Two studies of pre-exposure prophylaxis (PrEP) in heterosexuals in Africa, both of which reported significant efficacy in preventing HIV infection last year, published their final results in the New England Journal of Medicine last week.
Drug level tests found that the relatively high efficacy found in the Partners PrEP trial (Baeten)and the TDF2 trial (Thigpen) were associated with high levels of adherence, with participants who did not acquire HIV infection taking about 80% of their doses, on average.
Although the studies do seem to show that high levels of adherence to PrEP are achievable, they also included some findings that underline concerns sometimes expressed about PrEP. One study found that a significant degree of bone loss was found in people taking tenofovir, and in both studies there were cases where participants had acute HIV infection when they started taking PrEP, which was only diagnosed later, and in some cases developed high levels of resistance to tenofovir and/or FTC.
Efficacy of PrEP in the two studies
Partners PrEP was a study in 4758 couples of differing HIV status in Kenya and Uganda, where the HIV-positive partner was not yet eligible for HIV treatment (their median baseline CD4 count was 495 cells/mm3) and the HIV-negative partner took daily tenofovir, Truvada (tenofovir/FTC) or placebo. TDF2 was a study in 1219 heterosexual men and women in Botswana, 90% of them in their 20s, who took either Truvada or placebo.
Efficacy results were announced at the International AIDS Society conference in Rome last year. In Partners PrEP, Truvada reduced HIV infections, compared to placebo, by 75% (annual incidence on placebo 2%; on Truvada 0.5%). In TDF2, it reduced infections by 62% (incidence on placebo 3.1%; on Truvada 1.2%). In Partners PrEP, the lower bound of the 95% confidence interval, which means the lowest likely “real” reduction in infections, given the possibility of random effects, was 55%.
Because it was a smaller study, TDF2 could not demonstrate this degree of certainty about its result (lower bound of 95% confidence interval, 21.5%). However the researchers conducted a separate analysis where they stripped out from the results 24 participants who had not returned for follow-up visits more than a month after their last dose of study medication (placebo or Truvada) ran out, and who were therefore unlikely to be taking it. When this non-adherent group was excluded, the efficacy of Truvada versus placebo was 78% and the lower bound of the 95% confidence interval was 41%.
Drug levels and adherence
Both studies tested drug levels in a random selection of participants who stayed free of HIV and compared them with drug levels in people who had become infected. In Partners PrEP 82%, and in TDF2 80%, of trial volunteers who did not become infected had detectable drug levels in their blood.
In the TDF2 report the researchers quote the actual level and it is consistent with reasonable adherence (30ng/ml). In contrast, in people who became infected, drug levels were detectable in 31% of participants in Partners PrEP and 50% of participants in TDF2, but in TDF2 these levels were on average a hundred times lower than in non-infected people (0.3ng/ml), suggesting extremely inconsistent adherence.
In Partners PrEP, about 50% of participants managed high levels of adherence throughout the study, though in others it declined over time. In TDF2, the reason the study was less able to demonstrate efficacy was due both to a decline in HIV risk (because people had fewer than expected partners) and to a very high drop-out rate. In this young, mobile population, many participants left their area to work or study, and there was a 36% dropout rate in the Truvada arm and a 32% dropout rate in the placebo arm. The study would have had to be expanded to 2500 participants to achieve the statistical power to demonstrate the efficacy the researchers had hoped for, which was not practicable. In Partners PrEP sexual risk behaviour also declined, mainly due to an increase in condom use over time.
Testing and resistance
In both studies, some participants were found to have primary HIV infection when they joined the study: eight in Partners PrEP and three in TDF2 (compared with 96 and 62, respectively, who were infected during the study).
In three cases, these participants developed HIV that was resistant to their PrEP drugs. One participant who took tenofovir alone in the Partners PrEP trial developed high-level resistance to tenofovir and one taking Truvada developed resistance to FTC, while one participant in the TDF2 trial developed resistance to both drugs. One participant in TDF2 who had primary HIV infection at baseline, but took placebo, had very low-level resistance to tenofovir, probably a transmitted resistant virus. No participants who became infected with HIV after enrolment developed drug resistance.
Safety and side-effects
In both studies, participants taking tenofovir or Truvada had increased levels of gastrointestinal symptoms (diarrhoea, vomiting and especially nausea, which was over twice as common) than participants taking placebo. There were no indications of kidney problems related to the drugs.
TDF2, however, also measured bone mineral density (BMD), and observed a significant and continuing loss of BMD over the two years of the study, in contrast to participants taking placebo, who gained BMD. In contrast, in TDF2, participants taking placebo had a higher rate of urethral STI symptoms than people taking tenofovir, though the researchers do not comment on whether the study drugs may have had some effect on this.
Taken together, the two studies show that adherence to PrEP can be maintained at quite high levels over two years, and that this is associated with high efficacy; although adherence tailed off over time, so did sexual risk behaviour. However, they also underline how essential it is to ensure that people do not start taking PrEP when they have just become infected with HIV, underlying the need for rigorous testing before it is prescribed. Although PrEP was generally safe, the decline in bone mineral density seen in TDF2 is of concern, and underlines the need to research PrEP regimens not based on tenofovir.
Baeten JM et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. NEJM DOI: 10.1056/NEJMoa1108524. 2012.
Thigpen MC et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. NEJM DOI: 10.1056/NEJMoa1110711. 2012.