London, UK; Centre for Emergency Preparedness and Response, Health Protection Agency, Porton Down, Salisbury, UK; Division of Retrovirology, National Institute for Biological Standards & Control, South Mimms, UK; Department of Virology, Biomedical Primate Research Centre, Rijswijk, Netherlands; Department of Veterinary Medicine, University of Cambridge, Cambridge, UK; University of North Carolina Centers for AIDS Research, Chapel Hill, NC; Center for Prevention Research, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, CA.

Editorial

In a commentary accompanying the Cranage article, Florian Hladik of the Fred Hutchinson Cancer Research Center in Seattle and Charlene Dezzutti of the Magee-Womens Research Institute and Foundation at the University of Pittsburgh summarized recent animal PrEP findings and discussed their implications for humans.

After noting that animal studies did predict the failure of vaginal microbicides in large clinical trials in humans, the authors wrote that rectal SIV or HIV challenge "bears a much higher transmission probability than vaginal challenge," and that "successful prevention of rectal transmission is therefore likely to have a better predictive value for human trials than vaginal challenge models."

Given that anal sex among heterosexuals has been underestimated in the past, they concluded that, "means to prevent rectal HIV transmission are thus urgently needed for both women and men who have unprotected anal intercourse."

10/07/08

References

JG García-Lerma, RA Otten, SH Qari, and others. Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Medicine 5(2): e28.

M Cranage, S Sharpe, C Herrera, and others. Prevention of SIV rectal transmission and priming of T cell responses in macaques after local pre-exposure application of tenofovir gel. PLoS Medicine 5(8): e57. August 8, 2008.

F Hladik and CS Dezzutti. Can a topical microbicide prevent rectal HIV transmission? PLoS Medicine 5(8): 167. August 8, 2008.