requirement that all participants take hormonal contraceptives may
have been what led to the disappointing failure of a study of
pre-exposure prophylaxis (PrEP) targeted at single women, the International Microbicides Conference in Sydney was told today.
The FEM-PrEP study was stopped in April 2011 because almost as many HIV
infections had occurred in women given tenofovir/FTC (Truvada)
pills (33 infections) as in women given inert placebo pills (35).
This result contradicted efficacy results seen
previously in gay men and subsequently in two other PrEP trials
involving women, Partners
PrEP and TDF2, where Truvada
stopped between a half and two-thirds of the HIV infections that
would otherwise have occurred in female trial participants.
such a different result in FEM-PrEP? A
study presented recently at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle showed
that fewer than 40% of women actually took the pills with reasonable
frequency. Since then, as Connie Celum (principal researcher in the
Partners PrEP study) told the conference today, drug
level studies have established it was even worse: only 26% of
participants who did not
acquire HIV took the drug as prescribed.
was also an extraordinary contradiction between participants'
adherence based on pill counts and self-reports, and their actual
adherence. Self-reported adherence is usually higher than it is
in reality, as are other 'good' behaviours like condom use or not
breastfeeding, but are usually correlated with actual adherence to
some extent. In FEM-PrEP there was no relationship between the two:
self-reported adherence was 95% and adherence based on pill count was
was adherence so low in FEM-PrEP and misreporting it so
disproportionately high? One answer may lie in the requirement that
all participants take hormonal contraception. Because safety
requirements around drugs in pregnancy are so strict, PrEP trials in
women have required either that they drop out of the trial if
pregnant or use contraception in order not to become pregnant.
pregnancy leads to trial exclusion, this may make the trial too small
to produce a meaningful result, as may have happened in the
trial of PrEP in west Africa. So the FEM-PrEP researchers
required all participants either to be on hormonal contraception or
to start it.
the start of the trial, 38% of participants were using injectable
hormonal contraceptives, 8% were using the contraceptive pill and
2.5% other non-barrier methods like IUDs. Of the other 50% of
participants, one-third (17% of participants) were using condoms as
their birth control method and two-thirds were not practising birth
the women not already using hormonal contraceptives, 55% (28% of
participants) decided to take an injectable contraceptive but 43%
(22% of participants) took the oral contraceptive pill, a much higher
proportion than that of existing users of contraceptives. Previous non-users tended to be younger
(23.5 versus 25 years) and were much less likely to be married (22
versus 40%) than existing users. They were at just as much risk of
HIV, had the same number of sexual experiences, and had the same high
rate of STIs (one woman in six had an STI diagnosed).
this, 70% thought they were "not at high risk of HIV" even though
local background incidence is five infections per 100 women a year.
Women starting contraception were therefore starting two new medications – the
contraceptive and PrEP – and if they were taking the contraceptive pill, both
medications had to be taken every day. Far more of the women who were new to
hormonal contraception (6%) than women who were already using contraception (2%)
told the researchers they had switched the method of contraception they were
using during the trial. Among women taking oral contraception, 13% of those who
were new to contraception and 8% of women already using contraception switched
during the trial.
of adherence to oral contraceptives must have been much lower than
this. The pregnancy rate in trial participants was high, despite the
contraceptive requirement. Overall, 8% of participants became
pregnant per year. In new initiators of contraception it was higher –
14% – and in those who started oral contraceptives it was a sky-high
30% a year. In contrast, it was 2% in those taking injectable
contraceptives, regardless of whether they were new or existing
users. Clearly, adherence to the contraceptive pill must have been very low.
there a link to low Truvada
adherence? Yes, there was, to the extent that if FEM-PrEP had been
restricted to women already using injectable contraception, the study
would have very nearly produced a positive result. The risk of HIV
acquisition was 80% higher than average in women who initiated the
oral contraceptive pill; conversely, it was 53% lower than average in
current users of injectable contraceptives. Because of the small
number of infections, neither of these differences was statistically
significant, but the 53% reduction nearly was (95% confidence
interval 79% to minus 4%).
adherence to Truvada was
modestly lower in contraceptive initiators and they were, as already
pointed out, younger and more likely to be single and, if they became
pregnant, to do so for the first time. These effects moderate the
lower adherence to Truvada and
summary, adherence to contraception was extremely low in those taking contraceptive pills as well as in general to Truvada. These
results don't imply a causal link between the contraception
requirement and the trial failure but they could help to explain why
self-reported adherence was so unreliable; women applying to the
trial, who may already not think themselves at enough risk of HIV to
remember a daily PrEP pill, may also have to remember to take an oral
contraceptive pill – or may have had no intention of taking it.
They then also have to 'confess' to researchers that they have taken
neither of their medications.
conclusion, presenter Douglas Taylor said, the results of the
FEM-PrEP study require researchers to reflect on how better to screen
trial applicants and to support adherence non-judgementally during