[e-drug] Perinatal prevention of HIV with 2 drugs

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E-drug: Perinatal prevention of HIV with 2 drugs
---------------------------------------------

[Warning long message!  This important article 
provides the rationale for using 2 ARV drugs for 
the perinatal prevention of mother to child 
transmission.  Zidovudine is combined with 
nevirapine to reduce the development of 
resistance. This week's New England Journal of 
Medicine - see next posting - follows up .  BS]

Date: Sat, 24 Apr 2004
  Prior Nevirapine Exposure for Pregnant women can 
contribute to treatment failure

HIV Treatment Bulletin - Vol. 5, No. 3, April 2004
Polly Clayden, HIV i-Base
**********************

Summary

Studies to evaluate levels of nevirapine 
resistance following a single maternal 
prophylactic dose  and the effect of nevirapine 
resistance on subsequent nevirapine-containing 
HAART found:
·                    high levels of resistance
·                    better efficacy with two drugs
·                    compromised subsequent therapy for mother

A group of 623 HIV-positive mothers from two 
South African hospitals were enrolled late in 
their third trimester of pregnancy (32 to 38 
weeks). Dr Martinson reported preliminary 
genotypic findings at baseline and at a scheduled 
six weeks follow up, for which data were 
available for 455 (73%) of the   women. The study 
investigators defined high-level nevirapine 
resistance as having acquired the K103N, V106A/M, 
Y181C, YI88C, and G190A mutations. 

Martinson M, Morris L, Gray G et al. HIV 
resistance and transmission following single-dose 
nevirapine in a PMTCT cohort.  Conf Retroviruses 
Opportunistic Infect. 2004 Feb 8-11;11th: 
Abstract No. 38.   

Dr Neil Martinson presented findings from a study 
assessing nevirapine induced genotypic resistance 
in women exposed to single dose NVP to reduce 
mother to child transmission1. 
A group of 623 HIV-positive mothers from two 
South African hospitals were enrolled late in 
their third trimester of pregnancy (32 to 38 
weeks). Dr Martinson reported preliminary 
genotypic findings at baseline and at a scheduled 
six weeks follow up, for which data were 
available for 455 (73%) of the   women. The study 
investigators defined high-level nevirapine 
resistance as having acquired the K103N, V106A/M, 
Y181C, YI88C, and G190A mutations.

The women had a median baseline CD4 and viral 
load of 392 cells/mm3 and 28,700 copies/mL 
respectively. All but four were clade-C and no 
previously unexposed women had baseline 
resistance. Follow up visits were at a median of 
7 weeks postpartum (IQR between 6.3 and 10.3 
weeks). Dr Martinson reported 38.8% of mothers 
and 42.4% of their infants as having genotypic 
nevirapine resistance. There was a decline in 
detectable resistance in mothers with longer time 
to follow up: 43% in the first analysis (4 to 6 
weeks postpartum), 44% in the second (6 to 7 
weeks), 44% in the third (7 to 10 weeks) and 24% 
in the fourth (10 to 36 weeks) (test for trend 
p=3D0.006).

Mutations reported in the mothers included K103N 
(31%), Y181C (12%), and Y188C (8.1%); 21% had a 
single mutation, 13% had two, and 5%, three or 
four mutations. The babies' mutations included 
Y181C (32%), K103N (12%) and Y188C (5%). The 
K103N was the most frequent in both mothers and 
babies.

At 10 weeks the overall mother to child 
transmission rate was 8.6% (95% CI: 6.0 to 11.2). 
The investigators found an association between 
maternal nevirapine resistance and transmission 
(OR 2.9, 95%CI: 1.4 to 6.1) in univariate 
analysis but not after correcting for viral load. 
Dr Martinson cited baseline CD4, baseline viral 
load, the time from labour to the nevirapine dose 
to the postpartum blood draw and the total number 
of times a mother took nevirapine during her 
pregnancy (51% had taken one or more prior doses 
in pregnancy due to false labour)as being 
statistically significantly associated with 
development of resistance. In multivariate 
analysis only maternal viral load was 
significant. Mode of delivery was not important.

Dr Martinson concluded his talk with some 
recommendations from the authors which included: 
limiting nevirapine exposure ie avoiding multiple 
doses in pregnancy; nevirapine to the baby only 
and nevirapine plus two nucleosides to reduce 
mother to child transmission. He said: "ARV 
rollout must include MTCT," and added that the 
effect of nevirapine single dose on subsequent 
HAART and subsequent pregnancies must be 
considered. There are concerns about transmission 
of nevirapine resistant virus and for women 
exposed to single dose nevirapine, protease 
containing regimens may be more appropriate than 
the WHO recommended first line NNRTI containing 
HAART.

Two drugs are better than one...

Two late breakers in the same session presented 
results from a Thai study - PHPT-2 - designed to 
evaluate whether greater mother to child 
transmission efficacy could be gained by adding 
single dose nevirapine to standard AZT 
prophylaxis2.

In this study 1,844 women were enrolled and 
mother and infant pairs were randomised to three 
arms: single 200mg nevirapine dose to the mother 
in labour and 6mg to the baby within 72 hours of 
birth (the nevirapine-nevirapine arm); nevirapine 
dose to the mother and placebo to the infant 
(nevirapine-placebo) and both mother and baby 
receiving placebo (placebo-placebo). Additionally 
all mothers received AZT from 28 weeks of 
gestation and infants one week of AZT and formula 
feeding. The study endpoint was HIV infection of 
the infant.

Presenting author Dr Marc Lallemant reported that 
the placebo-placebo arm was discontinued 
following the trial's first interim analysis due 
to the highly significant reduction in 
transmission among those receiving the additional 
drug: 1.1% in the nevirapine-nevirapine arm and 
6.3% in the placebo-placebo arm, an 80% reduction 
(p=3D0.00026). Transmission rates between the 
nevirapine-nevirapine and the nevirapine-placebo 
arms did not differ dramatically: 2.0% and 2.8% 
respectively.

He reported that in these findings, although 
transmission was also associated with viral load 
and CD4 count and slightly associated with 
prematurity and onset of ZDV prophylaxis, the 
effect of nevirapine was observed across most sub 
groups, and that such a reduction "...was much 
higher than we had hypothesised when the study 
was designed".

...But subsequent treatment response is compromised

A second late breaker from the same group 
presented by Dr Gonzague Jourdain assessed the 
effect of nevirapine exposure in PHPT-2 on 
subsequent NNRTI containing HAART regimens.   Dr 
Jourdain reported that a 12 day postpartum sample 
was assessed for genotypic nevirapine resistance, 
this was first performed in a random sample of 90 
women of which 18% of those tested were found to 
have NNRTI mutations (K103N, G190A, or Y181C). In 
a PK analysis the investigators also found that 
77% of women had detectable blood plasma levels 
of nevirapine at 5 to 15 days post partum and one 
woman at 19 days postpartum. Of the women who 
participated in the PHPT-2 study 25% needed 
treatment and subsequently received an NNRTI 
containing regimen - nevirapine/3TC/d4T - and 
those for whom viral load could be assayed at 3 
and/or 6 months were also assessed.3

Of these 255 women starting HAART, 42 had not, 
and 213 had, been exposed to nevirapine. Six 
percent of the women switched to efavirenz.

At six months, 75% of the unexposed, 53% of the 
exposed but with no detectable mutations and 34% 
of the women exposed and with mutations were 
below 50 copies. Later initiation of therapy six 
months or more after exposure was associated with 
a modest improvement in virological response at 
six months duration of therapy (although this was 
not statistically significant).   Comments from 
the floor after the presentation included Dr John 
Mellors who remarked that these findings echoed 
those from his group from ACTG 398- presented as 
an oral abstract in the same session4, and first 
reported at the XII Resistance meeting in Mexico 
in 20035, in which patients receiving efavirenz 
containing regimens had responded less well if 
previously exposed to an NNRTI even without 
detectable resistance. This report concluded that 
prior NNRTI exposure could select minor resistant 
variants that are not detected by standard 
genotype assays and can contribute to failure of 
NNRTI containing regimens. Another speaker added: 
"Don't you think the time has come to abolish the 
use of suboptimal regimens and use generic HAART?"

Comment   These studies confirm the efficacy of 
nevirapine to reduce mother-to-child transmission 
and to rapidly select resistance mutations. The 
novel finding that single dose nevirapine 
exposure can impact future outcome to such a 
dramatic extent must lead to a rapid change in 
policy especially in those countries rolling out 
combination therapy. The potential of NNRTIs as 
subsequent therapy for the mother must be 
protected with their use restricted to effective 
combinations only and with due consideration to 
their prolonged clearance which varies 
considerably between individuals.

On 5th and 6th February the World Health 
Organisation (WHO) convened a technical 
consultation in Geneva to review the experience 
with programmes and evidence to date on safety 
and efficacy of antiretroviral use in the 
reduction of mother-to-child transmission. Prior 
to this consultation the WHO had issued a draft 
set of recommendations for public comment, this 
is now under revision in view of comments 
received and the recommendations made at the 
technical consultation.6

Summary of the key recommendations:

* Women who need ARV treatment for their own 
health should receive it. The use of ARV 
treatment when indicated during pregnancy will 
improve maternal health and reduce the risk of 
transmission of HIV to the infant. 

* Women who do not need treatment for their own 
health, or do not have access to treatment, 
should be offered ARV prophylaxis to reduce 
mother to child transmission using one of a 
number of ARV drug regimens known to be safe and 
effective.

* The most efficacious regimen among those 
recommended for reduction of MTCT for women with 
HIV who do not need ARV treatment is zidovudine 
(ZDV) from 28 weeks with single dose nevirapine 
(NVP) at onset of labour for the mother and 
single dose NVP plus one week ZDV for the infant.

* Alternative but less efficacious regimens 
include one based on ZDV alone (from 28 weeks of 
pregnancy and through labour for the mother and 
for one week for the infant), one using the 
combination of ZDV plus lamivudine (3TC) (from 36 
weeks of pregnancy, through labour and one week 
postpartum for the mother, and for one week for 
the infant), and a regimen comprising a single 
dose of NVP to the mother and to the infant 
(which does not need to be initiated until 
labour).

* The selection of the ARV drug regimen should be 
made at national level, based on issues of 
efficacy, safety, drug resistance, feasibility, 
and acceptability.

* This consultation included a review of 
available maternal and infant resistance data and 
the Lallemant et al. findings were taken into 
account in developing the above recommendations. 
The WHO press release states: "Consultation 
participants felt that the implications of these 
preliminary data on subsequent treatment options 
for women were unclear and require further 
study...Until further evidence is available it 
was the group's expert opinion that the ZDV plus 
single-dose NVP regimen can be recommended for 
the prevention of MTCT because of its 
considerable efficacy in reducing MTCT (by 80%, 
from the transmission rates observed with 
short-course ZDV alone, down to an absolute level 
under 2%), its simplicity and its safety profile 
for mother and infant. In view of these results, 
the government of Thailand is implementing this 
regimen nationwide for the prevention of MTCT, 
alongside its efforts to scale up ARV treatment 
for all in need."

References:

Unless otherwise stated, references are to the 
Programme and Abstracts of the 11th Conference on 
Retroviruses and Opportunistic Infections, 8-11 
February 2004, San Francisco.

1 Martinson M, Morris L, Gray G et al. HIV 
resistance and transmission following single-dose 
nevirapine in a PMTCT cohort. Conf Retroviruses 
Opportunistic Infect. 2004 Feb 8-11;11th: 
Abstract No. 38.

2 Lallemant M, Jourdain G, Le Coeur S et al. A 
randomised, double-blind trial assessing the 
efficacy of single-dose perinatal nevirapine 
added to a standard zidovudine regimen for the 
prevention of mother-to-child transmission of 
HIV-1 in Thailand. Conf Retroviruses 
Opportunistic Infect. 2004 Feb 8-11;11th: 
Abstract No. 40LB.

3 Jourdain G, Ngo-Giang-Huong N,Tungyai P et al. 
Exposure to intrapartum single-dose nevirapine 
and subsequent maternal six-month response to 
NNRTI-based regimens. Conf Retroviruses 
Opportunistic Infect. 2004 Feb 8-11;11th: 
Abstract No. 41LB.

4 Mellors J, Palmer S, Nissley D et al. Low 
frequency NNRTI-resistant variants contribute to 
failure of efavirenz-containing regimens. Conf 
Retroviruses Opportunistic Infect. 2004 Feb 
8-11;11th: Abstract No. 39.

5 Mellors J et al - Low frequency non-nucleoside 
reverse transcriptase inhibitor (NNRTI)-resistant 
variants contribute to failure of 
efavirenz-containing regimens in 
NNRTI-experienced patients with negative standard 
genotypes for NNRTI mutations. Int'l HIV Drug 
Resist Wkshp. 2003 Jun 10-14;12th: Abstract No. 
134.

6 "Antiretroviral drugs and the prevention of 
mother-to-child transmission of HIV infection in 
resource-limited settings Expert consultation, 
Geneva, 5-6 February 2004 A summary of main 
points from the meeting", WHO press statement

  (c)2004. I-BASE HIV Treatment Bulletin.

Source: AEGIS (23 Apr 2004)
http://www.aegis.org/pubs/i-base/2004/IB04050321.html>http://www.aegis.org/pubs/ibase/2004/IB040503-21.html

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