title: Emergence of minor drug-resistant HIV-1 variants after triple antiretroviral prophylaxis for prevention of vertical HIV-1 transmission.
abstract: BACKGROUND
  WHO-guidelines for prevention of mother-to-child transmission of HIV-1 in resource-limited settings recommend complex maternal antiretroviral prophylaxis comprising antenatal zidovudine (AZT), nevirapine single-dose (NVP-SD) at labor onset and AZT/lamivudine (3TC) during labor and one week postpartum. Data on resistance development selected by this regimen is not available. We therefore analyzed the emergence of minor drug-resistant HIV-1 variants in Tanzanian women following complex prophylaxis.
  
  
  METHODS
  1395 pregnant women were tested for HIV-1 at Kyela District Hospital, Tanzania. 87/202 HIV-positive women started complex prophylaxis. Blood samples were collected before start of prophylaxis, at birth and 1-2, 4-6 and 12-16 weeks postpartum. Allele-specific real-time PCR assays specific for HIV-1 subtypes A, C and D were developed and applied on samples of mothers and their vertically infected infants to quantify key resistance mutations of AZT (K70R/T215Y/T215F), NVP (K103N/Y181C) and 3TC (M184V) at detection limits of <1%.
  
  
  RESULTS
  50/87 HIV-infected women having started complex prophylaxis were eligible for the study. All women took AZT with a median duration of 53 days (IQR 39-64); all women ingested NVP-SD, 86% took 3TC. HIV-1 resistance mutations were detected in 20/50 (40%) women, of which 70% displayed minority species. Variants with AZT-resistance mutations were found in 11/50 (22%), NVP-resistant variants in 9/50 (18%) and 3TC-resistant variants in 4/50 women (8%). Three women harbored resistant HIV-1 against more than one drug. 49/50 infants, including the seven vertically HIV-infected were breastfed, 3/7 infants exhibited drug-resistant virus.
  
  
  CONCLUSIONS
  Complex prophylaxis resulted in lower levels of NVP-selected resistance as compared to NVP-SD, but AZT-resistant HIV-1 emerged in a substantial proportion of women. Starting AZT in pregnancy week 14 instead of 28 as recommended by the current WHO-guidelines may further increase the frequency of AZT-resistance mutations. Given its impact on HIV-transmission rate and drug-resistance development, HAART for all HIV-positive pregnant women should be considered.
authors.affiliation: Institute of Tropical Medicine and International Health, Charité - Universitätsmedizin Berlin, Berlin, Germany. andrea.hauser@charite.de
authors.forename: Andrea
authors.initials: A
authors.lastname: Hauser
authors.forename: Julius
authors.initials: J
authors.lastname: Sewangi
authors.forename: Paulina
authors.initials: P
authors.lastname: Mbezi
authors.forename: Festo
authors.initials: F
authors.lastname: Dugange
authors.forename: Inga
authors.initials: I
authors.lastname: Lau
authors.forename: Judith
authors.initials: J
authors.lastname: Ziske
authors.forename: Stefanie
authors.initials: S
authors.lastname: Theuring
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuecherer
authors.forename: Gundel
authors.initials: G
authors.lastname: Harms
authors.forename: Andrea
authors.initials: A
authors.lastname: Kunz
mesh_terms: D000328:Adult; D000483:Alleles; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D019259:Lamivudine / Q000008:administration & dosage; D009154:Mutation; D019829:Nevirapine / Q000008:administration & dosage; D009841:Oligonucleotides / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D013636:Tanzania; D015215:Zidovudine / Q000008:administration & dosage
chemical_list: D044966:Anti-Retroviral Agents; D009841:Oligonucleotides; D019259:Lamivudine; D015215:Zidovudine; D019829:Nevirapine