Four doses of PrEP a week may be enough to protect

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Further testing of drug levels in the blood and immune cells of gay men participating in the iPrEx trial of tenofovir/FTC (Truvada) pre-exposure prophylaxis (PrEP) has found that HIV infection in men assigned to Truvada was associated with a lapse in taking the drug after initially adhering reasonably well, rather than never having taken it at all, which was what the researchers originally thought. The research was presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI), in Seattle.

The testing also found that only a minority of participants appeared to be taking their drugs as prescribed, seven days a week, but that protection levels were very high – in the order of 96% of infections prevented – as long as participants took four or more doses a week.

Drug levels plummet three months before infection

The results of iPrEx, a large multi-country study of PrEP in gay men, were announced in 2010 and showed an overall efficacy of 42% – in the trial subjects as a whole, four out of ten HIV infections that would otherwise have happened were prevented if subjects were given Truvada pills to take daily rather than placebo pills. When drug levels were tested in the 48 participants who became HIV-infected on Truvada, and a random sample of uninfected participants, it was found, perhaps not surprisingly, that drug was detectable in only 10% of the infected participants but also, perhaps more surprisingly, in only 50% of the uninfected ones.

New measurements have now looked back at drug levels in stored samples in the months prior to infection and compared with drug levels in the same time period in uninfected participants. In the uninfected participants, consistently 45% or so had detectable drug in their samples across the whole length of the study – confirming that at least half of the participants simply never took their pills. In the infected participants average adherence rates started off the same as in the uninfected. They showed a slight decline in the first year of the trial but then declined to 10% in the three months preceding infection. This suggests a role for quarterly adherence reinforcement.

What levels of tenofovir are protective?


detectable viral load

When viral load is detectable, this indicates that HIV is replicating in the body. If the person is taking HIV treatment but their viral load is detectable, the treatment is not working properly. There may still be a risk of HIV transmission to sexual partners.


Studies aim to give information that will be applicable to a large group of people (e.g. adults with diagnosed HIV in the UK). Because it is impractical to conduct a study with such a large group, only a sub-group (a sample) takes part in a study. This isn’t a problem as long as the characteristics of the sample are similar to those of the wider group (e.g. in terms of age, gender, CD4 count and years since diagnosis).


A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.


How well something works (in a research study). See also ‘effectiveness’.


The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.

The researchers also wished to find out what levels of tenofovir in the blood were associated with protection against HIV. They did this by comparing drug levels in iPrEx participants with drug levels in a small study called STRAND, presented at last year’s conference (Liu),which gave participants directly-observed doses of tenofovir twice, four time or seven times a week and then measured drug levels in their hair. By then comparing the levels of protection seen in participants with specific drug levels in iPrEx, the researchers were able to compute what drug level was protective.

In iPrEx the average drug levels seen in infected people were consistent with less than one dose of tenofovir a week, but drug levels in those who were not infected were consistent with only about three doses a week. Only 18% of iPrEx participants had drug levels consistent with taking seven doses a week. The investigators used very sensitive tests to look at levels of metabolised tenofovir inside cells and found that a reduction of 90% in the risk of HIV infection correlated with a drug level of 16 femtomoles per mol (fm/M). The average level associated with seven doses a week in STRAND was about 38 fm/M and with four doses a week about 32 fm/M.

This enabled them to calculate that the protection offered by taking four doses of tenofovir a week was high, and more or less the same as taking seven doses – that is, in the order of 96%, with a minimum likely protectiveness of 90%. They also calculated that absolutely perfect adherence would offer 99% protection. Taking two doses a week (consistently) would still offer 72% protection, though within wide confidence intervals (56% to 96%) while the 42% level of protection actually seen in iPrEx was consistent with participants taking, on average, one dose a week.

This study has important limitations. STRAND did not measure FTC levels so the iPrEx researchers could not calculate what extra protection was offered by that drug. They also could not measure drug levels at the actual moment of exposure – they were measured at anything between 15 and 90 days after infection. And of course the ‘number of doses a week’ measure is purely an average – most participants probably had much more irregular patterns of taking their pills, with (amongst the 50% who took it at all) periods of good adherence interspersed by periods off drug, maybe correlated with times on and off sex. But it does give a guide to the likely minimum levels of tenofovir that people need to maintain in order to be protected from HIV.

For more on the importance of drug levels in PrEP, see also the stories on the FEM-PrEP and Partners PrEP studies and on the injectable formulation of rilpivirine.


Anderson P et al. Intracellular tenofovir-DP concentrations associated with PrEP efficacy in MSM from iPrEx. 19thConference on Retroviruses and Opportunistic Infections, Seattle, abstract 31LB, 2012. The abstract is available on the official conference website

Liu A et al. Validating Hair as a Biological Marker of TFV Drug Exposure in HIV PrEP. 18th Conference on Retroviruses and Opportunistic Infections, Boston, abstract 995, 2011. The abstract is available on the official conference website.

A webcast of the session HIV prevention: PrEP, microbicides and circumcision, is available through the official conference website.