To the Editor: The articles by Lallemant et al. and Jourdainet al. (July 15 issue)1,2 highlight a dilemma. Should we impairthe health of one patient to help another patient? Of the womenreceiving nevirapine, 32 percent showed resistance mutationsto nonnucleoside reverse-transcriptase inhibitors (NNRTI) at10 days post partum.2 However, viral rebound may occur 21 days3after receipt of the drug and result in an even higher rateof resistance mutations to NNRTI. Of the mothers receiving zidovudinemonotherapy, 6.3 percent transmitted the human immunodeficiencyvirus (HIV) to their infants, as compared with 2.8 percent ofmothers treated with additional nevirapine.1 Unfortunately,no data are given on resistance mutations in infected babies.Resistance mutations might be present in 46 percent of verticallyinfected babies after nevirapine prophylaxis.4
With the use of zidovudine monotherapy in 1000 HIV-1–positivewomen, 63 infected babies will be delivered. If nevirapine isadded to their treatment, 320 of the 1000 will have NNRTI resistancemutations, 24 infected infants will be born, and possibly 11of them will harbor NNRTI resistance mutations. Thus, addingsingle-dose nevirapine to zidovudine prophylaxis will prevent39 transmissions but may leave 11 babies and 320 mothers withNNRTI resistance mutations. These mutations may reduce theirtreatment options and worsen their prognosis.5 This risk mustbe considered when giving additional nevirapine during labor.Infected children should be tested for resistance mutationsto allow for optimal future care.
Christian Herzmann, M.D. Royal Free Hospital London NW3 2QG, United Kingdom christian.herzmann{at}web.de
Heiko Karcher, M.D. German Agency for International Developmentand Cooperation 14050 Berlin, Germany
References
Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004;351:217-228. [Free Full Text]
Jourdain G, Ngo-Giang-Huong N, Le Coeur S, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004;351:229-240. [Free Full Text]
Mackie NE, Fidler S, Tamm N, et al. Clinical implications of stopping nevirapine-based antiretroviral therapy: relative pharmacokinetics and avoidance of drug resistance. HIV Med 2004;5:180-184. [CrossRef][Web of Science][Medline]
Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS 2001;15:1951-1957. [CrossRef][Web of Science][Medline]
Clavel F, Hance AJ. HIV drug resistance. N Engl J Med 2004;350:1023-1035. [Free Full Text]
To the Editor: The study by Lallemant and colleagues unexpectedly suggested that the rate of mother-to-child transmission of HIVin utero was significantly reduced by the addition of a doseof nevirapine at delivery to the antiretroviral drug therapythe pregnant women were receiving. Twenty-seven percent of thecases of HIV detected at the first interim analysis in the nevirapinegroups represented in utero transmission. In contrast, in theHIV Network for Prevention Trials (HIVNET) 012 study in Uganda,1and in our study in Durban, South Africa, 73 to 78 percent ofthe infected infants had HIV at birth after perinatal administrationof nevirapine. These discrepancies may relate to the methodof detection of in utero infection. In the HIVNET 012 study,50-µl peripheral-blood samples obtained by finger prickwere used; in our study, we used a quantitative reverse-transcriptase–polymerase-chain-reaction(RT-PCR) assay with a 500-µl plasma sample. On the basisof our data (Figure 1), approximately 50 percent of infectionstransmitted in utero would go undetected with the use of thefinger-prick assay.2
Figure 1. Changes in Viral Load during the First Days of Life in Infants Infected in Utero Who Received Nevirapine.
Panel A shows viral-load changes in nine infants in the first five days of life, and Panel B shows viral-load changes in one infant to day 17. The dashed line in each panel is the lower limit of detection of HIV infection in tests with the use of 50-µl dried blood spots.
Testing with the use of DNA PCR, although reportedly less sensitivethan testing with RNA PCR,3 might lessen artifactual reductionin mother-to-child transmission. However, most viral DNA isunintegrated and labile. The decline in viral DNA tracks withthe level of viremia.4 These data are important in the earlydiagnosis of pediatric HIV infection and in the interpretationof the action of nevirapine as a prophylactic agent againstmother-to-child transmission.
Philip J.R. Goulder, M.D., D.Phil. Oxford University Oxford OX1 3SY, United Kingdom philip.goulder{at}ndm.ox.ac.uk
Natasha Blanckenberg, M.D. University of KwaZulu-Natal Durban 4015, South Africa
Krista Dong, M.D. Massachusetts General Hospital Charlestown, MA 02129
References
Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795-802. [Web of Science][Medline]
Cassol S, Gill MJ, Pilon R, et al. Quantification of human immunodeficiency virus type 1 RNA from dried plasma spots collected on filter paper. J Clin Microbiol 1997;35:2795-2801. [Free Full Text]
Reisler RB, Thea DM, Pliner V, et al. Early detection of reverse transcriptase activity in plasma of neonates infected with HIV-1: a comparative analysis with RNA-based and DNA-based testing using polymerase chain reaction. J Acquir Immune Defic Syndr 2001;26:93-102. [Web of Science][Medline]
Pierson TC, Zhou Y, Kieffer TL, Ruff CT, Buck C, Siliciano RF. Molecular characterization of preintegration latency in human immunodeficiency virus type 1 infection. J Virol 2002;76:8518-8531. [Free Full Text]
The authors reply: The proportion of infants in whom HIV infectionis diagnosed at birth is primarily influenced by the antiretroviralprophylaxis provided to the mother during pregnancy. In theHIVNET 012 study without zidovudine prophylaxis, the proportionof infants with HIV infection at birth was 8.2 percent, whereasin the Perinatal HIV Prevention Trial 1 (PHPT-1), which usedthe same diagnostic methods as those used in the Perinatal HIVPrevention Trial 2 (PHPT-2), the proportion was 5.1 percentwith zidovudine prophylaxis initiated at 35 weeks of pregnancyand 1.5 percent with zidovudine prophylaxis initiated at 28weeks.1,2 It is still possible, as Goulder et al. suggest, thatthe DNA PCR assay with 50 µl of blood, used in PHPT-2,was less sensitive than the quantitative RT-PCR assay with 500µl of plasma, used in the HIVNET 012 study. However, theproportion of children with HIV infection at birth in the PHPT-2placebo group was surprisingly high, at 3.1 percent, as comparedwith the overall transmission rate in the nevirapine–nevirapinegroup of 1.1 percent.3 This percentage cannot be explained bya lack of sensitivity of DNA PCR. Rather, it suggests that nevirapineprevented transmissions that would have occurred at the beginningof labor, and that would be detectable at birth.
Resistance mutations to nevirapine are also a concern for thechildren.4 However, we found that in mothers, the results ofgenotyping 10 days after exposure were very poor predictorsof treatment failure, and the clinical significance of resistancemutations will be even more difficult to evaluate in the smallnumber of children infected in our study of shortened zidovudineregimens. More generally, we feel that the dilemma posed byHerzmann and Karcher cannot be framed as impairing the healthof one patient to help another. The two patients are closelyrelated, and a mother may decide to give her unborn child thebest chances of avoiding infection. The risk for the child —HIV infection and lifelong antiretroviral therapy at best —is hardly comparable to that for the mother — a lowerchance to achieve an undetectable viral load at the 50-copiesthreshold after six months of NNRTI-based therapy while othertreatment options are available, as discussed in our report.Moreover, the risks for both mother and child associated withalternative interventions, such as triple antiretroviral combinationsduring pregnancy, regardless of the mother's immune status,are not yet fully documented, and no data from a comparativestudy are available to help balance these risks.
Marc Lallemant, M.D. Institut de Recherche pour le Développement Unité de Recherche 054 Chiang Mai 50200, Thailand
Gonzague Jourdain, M.D. Harvard School of Public Health Chiang Mai 50200, Thailand
Sophie Le Coeur, M.D., Ph.D. Institut National d'Etudes Démographiques Paris 75020, France
References
Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999;354:795-802. [Web of Science][Medline]
Lallemant M, Jourdain G, Le Coeur S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004;351:217-228. [Free Full Text]
Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. N Engl J Med 2000;343:982-991. [Free Full Text]
Eshleman SH, Mracna M, Guay LA, et al. Selection and fading of resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012). AIDS 2001;15:1951-1957. [CrossRef][Web of Science][Medline]
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