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Background:  Ditrame Plus was an open-label non-randomized trial. Consenting women with HIV-1 infection start oral zidovudine (ZDV) (300 mg twice daily) by or before 36 weeks' gestation and before beginning of labor when an oral dose of 600 mg ZDV+200 mg NVP is given. Neonates are treated for 1 week with ZDV syrup (2mg/kg/6h) + a single dose of nevirapine (NVP) syrup (2 mg/kg on day 2 to 3). This substudy evaluates the risk of emergence of NVP-resistance mutations at 4 weeks postpartum in a sample of women enrolled in this trial and in all infected neonates at week 4.

Methods: We enrolled 381 women in the Ditrame Plus trial of whom we studied 74 with samples available at baseline prior to treatment (32 weeks of amenorrhoea) and 4 week post-partum;  infants of 31 were infected (cases) and infants of 43 were uninfected (controls). Control maternal specimens were selected in 4 viral load classes (bDNA results). Maternal risk factors for emergence of NVP-resistance mutations were evaluated. Samples of 30 infected neonates were available. Plasma samples were tested for genotypic resistance analysis, performed by sequencing reverse transcriptase and protease genes. Phylogenetic analysis was performed on the RT gene.

Results:  Of 74 women, 21 (28.4 %:95%CI [18.4% to 40.1%]) developed a detectable NVP-resistance mutation at 4 weeks post-partum. None of these mutations was present in plasma collected prior to treatment. The most common mutation was 103N/K, which was present alone or in combination with other mutations in 6 cases. The risk for development of NVP resistance did not correlate with baseline maternal CD4 cell count and HIV-RNA viral load. Frequency of resistant virus was not different in non transmitting mothers (14/43,33%) compared with transmitting mothers (7/31,23%; p = 0.35). NVP-resistance mutations were detectable in 5 children at week 4 (16.6%:95%CI [5.6% to 34.7%]). The mutation 103 N/K was detected in 4 cases associated to 190A in 1 case and to 106A in 1 case. In the last case, the single mutation 106A was detected. No ZDV-associated mutation was observed. Phylogenetic analysis revealed 78% subtype CRF02, 15% A, and 7% CRF06.

Conclusions:  The incidence and the patterns of NVP resistance in this group predominantly infected with recombinant viruses are comparable to those reported earlier in East Africa and Thailand where viral populations are more homogeneous. The clinical follow-up of the cohort will allow the assessment of an eventual persistence of viral resistance and its impact on the treatment response.

Keywords: HIV-1 resistance; Mother-to-child transmission; Nevirapine