Tenofovir/Emtricitabine Pre-exposure Prophylaxis Prevents Rectal Transmission of HIV-like Virus in Monkeys

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Given recent disappointing results from trials of HIV vaccines, use of antiretroviral drugs for prevention of infection has received increased attention.

Pre-exposure prophylaxis (PrEP) refers to the use of antiretroviral drugs by HIV negative people prior to exposure to the virus in an effort to prevent infection. It is distinguished from post-exposure prophylaxis (PEP), which refers to taking drugs after a potential exposure - for example, a needle-stick in a healthcare setting or a broken condom - to prevent HIV from taking hold in the body.

Viread
Tablet

Emtriva
Capsule

In the February advance online edition of the open-access journal PLoS Medicine, researchers with the U.S. Centers for Disease Control and Prevention (CDC) reported on a study of the nucleotide reverse transcriptase inhibitor tenofovir (Viread) plus the nucleoside reverse transcriptase inhibitor emtricitabine (Emtriva) as PrEP to prevent monkeys from becoming infected with a SHIV, a simian/human virus related to HIV. Tenofovir and emtricitabine are the 2 drugs in the Truvada combination pill, and are coformulated with efavirenz (Sustiva) in the once-daily Atripla pill.

The investigators treated macaque monkeys (6 per group) with one of 4 PrEP regimens before exposing them to SHIV:

• Group 1: once-daily emtricitabine by subcutaneous injection at a dose equivalent to that typically used by human patients;

• Group 2: once-daily oral emtricitabine plus tenofovir at doses equivalent to those used by humans;

• Group 3: once-daily human-equivalent subcutaneous dose of emtricitabine plus a higher dose of tenofovir (3 to 4 times that usually used by patients);

• Group 4: intermittent PrEP regimen similar to that given to Group 3, but used only 2 hours before and 24 hours after each virus exposure rather than daily;

• Control group: no PrEP (n = 9 in this study, 9 historical controls).

Monkeys were challenged with weekly rectal exposures to SHIV, simulating receptive anal sex, for 14 weeks.

Results

• All PrEP regimens offered some degree of protection.

• The risk of infection among macaques in Group 1 was 3.8-fold less than that of the untreated control monkeys (P = 0.02).

• Of the 6 monkeys in this group, 2 were protected after 14 exposures, whereas 4 became infected after 5, 10, 12, and 13 exposures.

• The risk of infection among those in Group 2 was 7.8-fold lower than that of the control group (P = 0.008).

• In this group, 4 monkeys were protected, whereas 2 were infected after 9 and 12 exposures.

• None of the 6 monkeys in Group 3 were infected.

• All 6 monkeys in receiving intermittent PrEP in Group 4 were also protected.

• Macaques that experienced infection despite PrEP had lower viral loads compared with untreated monkeys.

• 2 treated monkeys developed drug resistance to emtricitabine; none developed resistance to tenofovir.

Conclusion

"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 wrote. "Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model."

Since none of the protected monkeys showed evidence of transient systemic infection, the researchers suggested this likely reflected the ability of emtricitabine and tenofovir to "effectively block the earliest SHIV infections, possibly at the mucosal point of entry, before significant systemic dissemination of the virus occurs."

While the data suggest that higher drug doses and combination therapy may be more effective than single drugs or lower doses, they also showed that PrEP may work if taken only around the time of exposure rather than daily, which would be less costly and less likely to cause long-term side effects (such as the kidney problems and bone loss associated with tenofovir in some studies).

The authors added that by reducing viral load if infection occurs, PrEP could reduce the risk of transmitting HIV to a partner before the first person is aware that he or she has been infected. A potential drawback is that partially effective PrEP could lead to drug resistance, which could reduce the options for treatment.

"Carefully designed human studies will be needed to determine which, if any, PrEP strategies will be effective in practice," the investigators concluded.

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.

2/29/08

Reference
J Gerardo Garcia-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. February 5, 2008 [Epub ahead of print].