a bid to reduce the risk of nevirapine resistance after the use of single-dose
nevirapine to prevent mother-to-child HIV transmission, several research groups
are now experimenting with the use of drugs that can speed up the clearance of
nevirapine from the mother’s bloodstream after giving birth.
example, adding single-dose carbamazepine, a cheap, readily available
anti-convulsant and enzyme inducer, to single-dose nevirapine for the
prevention of mother-to-child transmission (PMTCT) in HIV-infected women in
Tanzania at the start of labour had no effect on nevirapine levels in the blood
at delivery. But it considerably reduced them one week later and at six weeks
showed a significant decrease in nevirapine resistance mutations, researchers
report in the advance online edition of the Journal
of Acquired Immune Deficiency Syndromes.
study is testing the effect of a seven-day course of the antiepileptic drug
phenytoin on nevirapine levels and drug resistance when used in conjunction
with a seven-day tail of AZT and 3TC.
it is the least effective treatment for PMTCT, single-dose nevirapine (sdNVP)
given to the mother at the start of labour and to the infant within 24 to 72
hours after birth is widely used in many resource-poor settings. It is
effective in reducing MTCT by 40%, simple to use and affordable.
non-nucleoside reverse transcriptase inhibitor (NNRTI), nevirapine is a highly
effective antiviral. However, it has a low genetic barrier which means one
mutation can result in high-level resistance. It is quickly absorbed and passes
rapidly through the placenta. It has a long elimination half-life (61 to 66
hours) in pregnant women given a single dose of 200mg, meaning sub-therapeutic
levels remain in the blood. This results in primary nevirapine resistance from
a single dose in 15 to 75% of mothers.
this has three important consequences, note the authors:
virus means the efficacy of combinations of ART that include nevirapine or
another NNRTI are reduced.
Resistant virus can be transmitted to others so
limiting their treatment options.
Nevirapine resistance may reduce the
effectiveness of single-dose nevirapine in future pregnancies.
add, there is no evidence to support this last point.
address this issue of extended time on sub-therapeutic levels of nevirapine and
the development of resistance, the World Heath Organization (WHO) now recommends
adding zidovudine (AZT) and lamivudine (3TC) for seven days after birth. Other studies in
which single-dose tenofovir and emtricitabine (FTC) have been added to sdNVP and
short-course zidovudine also showed reduced NNRTI resistance. Yet, note the authors,
these have not been successful in eliminating nevirapine resistance, “which
remains a serious and growing concern.”
authors chose to look at an alternative strategy involving a pharmacological
intervention to reduce the nevirapine elimination half-life.
is eliminated primarily through a pathway known as cytochrome P-450 3A4 and 2B6
enzymes. So an inducer of these enzymes might speed up the process of
elimination and so reduce the development of resistance.
a pilot study of healthy volunteers comparing eight different enzyme inducers,
the authors found nevirapine elimination half-life was reduced the most (by
35%) by adding single-dose carbamazepine. As a follow-up the authors undertook
a phase II trial to see what the levels of nevirapine in the blood would be at
one week after delivery and nevirapine resistant mutations at six week after
HIV-infected pregnant women aged 18 to 40, with CD4 cell counts greater
than 200 cells/mm3 and attending antenatal clinics in Moshi, Tanzania, were
enrolled on a 1:1 basis at alternate allocations to get either 200mg of sdNVP
alone or in combination with open-label 400 mg single-dose carbamazepine (sdNVP/CBZ)
February 2006 and April 2009, 354 women were screened, of whom 54% (192) were
eligible for the study, with a final number of 158 taking part at delivery. In 61 (83%) of
the women who got sdNVP, and in 72 (87%) of those who got sdNVP/CBZ, median
levels of nevirapine in the blood at delivery was comparable to findings in
other studies: 1.55 (0.88-1.84mg/L) and 1.40 (0.93-1.97) mg/L, p=0.91
respectively. Importantly, the addition of an enzyme inducer did not take away
from the protective effect of nevirapine, note the authors.
week after giving birth, nevirapine levels were 36% lower in the sdNVP/CBZ
group. Levels of nevirapine in the blood are determined by nevirapine
elimination half-life, so this means a significantly higher elimination
half-life in the sdNVP/CBZ group. There was also a trend to a greater
proportion with undetectable nevirapine levels (<0.05 mg/L) in the sdNVP/CBZ
groups, compared to those in the sdNVP groups (24% [15/63] and 12% [6/52]
respectively [chi-squared p=0.09]).
weeks after having given birth, nevirapine mutations were seen in 21% (11/52)
and 11% (6/55) in the sdNVP and sdNVP/CBZ groups respectively (OR: 0.46, 95%
CI: 0.16-1.34, p=0.15).
authors note their approach - in common with that of Chi and colleagues (single-dose emtricitabine + tenofovir with sdNVP in 400 women resulting in a 50%
reduction in resistance) - maintains simplicity. Their pharmacologic approach,
however, targets a different mechanism and so may have an additive effect, they
include a high loss to follow-up. The randomisation list was only partially
randomised; and sample sizes were far smaller for resistance testing than
designed, so limiting the power to determine resistance between the groups.
Standard HIV genotyping assays could only detect viral mutations found in more
than 20% of the overall HIV population.
was chosen because of it simplicity. The authors believe it could improve
adherence, and is likely to reduce the emergence of NNRTI resistance further.
It is very low cost and is available in most clinics in resource-poor settings.
authors conclude: “Enzyme inducers such as carbamazepine, show new possibilities
for PMTCT programmes to reduce the development of nevirapine resistance in
settings where other options are limited.”