13th International HIV Drug Resistance Workshop


8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain


PERSISTANCE OF NEVIRAPINE-RESISTANT VIRUS AND PHARMACOKINETIC ANALYSIS IN WOMEN WHO RECEIVED INTRAPARTUM NVP ASSOCIATED TO A SHORT COURSE OF ZIDOVUDINE (ZDV) TO PREVENT PERINATAL HIV-1 TRANSMISSION: THE DITRAME PLUS ANRS 1201/02 STUDY, ABIDJAN, CÔTE D'IVOIRE

Antiviral Therapy 2004; 9:S176 (abstract 160)

ML Chaix1, DK Ekouevi2, G Peytavin3, F Rouet4, L Bequet2, C Montcho4, I Viho2, P Fassinou5, V Leroy6, F Dabis6, C Rouzioux1 and The Ditrame Plus Study Group
1Virologie, CHU Necker-EA MRT 3620, Paris, France; 2Projet ANRS Ditrame Plus, Programme PACCI, Abidjan, Côte d'Ivoire; 3 Pharmacologie, CHU-Bichat, Paris, France; 4CeDreS, Programme PACCI, Abidjan, Côte d'Ivoire; 5Pédiatrie, CHU Yopougon, Abidjan, Côte d'Ivoire; and 6INSERM U593, Bordeaux, France

BACKGROUND: Ditrame Plus was an open-labelled non-randomized trial. Consenting women with HIV-1 infection started oral ZDV (300 mg twice daily) ≥36 weeks gestation. One oral dose of 600 mg ZDV+200 mg NVP was given just before beginning of labour. Neonates were treated for 1 week with ZDV syrup (2 mg/kg/6 h) + one single dose of NVP syrup (2 mg/kg on day 2–3). 381 women were enrolled in the DitramePlus trial and the vertical transmission rate was 6.4% at week 6 post-partum (PP). 74/381 women were included in resistance substudy.

METHODS: Genotypic resistance analysis by sequencing reverse transcriptase gene was performed on mothers DNA-PBMC at week 4 PP when a NVP-R (resistant) mutation was detected in concomitant plasma samples. The same analysis was performed at week 4 of life, 3 months and 12 months, on DNA-PBMC of children who had detectable NVP-R in plasma samples at week 4. Mothers’ NVP-plasma concentrations were determined by a validated HPLC assay at 48 h PP (LOQ 50 ng/ml).

RESULTS: Twenty-one (33%) out of 74 women developed a detectable NVP-R mutation at 4 week PP. NVPR mutations were detectable in six children at wk 4 (23%). DNA samples were available at week 4 PP for 20/21 women who developed NVP-R mutations in plasma. DNA-PBMC NVP-R mutations were detected in 15/20 women (75%). Follow-up plasma and DNAPBMC samples collected 12 months after delivery for three women lacked detectable mutation. All six children who developed NVP-R mutations in plasma sample at week 4, had detectable DNA-PBMC NVP-R mutations. Follow-up plasma and DNA-PBMC samples collected at 3 months (one child) and until 12 months (one child) revealed the persistance of NVP-R mutations. The median plasma NVP concentration normalized to 48 hours PP was 598 ng/ml [315–885] for the mothers who had not acquired NVP-R virus compared to 851 ng/ml [633–1063] for the mothers harbouring NVP-R virus (P=0.014).

CONCLUSIONS: NVP concentration analysis showed wide inter-individual variability. Therefore, emergence of NVP-R mutations strongly correlated with a high level of NVP concentration, owing to a prolonged period of viral replication under NVP selective pressure. The clinical follow-up of the cohort confirms the archival of viral resistance. Its impact on the response to treatment for mothers and children should be evaluated.

PRESENTING AUTHOR: ML Chaix

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2004-06-08
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