The recent WHO guidance comes as a result of a study
conducted in Thailand, which found that future treatment
options for mothers were compromised by exposure to short
course nevirapine treatment, even when given with AZT from week
28 of pregnancy. The same study found that a combination of
AZT, given from week 28 of pregnancy, and a single dose of
nevirapine, appears to be almost as effective as Highly Active
Antiretroviral Therapy for the mother in blocking HIV infection
of the infant. The findings were presented at the Eleventh
Conference on Retroviruses and Opportunistic Infections in San
Francisco on February 9th.
The study, called PHPT-2, recruited 1844 pregnant
HIV-positive women, and randomised them and their newborns to
receive either:
**one dose of nevirapine for the mother at delivery and
nevirapine within 72 hours of birth for the infant (the
nevirapine/nevirapine arm)
**nevirapine for the mother at delivery and a placebo for
the infant (the nevirapine/placebo arm)
**placebos for both mother and infant (the placebo/placebo
arm)
All mothers received AZT for the last three months of their
pregnancy, and all infants received AZT syrup for the first
week of life. No infants were breastfed.
The placebo/placebo arm of the study was stopped after an
interim analysis showed a higher rate of HIV transmission from
mother to child in this arm (6.3% vs 1.1% in the
nevirapine/nevirapine arm, p=0.00026).
The final analysis of the study showed that the
nevirapine/nevirapine
regimen proved only slightly superior to the nevirapine/
placebo arm in reducing the rate of transmission (2.0% vs
2.8%). This difference was not statistically significant. HIV
DNA testing was carried out at birth, week 6 and months 4 and 6
to determine if the child had become infected.
A random sample of 90 women exposed to nevirapine showed
that
NNRTI-associated mutations were present in 18% of women
tested 12 days after delivery, whilst a pharmacokinetic study
showed that 77% of the women had detectable levels of
nevirapine 5-15 days after delivery, and detectable levels of
nevirapine were still present in one woman 19 days after
delivery.
A sub-analysis of mothers (n=255) who needed to start triple
antiretroviral therapy with d4T/3TC/nevirapine due to CD4
counts below 250 cells/mm3 after delivery showed
that women exposed to nevirapine at delivery had significantly
poorer virologic responses after six months of treatment if
they showed evidence of nevirapine resistance six weeks after
delivery, with a trend towards poorer response also evident in
women who
were exposed to nevirapine without developing detectable
resistance to the drug.
A quarter of women who participated in PHPT-2 needed
antiretroviral treatment after delivery, and the researchers
found that when virologic response was measured using an
ultrasensitive viral load assay, only 34% of women with at
least one nevirapine-associated mutation had viral load below
50 copies/ml after six months of treatment (n=65), compared to
75% of women not exposed to nevirapine (n=42) (p=0.001). 53% of
women exposed to nevirapine without evidence of resistance had
viral load below 50 copies at this point, leading Professor
John Mellors of Pittsburgh University School of Medicine to
note that this trend mirrored results from a study presented by
his group in the same session.
Dr Mellors group found that participants in the ACTG 398
study who added efavirenz to HAART were significantly more
likely to experience virologic failure if they had been exposed
previously to another NNRTI, even in the absence of resistance
detectable by normal assays. Using a highly sensitive
resistance assay, the ACTG 398 researchers found that between
0.6% and 7% of the virus population in previously exposed
patients already carried the same mutation at baseline that
would later emerge upon failure of the efavirenz-containing
regimen. This result would be missed by standard genotypic
resistance testing, which cannot detect minority populations
that comprise less than 10-20% of the total virus population in
a blood sample.
In the PHPT-2 sub-study women who started treatment more
than six months after delivery had a better response to
treatment, suggesting that starting treatment earlier is likely
to result in a sub-optimal response.
Although treatment responses appeared equivalent when
measured by CD4 cell response, experts argue that poorer
virologic responses at six months signals a higher risk of
treatment failure.
Dr Diana Gibb urged some caution over interpretation of
these results. I think these results need to be replicated on a
larger scale for longer before we throw out nevirapine short
course treatment. One of the questions I have is whether the
poorer response was because those women with mutations were
also more likely to have advanced disease, and disentangling
the effects of these two on response is difficult.
Dr Haruna Jibril of Botswanas MTCT programme told us that
investigators in the MASHI study of AZT plus nevirapine will
look at virologic response to nevirapine in mothers previously
exposed to the drug one year after they start HAART. This
analysis will evaluate response in approximately 230 women who
have begun antiretroviral therapy since being exposed to
nevirapine at delivery.