Genotypic testing performed on fifteen pregnant women who received a single dose of nevirapine at the onset of labour detected the presence of a key mutation associated with resistance to nevirapine, and to other NNRTIs, in three cases (Eshleman).
The women were enrolled in HIVNET 006, a phase I/II pilot run in Ugandan women prior to the larger HIVNET 012 trial. The latter reported a significant reduction in mother-to-child HIV transmission in women and infants receiving nevirapine prophylaxis compared to a very short course of AZT (Guay).
Genotypic sequencing was performed prior to administration of nevirapine and at six weeks after delivery. Though no mutations were detected pre-therapy, K103N, an NNRTI resistance signature mutation, was found in three of the fifteen women following treatment. Y181C, another common NNRTI resistance mutation, was not detected in any sample.
Three of fiteen women genotyped transmitted HIV to their infants despite the use of nevirapine. Of the three women in whom K103N was detected, one of these transmitted HIV infection; the remaining two did not. Presenting these important data, Eshleman suggested the occurrence of these mutations should not deter the pressing need to implement this regimen in the prevention of mother-to-child transmission in resource-poor countries.
These findings sparked concern, however, amongst clinicians caring for HIV-positive women in the developed world, where a large international trial, ACTG 316, is currently evaluating the use of a single dose of nevirapine in pregnant women receiving other antiretrovirals. Where treatment has failed to reduce maternal viral load to undetectable levels, it seems a single dose of nevirapine may result in NNRTI resistance in some cases, narrowing options for future therapy. The potential for selection of nevirapine resistance mutations where viral load is fully suppressed ought to be lower.
HIVNET 012 investigators plan to evaluate the frequency of resistance mutations in study participants in due course. It is expected that in 012, maternal blood plasma samples will be available from timepoints closer to delivery than in HIVNET 006. It seems possible that sampling at six weeks postpartum may have underestimated the frequency of resistance mutations, as resistant sub-populations may already have 'disappeared' from circulation at this point.
Eshleman SH et al. Selection of the K103N nevirapine (NVP) resistance mutation in Ugandan women receiving NVP prophylaxis to prevent HIV-1 vertical transmission (HIVNET-006). Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 658, 2000.
Guay LA et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354(9181):795-802, 1999.