Rapid development of genotypic resistance to lamivudine when combined with zidovudine in pregnancy

Abstract

The prevention of mother to child transmission of HIV-1 by zidovudine monotherapy is well known, but increasingly combination anti-retroviral therapy is prescribed during pregnancy. In this prospective study, 19 pregnant women with human immunodeficiency virus-1 (HIV-1) infection who elected to take anti-retroviral therapy during the second and third trimesters were treated with zidovudine or zidovudine plus lamivudine. Fourteen women treated with zidovudine monotherapy had a mean 0.3 log(10) reduction in viral load and a mean 52 x 10(6)/L (17%) increase in CD4+ lymphocytes at delivery compared with pre-treatment samples. Genotypic mutations associated with decreased susceptibility to zidovudine were detected in 2 of 10 women at delivery. Five women with more advanced HIV-1 infection were treated with zidovudine plus lamivudine and a mean 1.5 log(10) reduction in viral load together with a mean 30 x 10(6)/L (33%) increase in CD4+ lymphocytes was observed in this group. However, four of five women in the dual therapy arm had the M184V mutation in the reverse transcriptase gene associated with decreased susceptibility to lamivudine at delivery. We conclude that zidovudine plus lamivudine reduced HIV-1 plasma viraemia to low levels in pregnant women with advanced HIV-1 disease but the rapid development of genotypic resistance to lamivudine indicates that additional therapy is required both for the long-term benefit of the mothers and to prevent the development of resistant virus that may be transmitted to the infant.

HIV-1 mother-to-child transmission and drug resistance among Brazilian pregnant women with high access to diagnosis and prophylactic measures

“…In our study the most prevalent NRTI M184V mutation, leads to resistance to 3TC and increases susceptibility to ZDV/d4T. 14,15 Two women under HAART had the NRTI T215Y mutation that removes ZDV and d4T incorporated into the DNA when associated with M184 V mutation. One MDR patient under HAART had thymidine analogue resistance mutations (TAMs) in codons 67/70/215 and accumulation of TAMs may lead to cross-resistance between NRTIs.…”

Pharmacokinetics of Didanosine and Drug Resistance Mutations in Infants Exposed to Zidovudine During Gestation or Postnatally and Treated With Didanosine or Zidovudine in the First Three Months of Life

“…This is in contrast to studies that used the combination of ZDV and lamivudine, in which the M184V mutation resulting in high level resistance developed rapidly among patients who received this combination. [21][22][23] The ZDV/lamivudine combination is being used as part of the postnatal portion of the 3-part regimen to prevent perinatal transmission of HIV in the developing world, where breast-feeding is common and where HAART is not available. 24 An alternative strategy might be to use ZDV/ddI in the postnatal period.…”

A pilot study to evaluate the safety and feasibility of the administration of AZT/3TC fixed dose combination to HIV infected pregnant women and their infants in Rio de Janeiro, Brazil

“…Other studies have looked at viral resistance and it is clear that vertical transmission of HIV resistant virus to many classes of antiretrovirals can occur. [15][16][17][18] A number of small phase 1 studies have been conducted with the AZT/3TC combination, revealing both initial safety and pharmacokinetic data on this combination. [19][20][21] Of note, 3TC efficiently crosses the placenta, with similar levels in the umbilical cord as in the newborn circulation; median concentrations of 3TC in the amniotic fluid were up to five times higher than in the maternal plasma.…”