Addition of Short-course Combivir to Single-dose Nevirapine Reduces the Selection of NPV-resistant HIV-1 with Infrequent Emergence of 3TC-resistant Variants
Sarah Palmer*1, V Boltz1, F Maldarelli1, N Martinson2, J McIntyre2, G Gray2, M Hopley3, D Hall4, J Coffin1, and J Mellors5
1HIV Drug Resistance Prgm, NCI, NIH, Frederick, MD, US; 2Chris Hani Baragwanath Hosp, Univ of the Witwatersrand, Johannesburg, South Africa; 3Boehringer Ingelheim ZA, Johannesburg, South Africa; 4Boehringer Ingelheim Pharma, Ridgefield, CT, US; and 5Univ of Pittsburgh, PA, US
Background: Single-dose nevirapine
(NVP) to prevent mother to child HIV-1 transmission selects NVP-resistance in
70 to 80% of mothers as detected by allele-specific polymerase chain reaction
(AS-PCRP). A randomized trial (TOPS) studied the effect of short course zidovudine (AZT)/lamivudine (3TC)
(combivir; CBV) on the selection of NVP resistance in
women receiving single-dose NVP. This trial showed that 4 or 7 days of CBV
reduced NVP resistance from 60% to about 10% without selecting AZT or 3TC
resistance as determined by standard genotype. To improve the detection of NVP-
and 3TC-resistant variants, we analyzed samples from TOPS with AS-PCR that
detects 103N, 181C, 190A, and 184I/V variants at frequencies to 0.1%.
Methods: Baseline and post-therapy samples from a
subgroup of 61 women were analyzed from each of the study arms: single-dose NVP (21) and single-dose NVP + 4
or 7 days of CBV (20 each). Samples from
the CBV arms were negative for reverse transcriptase inhibitor resistance by
standard genotype. AS-PCR was performed as published.
Results: AS-PCR detected 103N, 181C, or 190A variants in week-6
samples from 68% of women receiving single-dose NVP alone (mutant frequency 0.8
to 75%, median 7%) and 9 of 40 (23%) of women receiving single-dose NVP + 4 or
7 days of CBV (frequency 0.2 to 8%, median 1.2%). There was no difference
between the 4 and 7 day CBV arms in the proportion of women with NVP-resistant
variants or their frequency. Of 40 patients, 1 received single-dose NVP + 4 or
7 days of CBV had selection of M184I (frequency 1.7%); M184V was not detected.
Conclusions: Short-course CBV (4 or 7 days) reduces, but does not
eliminate, selection of NVP-resistant variants following single-dose NVP. In
addition, the frequency of NVP-resistant mutants in the virus population is
reduced about 7-fold by CBV. Selection of 3TC resistance was infrequent (1 of
40). Short-course CBV is a viable strategy for reducing NVP resistance
following single-dose NVP. The clinical significance
of low-frequency NVP-resistant variants and the optimal duration of CBV to
prevent reverse transcriptase inhibitor resistance need to be established.