14th International HIV Drug Resistance Workshop 7-11 June 2005, Québec City, Canada

HIGH FREQUENCY OF NEVIRAPINE RESISTANT MUTATIONS IN THE HIV QUASI SPECIES FOUND IN NVP-TREATED PARTICIPANTS OF AN MTCT UGANDAN COHORT

Antivir Ther. 10, Suppl 1:S14 (abstract no. 12)

R Troyer¹, M Lalonde¹, F Kyeyune², K Demers², M Kamya³, C Whalen¹, P Mugyenyi², F Bajunirwe⁴ and E Arts^1,2
1Case Western Reserve University, Cleveland, OH, USA; ²Joint Clinical Research Centre, Kampala, Uganda; ³Mulago Hospital – Markerere Medical School, Kampala, Uganda; ⁴Mbarara University, Mbarara, Uganda

BACKGROUND AND HYPOTHESIS: The effectiveness of nevirapine (NVP) treatment and emergence of drug resistance was examined in an observational mother-to-child HIV transmission (MTCT) cohort in Uganda. NVP-resistant viruses can be transmitted or emerge independently in either the mother or infant. Given the dominance of NVP resistance after single dose in some cases, we suspect that NVP resistant clones may be at high frequencies in the HIV population in most NVP treated mothers and infants.

METHODS: Mother-infant pairs from an AZT-treated (n=48), NVP-treated (n=61), and untreated group (n=90) were enrolled at postnatal clinics in Kampala, Uganda. Detailed phylogenetic analyses were performed on the mother and infant HIV-1 RT sequences. A quantitative radiolabelled oligonucleotide DNA ligation assay (OLA) was used to detect very low frequencies of drug resistance mutations (K70R, K103N, and Y181C at <1%) in the patient quasispecies. Ligation partners accommodated intersubtype variability with inosine or uracil at polymorphic sites in the DNA oligonucleotides.

RESULTS: HIV transmission rates were similar in the nevirapine (NVP) (16.4%) and AZT (16.7%) groups and offered protection as compared to the naïve group (48%, P=0.0001). The subtype prevalence in the mothers was 58% A, 23% D, 3% C, and 15% recombinants (A/D, C/D) and transmission was not skewed for a particular subtype. In the 6 week post-partum sample, mothers and infants treated with NVP harbored HIV-1 with a dominant K103N (n=2) or Y181C (n=5) (16%) whereas AZT resistant mutations were absent in AZT-treated pairs. A quantitative OLA identified 181C or 103N (at 1–40%) in another 22 of 44 infected mother or infants treated with NVP (50%) and in one of 63 untreated mothers or infants. K70R was not detected in the HIV quasispecies of AZT, NVP, or untreated groups.

CONCLUSIONS: These analyses suggest that NVP resistant mutations can be detected in over 75% of the NVP-treated infected mothers and infants. Prominence of these mutations in the quasispecies of HIV-infected mothers and infants 6 weeks post-partum and single-dose NVP treatment is of concern for prevention of MTCT and future treatment of NVP-containing treatment regimens in Uganda.

PRESENTING AUTHOR: E Arts

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2005-06-07
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