Just five months after the announcement of iPrEx’s promising
results, a large trial of pre-exposure prophylaxis in women was closed in April
2011. The investigators concluded that even if it continued for its originally
planned duration, the FEM-PrEP trial was highly unlikely to show a significant
protective effect of Truvada against
HIV infection in this population.
However the trial organisers, Family Health International,
stressed that based on the interim
trial results, it could not be determined whether or not Truvada was effective in the prevention of HIV infection in women.
Further analyses (ongoing at the time of writing) are required before any
conclusions can be made.
The FEM-PrEP study recruited 1951 HIV-negative women aged 18
to 35 at risk of HIV infection in South Africa,
Kenya and Tanzania. Women
were randomised to receive daily oral Truvada
(tenofovir and FTC in one pill) or placebo. On average, participants took the
study drug for 12 months and attended study visits for 14 months.
Among all trial participants the approximate annual rate of
new HIV infections was 5% per year, and a total of 56 new infections had been
recorded up to February 2011. These were equally distributed between the Truvada and placebo groups (28 in each
The decision to halt recruitment early indicated that the
Independent Data Monitoring Committee, which scrutinised the trial, came to the
conclusion that even if another 2000 women were to be enrolled onto the trial
and followed for a year each (as planned), it was highly unlikely that any
protective effect of Truvada that
might emerge would be enough to demonstrate a statistically significant benefit
This might be because the magnitude of effect seen in the
first 1951 women was somewhat too small to be statistically significant, or
because there was no substantial difference, and more analysis of the trial
data will be needed.
In particular it is unclear whether the women in the two
study arms had a similar total exposure to their assigned study medication: an
equal number of infections at month 12 may not translate into an equal rate of
infection, because women in one group may have a higher number of total months
covered by study medication.
The investigators said they planned to concentrate further
analyses on two linked areas: a detailed investigation of adherence, and of
drug levels in women taking Truvada.
Overall adherence (based on participant’s self-report) was
95%, but at the time of writing, there are no data on differences in adherence
between study arms, differences in adherence over time or differences in adherence
according to the adherence measures used.
Monitoring will look into whether drug levels in blood are
matched by levels in the vagina. Studies have found that oral tenofovir tends
to reach higher levels in rectal tissues than in vaginal tissue. Although a
study presented at the 2011 Conference on Retroviruses and Opportunistic
Infections (CROI) found adequate levels in vaginal tissue, presenter Craig
Hendrix warned that “what is ‘enough’ for prevention is yet to be defined”.1
There were significantly more pregnancies in women taking Truvada than placebo. This could explain
the lack of efficacy. Pregnancy excluded women from the trial, which would mean
women on Truvada spent more time not
taking pills, on average, than women on placebo. Any protective effect of Truvada may be so attenuated that it was
not demonstrably better than placebo.
The more troubling possibility is that Truvada had an unexpected drug interaction with the women’s
contraception (all participants were provided with free contraceptives, in most
cases injectable or oral hormonal contraceptives). If tenofovir or FTC altered
levels of contraceptive, this could also alter the thickness of the vaginal
mucous membrane and thus alter a woman’s vulnerability to HIV. However, no such
interaction has been described.
The third possibility is that side-effects amongst women
taking Truvada might have caused
their adherence to be poorer than in women taking placebo; the iPrEx study
found a higher rate of nausea in men taking Truvada
in the first month.
The result may indicate that antiretroviral drugs may show
different levels of effective prevention in different populations, social
groups and locations. This may be driven by differences in adherence or sexual
behaviour. It therefore underlines the importance of testing new prevention
technologies in a variety of different populations.