Oral Tenofovir Partially Effective in Preventing SIV Transmission in Monkeys

By Liz Highleyman

Pre-exposure prophylaxis (PREP) - the use of antiretroviral agents by HIV negative individuals to prevent infection - was a major topic at the recent XVI International AIDS Conference in Toronto.

Much of the interest surrounding PREP stems from several studies showing that this approach provides at least partial protection in monkeys. Two such studies were described in recent medical journal articles.

Protection from Rectal Exposure

In the first study, reported in the October 1, 2006 Journal of Infectious Diseases, researchers from the U.S. Centers for Disease Control and Prevention (CDC) examined whether tenofovir DF (Viread) effectively blocked infection with a hybrid simian/human immunodeficiency virus (SHIV) in Chinese rhesus macaque monkeys.

Of the 12 male macaques in the study, 4 received once-daily oral tenofovir, 4 received once-weekly oral tenofovir, and 4 control animals received no tenofovir. Once per week (for 14 weeks or until they became infected), the monkeys were exposed to SHIV, administered rectally, in doses that were about 5 times higher than the amount of HIV RNA in human semen during acute HIV infection (when viral load tends to be the highest, and the risk of transmission therefore greatest).

Results

The control animals not receiving tenofovir became infected after receiving a median of 1.5 virus inoculations (i.e., between weeks 1 and 2).

Macaques receiving once-daily tenofovir became infected after a median of 6 weeks, while those receiving the drug once weekly became infected after a median of 7 weeks.

1 monkey receiving daily tenofovir remained uninfected after all 14 SHIV exposures.

Although infection was delayed in macaques treated with tenofovir compared with control animals, the difference did not reach statistical significance (P = 0.315).

Conclusion

In conclusion, the authors wrote, "These data demonstrate that treatment with oral tenofovir DF provided partial protection against SHIV infection, but ultimately did not protect all tenofovir DF-treated animals against multiple virus challenges."

The researchers noted that this study was limited by the small number of monkeys evaluated, and by the variability in blood levels of tenofovir that resulted from oral dosing. Other animal studies have used injected tenofovir, but these are less relevant to how the drug would likely actually be used by people as part of a PREP regimen.
Protection from Oral Exposure in Infants

In the second study, published in the September 2006 Journal of Acquired Immune Deficiency Syndromes, researchers evaluated whether tenofovir and a related prodrug might be used to help prevent mother-to-child HIV transmission through breast-feeding.
Previous studies have shown that short-term injection of tenofovir was effective in protecting newborn macaques against infection after a single high-dose oral administration of a form of SIV (SIVmac251).

In the current study, researchers mimicked HIV transmission through breast-feeding by giving infant macaques repeated low doses of SIV by mouth. The baby monkeys received 10 mg/kg once-daily oral tenofovir or a topical preparation containing a low dose of a novel tenofovir prodrug, GS-7340.

Results

Topical administration of GS-7340 did not have detectable efficacy in protecting against SIV infection.

Oral tenofovir DF lowered the infection rate immediately after birth, but had lower efficacy against infection at 4 weeks of age.

Oral tenofovir DF produced cumulative partial prophylactic efficacy against repeated oral SIV challenges (P = 0.04).

Conclusion

The authors concluded that, "These prophylactic results further underscore the relevance of the current tenofovir DF prevention trials in pediatric and adult populations."

They suggested that the reduced protection at 4 weeks was "most likely because drug levels became suboptimal relative to those obtained with the current tenofovir regimen in humans."

Discussion

In their discussion, the authors of the second study noted that topical administration of a low amount of GS-7340 was not effective in lowering SIV infection rates, although tenofovir GS-7340 was given at a high concentration combined with a relatively low amount of virus. The lower initial viremia in the GS-7340-treated animals, the said, "suggests that the 'topical' administration of a low amount of tenofovir GS-7340 for 1 week may have led to some systemic intracellular levels of tenofovir, which were, as predicted, suboptimal and therefore only partially inhibited virus dissemination."
They added that in previous studies in dogs, GS-7340 had high oral bioavailability (> 70%) and "very efficient intracellular accumulation of tenofovir," about 34 times higher than that obtained with tenofovir DF.

In the infant macaque studies, the researchers predicted that a higher dose of tenofovir GS-7340 might have had some prophylactic efficacy because of systemic intracellular levels of tenofovir, rather than a direct topical effect; thus, studies "were not able to detect topical prophylactic efficacy" with tenofovir DF or GS-7340.

However, other preliminary research has found that a microbicide gel containing 1% tenofovir did protect against intravaginal SIV infection, suggesting that further study of topical administration is indicated.

As far as oral tenofovir DF, this study is relevant because it sheds light on the efficacy of a 2-dose oral tenofovir regimen (1 maternal dose and 1 infant dose) currently under investigation for the prevention of mother-to-child HIV transmission.

The once-daily 10-mg/kg dosage regimen was "quite effective" in protecting infant macaques against infection during the first set of oral SIV administrations shortly after birth. However, it became less effective at 1 month of age.

Pharmacological and virological data from infant macaques that became infected despite oral tenofovir suggest that the 10 mg/kg drug regimen produced suboptimal systemic drug levels. In previous studies, tenofovir administered by subcutaneous injection "always resulted in a strong reduction and delay of primary viremia and/or selection for the emergence of virus with reduced in vitro susceptibility and a K65R mutation in RT." In this study, in contrast, the oral tenofovir regimen "did not delay or dampen the initial viremia."

Taken together, the results of these two studies suggest that while oral tenofovir is partially effective in delaying or reducing the risk of transmission, it is not able to reliably prevent infection over the long term.

Data presented at the Conference on Retroviruses and Opportunistic Infections this past February showed that a combination of subcutaneous tenofovir plus emtricitabine (FTC, Emtriva) - the two drugs in the Truvada pill - led to a greater reduction in rectal SHIV infection in macaques than either drug alone, suggesting that combination therapy may be a superior PREP strategy.

09/12/06

References

S Subbarao, R A Otten, A Ramos, and others. Chemoprophylaxis with Tenofovir Disoproxil Fumarate Provided Partial Protection against Infection with Simian Human Immunodeficiency Virus in Macaques Given Multiple Virus Challenges. Journal of Infectious Diseases 194(7). October 1, 2006.

K A van Rompay, B P Kearney, B P Sexton, and others. Evaluation of Oral Tenofovir Disoproxil Fumarate and Topical Tenofovir GS-7340 to Protect Infant Macaques against Repeated Oral Challenges with Virulent Simian Immunodeficiency Virus. Journal of Acquired Immune Deficiency Syndromes 43(1): 6-14. September 2006.

J Garcia-Lerma, R Otten, S Qari, and other. Prevention of Rectal SHIV Transmission in Macaques by Tenofovir/FTC Combination. 13th Conference on Retroviruses and Opportunistic Infections, Denver, CO. February 5-8, 2006. Abstract 32LB.