Prior nevirapine exposure for pregnant women can contribute to treatment failure
Polly Clayden, HIV i-Base
Oral abstracts evaluating levels of nevirapine (NVP, Viramune) resistance following a single dose to reduce mother to child transmission, greater efficacy with a more complex intervention and the effect of nevirapine resistance on subsequent nevirapine containing HAART, unsurprisingly reported both high levels of resistance, better efficacy with two drugs and compromised subsequent therapy following single maternal dose.
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 transmission .
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=0.006).
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 prophylaxis .
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=0.00026). 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.
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 session , and first reported at the XII Resistance meeting in Mexico in 2003 , 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?”
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.
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.”
Unless otherwise atated, references are to the Programme and Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections, 8-11 February 2004, San Francisco.
- Martinson M, Morris L, Gray G et al. HIV resistance and transmission following single-dose nevirapine in a PMTCT cohort. Abstract 38.
- 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. Abstract 40LB.
- 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. Abstract 41LB.
- Mellors J, Palmer S, Nissley D et al. Low frequency NNRTI-resistant variants contribute to failure of efavirenz-containing regimens. 11th CROI 2004, Abstract 39.
- 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. XII International HIV Drug Resistance Workshop, Los Cabos, Mexico, 10-14 June 2003. Abstract 134
- WHO press statement.