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AZT Monotherapy To Prevent Perinatal Transmission
  "Drug resistance is uncommon in pregnant women with low viral loads taking zidovudine monotherapy to prevent perinatal HIV transmission"
AIDS 2003; 17(18):2665-2667 (authors at bottom of article)
Zidovudine monotherapy is used to reduce perinatal HIV transmission in women with low viral loads. There are few data on the risk of drug resistance in this select cohort of women. We determined the prevalence of newly acquired mutations conferring reduced sensitivity to zidovudine after exposure during pregnancy, and found that the development of mutations was uncommon and was restricted to women treated before 1998 who had higher baseline viral loads than those currently recommended monotherapy.
Since 1994, monotherapy with zidovudine has been recommended to reduce mother-to-child transmission of HIV-1. There is also strong evidence for pre-labour Caesarean section and exclusive formula feeding. Treatment guidelines produced in 1997 recommended that pregnant women with advanced HIV infection should be managed, like non-pregnant women, with combination antiretroviral therapies. In the UK, zidovudine monotherapy is still recommended for women with asymptomatic infection, CD4 lymphocyte counts above 200-350 cells/mm3 and a viral load below 10-20 000 HIV-1-RNA copies/ml, but is deferred until the start of the third trimester. In this group of women, combined with elective Caesarian section, the risk of mother-to-child transmission is low. The low viral load makes the development of resistance unlikely and the fetus is exposed to only one drug, the longer-term effects of which, like all antiretroviral drugs, are currently unknown. In the United States, as a result of concerns that drug resistance may develop at higher viral loads, zidovudine is reserved for pregnant women with viral loads less than 1000 HIV-RNA copies/ml, but treatment is initiated much earlier than in the UK, starting from the end of the first trimester.
Prolonged monotherapy is likely to lead to the emergence of drug-resistant virus, which may compromise the future treatment of the mother and any infected infant. Currently, there are limited and conflicting data on the prevalence of resistance mutations after zidovudine monotherapy in pregnancy. Most data are from studies that included women with higher baseline viral loads, lower CD4 cell counts and more zidovudine exposure than is now recommended.
We have therefore determined the prevalence of such drug-resistant mutations in a contemporary cohort of pregnant women with low viral loads, after the use of zidovudine monotherapy, according to current UK guidelines.
We identified 91 HIV-1-infected pregnant women presenting to four London centres between January 1996 and March 2001 for whom zidovudine monotherapy had been prescribed. Eighty-four per cent of the cohort were black African, 6% were black Caribbean and 10% were Caucasian. This demography was reflected in the observation that 82% of infections were with non-B subtypes of HIV-1, as determined using a peptide-based enzyme immunoassay. Since 1998, combinations of three or more drugs have been used in pregnancy for women with advanced disease. We were therefore able to compare the unselective use of zidovudine monotherapy before 1998 with its selective use thereafter.
Viral loads measured using the branched DNA and nucleic acid sequence-based amplification assays were converted to Roche equivalent values by methods previously described. Values that were below the limit of detection were assumed to have a Roche equivalent value of 400 copies/ml in any analysis. Viral loads and CD4 cell counts were compared between groups using the Mann-Whitney U test, chi-squared test and Fisher's exact test, as appropriate.
Compared with 1998 onwards the pre-treatment median CD4 cell number was lower before 1998 (299 versus 463 cells/mm3), and the median viral load at baseline and delivery was higher. Zidovudine monotherapy was initiated at a median gestation of 28 weeks. The median duration of zidovudine exposure before genotyping was 9.5 and 9 weeks, respectively.
Stored plasma taken at or within 4 weeks of delivery was available for 65 of the 91 women treated with zidovudine. The viral load was below the limit of detection in 16, and therefore 49 samples were suitable for genotypic resistance analysis.
Samples from three centres (n = 36) were genotyped using the Visible Genetics Trugene HIV-1 assay and reverse transcriptase (RT) sequences were obtained from 28. The remaining 13 samples were genotyped using a reverse hybridization line probe assay (LIPA; Murex Biotech Ltd.) and results were obtained for 12. RT data was therefore available for 40 of the 49 samples tested (82%).
In the pre-1998 group, for whom genotyping data were available (n = 19) four had RT mutations at the time of delivery. The T215Y mutation, which confers high-level resistance to zidovudine, was detected in one woman who commenced monotherapy at 15 weeks' gestation (25 weeks zidovudine exposure), which is much earlier than currently recommended in the UK. The T215Y mutation was also detected in a woman with a high viral load at delivery (350, 981 HIV-RNA copies/ml), who received zidovudine for 14 weeks. An M41L mutation, associated with low-level resistance to zidovudine, was present at baseline and at delivery in a woman with previous zidovudine exposure. An A98G mutation associated with reduced sensitivity to non-nucleoside RT inhibitors was detected in a woman who was non-nucleoside RT inhibitor naive. No RT mutations were detected in the group from 1998 onwards (n = 21).
An increased risk of HIV transmission has been reported in the presence of RT mutations conferring zidovudine resistance. Three transmissions (all pre-1998) occurred among the 91 women in our cohort, one from a mother in whom the T215Y mutation was detected. Transmission in the latter case was associated with a high viral load at delivery, and wild-type not drug-resistant virus was transmitted to the infant. The two other transmissions occurred in settings of incomplete adherence to the recommended interventions.
In previous studies, the frequency of mutations associated with decreased susceptibility to zidovudine has ranged from 3% in the Paediatric AIDS Clinical Trials Group 076 study to 24% in the Women and Infant Transmission cohort Study, with viral load, CD4 cell count and duration of drug exposure as significant variables. In our study, the development of new zidovudine mutations was uncommon at two out of 40 (5%) and was restricted to women treated before 1998. From 1998 onwards, the characteristics of the cohort changed, reflecting the increased use of triple therapy in women with more advanced HIV infection. As a consequence, zidovudine monotherapy is now restricted to mothers with low viral loads and better immune function, who are at lower risk of perinatal transmission. Among this group of women, who reflect the current recommended target group for zidovudine monotherapy in the UK, no zidovudine mutations were detected.
Zidovudine monotherapy remains an attractive intervention in this setting, as it limits fetal drug exposure and is well tolerated. These data suggest that future maternal treatment options are preserved. Current genotyping assays may not, however, detect drug resistance in minority species of HIV-1. Although we have not seen any RT mutations in women treated since 1998, the number of women included in the study was small. As a result, the upper limit of the 95% confidence interval would suggest that up to 16.1% of women in a similar situation could possess such mutations. It remains important, therefore, to follow up this group of womwomen carefully and if they subsequently start combination therapy to confirm they are not at a higher risk of treatment failure.
Nick Larbalestiera; Jane Mullenb; Siobhan O'Sheac; Fiona Cottamc; Caroline A. Sabind; Ian L. Chrystieb; Jan Welche; Mark Zuckermanf; Phillip Hayg; Phillip Riceh; Graham P. Taylori; Annemiek de Ruitera
Departments of aGenitourinary Medicine and bInfection, Virology Section, Guys, Kings and St Thomas' School of Medicine, and cDepartment of Infection, Virology Section, Guys and St Thomas' Hospital Trust, London SE1 7EH, UK; dHIV Research Unit, Department of Primary Care and Population Sciences, Royal Free and University College Medical School, Royal Free Campus, London NW3 2PF; UK; eDepartment of Genitourinary Medicine, Kings College Hospital, London SE5 9RS, UK; fSouth London Public Health Laboratory and Department of Infection, Guys, Kings and St Thomas' School of Medicine, Department of Virology, Kings College Hospital, Dulwich Hospital, London SE22 8QF, UK; Departments of gGenitourinary Medicine and hVirology, St Georges Hospital, London SW7 OQT, UK; and iGU Medicine and Communicable Diseases, Imperial College School of Medicine at St Mary's, London 2 1NY, UK.
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