NNRTI resistance in infants prophylaxed with single-dose nevirapine varies by the timing of infection
Polly Clayden, HIV i-Base
Ana Blanco and co-workers from the Mozambique Ministry of Health, Health Alliance International, Seattle, University of Washington, Seattle and Seattle Children’s Hospital Research Institute showed findings from an evaluation of infants infected with HIV despite receiving single dose nevirapine (sdNVP) prophylaxis.
The investigators hypothesised that the timing of nevirapine selective pressure relative to when the HIV first infects infants, effects the selection and persistence of NVP resistant virus. They suggest that:
- NVP pressure during “acute” (peri-partum) infection will result in transmission or significant selection of mutations that will populate long-lived viral reservoirs and mutations will persist over time.
- NVP pressure during “established” (in utero) infection will select mutations, however, as HIV-1 reservoirs are already established, fewer will be archived so mutant population will fade over time.
This report was from a prospective observational cohort study of 741 infants of whom 100% received single dose NVP (73% mothers). The investigators estimated the timing of infection using nested PCR for HIV-1 pol in dried blood spots, collected by heel stick, at birth and every 2 weeks for the first 2 months of life, and then every 4-8 weeks until one year of age.
Concentrations of resistant virus were determined using quantitative PCR oligonucleotide ligation assays (OLA) for K103N, V106M, Y181C and G190A.
HIV infection was detected by PCR in 53 infants followed between 0-8 weeks of age. 29 were infected in utero (HIV detected at birth), all had wild type virus and 23 had high and stable viral load at birth ie “established” infection, and 6 had low viral loads that later increased, suggesting “acute” infection at the time of birth.
The investigators reported that the selection and decay of NVP-resistant HIV-1 varied by timing of infection.
Infants with “established” infection had frequent selection of NVP-resistant HIV-1 (87%, 95%CI 66-97%).
Postpartum infant AZT+sdNVP vs. NVP decreased NVP-resistant HIV-1 (3/6 vs. 0/17, p=0.013). NVP-resistant viruses decayed rapidly compared to infants with peri-partum infection.
Compared to “established”, infants with “acute” in utero infection (ie low viral load at birth) had infrequent (33%) selection of NVP-resistant HIV-1, p=0.01. In this group of infants NVP-resistant HIV-1 appeared to decay more slowly.
Among infants with peripartum infection (n=24) there was infrequent selection of NVP-resistant HIV-1; (38%, 95%CI 19-59% ) compared to “established”, p=0.001. Few infants with NVP-resistance, initially had exclusively wild-type viruses vs. “established” (2/9; 22%, 95%CI 3-60% vs. 21/21 ; 100%, 95%CI 84-100%), p< 0.001. Also, most infants had 100% NVP-resistant HIV-1 in the first sample with detectable resistance vs. “established”, (6/9; 67%, 95%CI 30-93% vs. 0/22 ; 0%, 95%CI 0-15%), p< 0.001.
The investigators noted a non-significant trend for less NVP-resistance when mothers did not take sdNVP (0/5 vs. 9/19, p= 0.12).
- With “established” in utero infection, viral replication in utero generates mutations that are selected by sdNVP. AZT appears to reduce the selection of NVP mutations, “theoretically by increasing the genetic barrier and decreasing viral replication”. Rapid decay of NVP-resistant virus suggests that after an (undefined) interval, NVP-based HAART may be effective.
- With “acute” in utero infection there is frequently too little viral replication in utero to generate mutations, so there are no NVP-resistant mutations to select. But if selected NVP-resistant HIV-1 decays slowly suggesting that it populates long-lived reservoirs.
- With peri-partum infection, infections with 100% resistant virus suggests transmission of NVP-resistant HIV-1. Persistence of mutations at high concentrations suggests it populates reservoirs. Persistence of mutations suggests that NVP-containing HAART may fail.
The investigators noted a low rate of mother-to-child transmission among infants whose mothers received pre-partum AZT in addition to sdNVP. But this was only a minority of women and access needs to be improved.
Miceck MA, Blanco AJ, Beck IA et al. The selection, transmission and persistence of drug-resistant HIV-1 in infants prophylaxed with single dose nevirapine varies by the timing of infection. XVII IHDRW 2008, Sitges. Abstract 71.