differ between women taking first-line antiretroviral therapy based on
ritonavir-boosted atazanavir and efavirenz, investigators from the United
States report in the online edition of Clinical
Infectious Diseases. Women taking the boosted protease inhibitor had a
higher risk of virological failure than women treated with efavirenz. There was
also some evidence that outcomes differed between women and men treated with
were “unexpected”, but the investigators
believe they are of clinical significance. Currently, US guidelines recommend atazanavir/ritonavir as the preferred treatment during pregnancy because of the theoretical risk of birth abnormalities
associated with efavirenz.
Little is known
about the association between sex and antiretroviral treatment outcomes. This
is an import question to address as an increasing proportion of HIV infections
therefore designed the ACTG A5202 study. A total of 1857 participants, 322 of whom
were women, were recruited to the study at sites across the US and Puerto Rico
between 2005 and 2007. All the participants were aged 16 years and over and were
taking HIV treatment for the first time.
The study was
open-label and the participants were randomised to receive therapy based on
ritonavir (Norvir)-boosted atazanavir
(Reyataz) or efavirenz (Sustiva or Stocrin), in combination with a nucleoside/nucleotide backbone of
either 3TC/abacavir (Kivexa) or
endpoints were: virological failure (viral load above 1000 copies/ml between
weeks 16 and 24 of therapy, or a viral load above 200 copies/ml after 24 weeks of
treatment), and also safety and tolerability.
atazanavir/ritonavir and efavirenz had similar virological efficacy among
participants taking the Kivexa backbone. However, outcomes
differed significantly according to sex. The risk of virological failure was
higher for women randomised to atanzanavir/ritonavir than efavirenz, with
incidence rates of 12.52 per 100 person-years versus 4.86 per 100 person-years
(HR = 2.55; 95% CI, 1.20-5.41). Women taking atazanavir/ritonavir also had a
higher risk of virological failure then men taking this drug (HR = 1.72; 95%
differed by sex in the Truvada arms.
The risk of treatment failure was higher among women randomised to
atazanavir/ritonavir than among women taking efavirenz (incidence = 10.90 vs.
5.06 per 100 person years. HR = 2.16; 95% CI, 0.97-4.80). Women taking
atazanavir/ritonavir also had a higher risk of treatment failure than men
randomised to this drug (HR = 2.36; 95% CI, 1.30-4.26).
Adherence did not
differ by sex and did not affect the investigators' findings.
“This is the first
randomized clinical trial to identify a higher risk of VF [virological failure]
in women assigned to an ATV/r [atazanavir/ritonavir]-containing regimen
compared to a regimen with EFV [efavirenz],” comment the authors.
There were also
some differences in safety and tolerability outcomes between men and women.
There was also
some evidence that safety outcomes differed according to sex and nucleoside/nucleotide
Among the participants
randomised to take Kivexa, women were
more likely to experience side-effects than men (HR = 1.32; 95% CI, 1.03-1.70).
Women taking atazanavir/ritonavir also had a slightly increased risk of
gastrointestinal side-effects compared to men taking this protease inhibitor
(13 vs 7%) and also compared to women treated with efavirenz (13 vs 6%).
There was no
evidence that safety outcomes differed between men and women taking Truvada as their nucleoside/nucleotide
analysis showed that atazanavir oral clearance and trough concentrations
differed according to sex, with women having higher concentrations than men (p
= 0.004 and p = 0.003, respectively).
The investigators hypothesise
that “higher ATZ levels may lead to higher rates of low level (unmeasured)
toxicity that could affect outcomes”.
They conclude that this could have important clinical
implications, “given that RTV [ritonavir]-boosted PIs are often favored over
EFV for women of childbearing potential…the findings of the current study
should warrant additional investigation of antiretroviral regimens in
randomized clinical trials and cohorts with large enrollment of women.”