HIV PrEP Explained: Critical Prevention Opportunity

Published: April 25, 2011

In late 2010 the New England Journal of Medicine published an authoritative report of a trial of PrEP (pre-exposure prophylaxis) in over 2,000 HIV-negative but high-risk gay men, showing that one pill a day of the approved HIV medicine Truvada could prevent HIV infection.[1] Science magazine listed this study as one of the top 10 achievements of 2010 [2]; and President Obama issued a statement about this trial.[3] For background, see [4].

The headline result is that Truvada was 44% effective (compared to placebo) in preventing HIV transmission in this population. This sounds disappointingly low. Why then is the study considered so important?

Much of the answer is that 44% is not the whole story. In the group randomly assigned to take a placebo, 64 became infected during the study; in the group randomly assigned to take Truvada, 36 became infected. Because the sizes of the groups were almost exactly equal (1251 participants, vs. 1248), you can compute the 44% by simple arithmetic.

Fortunately the study did blood testing of the 36 people who became infected despite being assigned to take Truvada, to see if they were really taking the drug. About 90% of them (33 of the 36) had no drug in their body when tested, at the last blood draw before they were found to have HIV. (Truvada consists of two drugs, and no detectable level of either drug was found in any of the 33 people.) The drug-level testing methods had been carefully validated, and can detect the active form of at least one of the drugs two weeks after people stop using the pills. Clearly these study participants had not been taking the medicine when tested. When these trial volunteers who were assigned to take the drug (but had not in fact taken it) were not counted, the effectiveness was not 44%, but over 90%.

It gets better. The other 3 participants who became HIV infected during the trial had very low levels of the active forms of the drugs, just above the limit of detection. Clearly they had taken some Truvada, but were far from using it as directed.

So of the 100 participants who became HIV-infected during this trial, 97 had not used Truvada at the time of the last blood draw — and the other 3 had used it very poorly. Of those who actually took one Truvada pill per day throughout the study, not one became HIV-infected during this trial (vs. 64 of those who had been given the placebo). So for those who actually used the drug as directed, throughout the entire study, it was 100% effective in this trial, which had over 1,000 high-risk gay men assigned to take Truvada.

But the blood draws occurred in this study at weeks 4, 8, 12, 16, 24, and then every 12 weeks. So we cannot rule out the possibility that one or more people who had not taken Truvada for about two weeks or more before one of those visits, then got religion after the visit, and starting taking the pills daily — yet got infected despite having adequate drug levels. This seems unlikely in view of the overall findings. But if it did happen, then it would mean that the protection was less than 100% in those who were using the drug. It was not possible to have everyone wear a device that that could record drug levels continuously — and also tell exactly when they got HIV. So there is no way to be sure that nobody had enough drug in their body when they were infected. For this reason, 100% effectiveness is not claimed or reported.[5]

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