PrEP could work even if taken several days in advance

Gus Cairns, Michael Carter
Published: 09 February 2009

A study using tenofovir and FTC (Truvada) to prevent rectal SHIV infection in monkeys – so-called pre-exposure prophylaxis (PrEP) - has shown that it is as effective for the medication to be given up to three days before exposure as it is one day before. Even giving Truvada a full week before exposure resulted in a considerable reduction in the risk of infection.

In contrast, giving the medication only two hours before exposure resulted in a smaller protective effect, possibly because intracellular concentrations of the drugs had not reached high enough levels.

The study is not a ‘pure’ trial of the PrEP concept because in all cases the monkeys were also given a single post-exposure dose of Truvada. However it does demonstrate that constant PrEP is not necessary to confer significant protection and that intermittent dosing may, if anything, be even more effective, at least in the case of Truvada.

The study population consisted of a total of 51 male rhesus macaques. They had 14 weekly rectal exposures to SHIV, an artificial form of HIV adapted to infect monkeys (except one group that was exposed every two weeks).

The control arm included 27 animals that received no treatment. There were five treatment arms including a total of 30 animals all given two doses of drug. The dosing intervals in the five treatment arms were:

  • 1. Two hours before viral exposure and 22 hours afterwards
  • 2. Twenty-two hours before and two hours afterwards
  • 3. Three days before and two hours afterwards
  • 4. Seven days before and two hours afterwards (this group was exposed to the virus once every two weeks)
  • 5. An entirely post-exposure prophylaxis group, given Truvada two and 26 hours after viral exposure.

The monkeys were tested for SHIV RNA in the blood and inside cells and for antibodies to the virus. If all three were absent they were regarded as not infected.

All but one of the animals in the control arm became infected, after a median of two exposures.

Three of the six animals in group one were protected from infection. So were three of the animals in group five, who received PEP. This represented an approximately fourfold reduction in the risk of infection (p = 0.029).

Five macaques in group two were protected and five in group three, though the one in group three was infected slightly earlier. These represent respectively an approximately 16-fold risk reduction (p = 0.007) and a 14.5-fold risk reduction. (p = 0.01). These were statistically equivalent; in other words, it was as protective to take Truvada three days in advance as one day in advance.

Three animals in group four became infected but time to infection was delayed, indicating a tenfold reduction in risk even when Truvada was taken seven days in advance.

The investigators did a pharmacokinetic study in four animals, studying the way the drugs were absorbed and eliminated. It took five days for half of the tenofovir within cells to be eliminated and about 24 hours for FTC. There was no significant difference in blood or cellular drug levels between protected and unprotected animals.

Finally, as other studies have shown, animals that did become infected despite PrEP developed lower viral loads than the control group, at least initially. The viral load in animals that were given Truvada was 1.5 log or 30 times lower up to 13 weeks after infection. This may imply less immune damage during the initial phase of HIV infection.

References

Garcia-Lerma G et al. Prevention of rectal simian HIV transmission in macaques by intermittent pre-exposure prophylaxis with oral Truvada. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 47, 2009.