Pre-exposure prophylaxis may only offer limited benefit

Gus Cairns
Published: 27 February 2005

A trial of tenofovir as pre-exposure prophylaxis against rectal exposure to HIV in rhesus monkeys has produced disappointing results, the 12th Retrovirus Conference was told on its final day in Boston.

In the pioneering trials of tenofovir as a preventative drug in 1995, which achieved 100 per cent protection, Gilead scientists injected monkeys with a single massive dose of SHIV monkey/human chimeric HIV virus, containing 1000 times the viral load equivalent of human semen during acute HIV infection.

The Centers for Disease Control trial used a viral ‘challenge’ model resembling sexual exposure more closely than previous trials.

The monkeys in the current study were challenged with repeated weekly rectal inoculations containing about 400,000 copies of SHIV virus per ml – this is about 3-5 times the maximum seminal viral load in acute infection.

Four monkeys received tenofovir once-daily, four once-weekly, and four a placebo, two hours before the rectal SHIV inoculation.

Two of the control animals were infected after one inoculation, one after two, and one not till 11 inoculations.

In comparison tenofovir delayed but did not prevent infection in the other monkeys. Of those given a daily dose, two were infected after six inoculations, one after nine and one after 14.

Two of the weekly dosed monkeys were infected after six inoculations, one after eight and one after eleven.

The mean number of exposures needed to infect was 1.5 in the control monkeys, seven in the weekly-dosed monkeys and 7.5 in the daily-dosed ones.

In a commentary after the trial presentation, Bob Grant of the University of California, San Francisco counselled cautious optimism rather than disappointment. He said that if the tenofovir had been a vaccine, and considering each rectal exposure as a separate event, tenofovir offered 70 per cent protection: the likelihood of infection after one exposure was 50 per cent but tenofovir reduced it to 15 per cent.

He also said that though the rectal exposure model was more like human sex it still was not very comparable, “At least, not on a good day”.

The seminal viral load would be at least three to five times lower. Estimates of the number of episodes of anal sex required to infect 50 per cent of partners ranged from at least 20 in acute infection to several hundred in chronic infection rather just one, as in this trial. Tenofovir might therefore still play a valuable part in delaying infections.

However he also cautioned that human sex would involve many more exposures, and that this was not the first animal-exposure model of tenofovir to produce less than full protection. In a previous trial (Van Rompay 2001) tenofovir offered about 66 per cent protection to newborn macaques given large doses of SHIV orally to simulate exposure during birth. However three of the five animals infected had lower viral loads and delayed disease progression.

He ended by urging scientific and activist support for the tenofovir pre-exposure trials currently underway, which have caused considerable controversy.

References

Subbarao S. Chemoprophylaxis with oral tenofovir dispropoxil fumarate delays but does not prevent infection in rhesus macaques given repeated rectal challenges of SHIV. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 136LB, 2005.

Grant R. Pre-exposure prophylaxis. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 137, 2005.

Van Rompay K et al .Two low doses of tenofovir protect newborn macaques against oral simian immunodeficiency virus infection. J Infect Dis 184: 429-438, 2001.