Nevirapine plus Zidovudine to Prevent Mother-to-Child Transmission of HIV
http://www.100md.com
《新英格兰医药杂志》
To the Editor: The articles by Lallemant et al. and Jourdain et al. (July 15 issue)1,2 highlight a dilemma. Should we impair the health of one patient to help another patient? Of the women receiving nevirapine, 32 percent showed resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTI) at 10 days post partum.2 However, viral rebound may occur 21 days3 after receipt of the drug and result in an even higher rate of resistance mutations to NNRTI. Of the mothers receiving zidovudine monotherapy, 6.3 percent transmitted the human immunodeficiency virus (HIV) to their infants, as compared with 2.8 percent of mothers 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 vertically infected babies after nevirapine prophylaxis.4
With the use of zidovudine monotherapy in 1000 HIV-1–positive women, 63 infected babies will be delivered. If nevirapine is added to their treatment, 320 of the 1000 will have NNRTI resistance mutations, 24 infected infants will be born, and possibly 11 of them will harbor NNRTI resistance mutations. Thus, adding single-dose nevirapine to zidovudine prophylaxis will prevent 39 transmissions but may leave 11 babies and 320 mothers with NNRTI resistance mutations. These mutations may reduce their treatment options and worsen their prognosis.5 This risk must be considered when giving additional nevirapine during labor. Infected children should be tested for resistance mutations to allow for optimal future care.
Christian Herzmann, M.D.
Royal Free Hospital
London NW3 2QG, United Kingdom
christian.herzmann@web.de
Heiko Karcher, M.D.
German Agency for International Development and 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.
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.
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.
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.
Clavel F, Hance AJ. HIV drug resistance. N Engl J Med 2004;350:1023-1035.
To the Editor: The study by Lallemant and colleagues unexpectedly suggested that the rate of mother-to-child transmission of HIV in utero was significantly reduced by the addition of a dose of nevirapine at delivery to the antiretroviral drug therapy the pregnant women were receiving. Twenty-seven percent of the cases of HIV detected at the first interim analysis in the nevirapine groups represented in utero transmission. In contrast, in the HIV Network for Prevention Trials (HIVNET) 012 study in Uganda,1 and in our study in Durban, South Africa, 73 to 78 percent of the infected infants had HIV at birth after perinatal administration of nevirapine. These discrepancies may relate to the method of detection of in utero infection. In the HIVNET 012 study, 50-μl peripheral-blood samples obtained by finger prick were used; in our study, we used a quantitative reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay with a 500-μl plasma sample. On the basis of our data (Figure 1), approximately 50 percent of infections transmitted in utero would go undetected with the use of the finger-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 sensitive than testing with RNA PCR,3 might lessen artifactual reduction in mother-to-child transmission. However, most viral DNA is unintegrated and labile. The decline in viral DNA tracks with the level of viremia.4 These data are important in the early diagnosis of pediatric HIV infection and in the interpretation of the action of nevirapine as a prophylactic agent against mother-to-child transmission.
Philip J.R. Goulder, M.D., D.Phil.
Oxford University
Oxford OX1 3SY, United Kingdom
philip.goulder@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.
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.
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.
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.
The authors reply: The proportion of infants in whom HIV infection is diagnosed at birth is primarily influenced by the antiretroviral prophylaxis provided to the mother during pregnancy. In the HIVNET 012 study without zidovudine prophylaxis, the proportion of infants with HIV infection at birth was 8.2 percent, whereas in the Perinatal HIV Prevention Trial 1 (PHPT-1), which used the same diagnostic methods as those used in the Perinatal HIV Prevention Trial 2 (PHPT-2), the proportion was 5.1 percent with zidovudine prophylaxis initiated at 35 weeks of pregnancy and 1.5 percent with zidovudine prophylaxis initiated at 28 weeks.1,2 It is still possible, as Goulder et al. suggest, that the DNA PCR assay with 50 μl of blood, used in PHPT-2, was less sensitive than the quantitative RT-PCR assay with 500 μl of plasma, used in the HIVNET 012 study. However, the proportion of children with HIV infection at birth in the PHPT-2 placebo group was surprisingly high, at 3.1 percent, as compared with the overall transmission rate in the nevirapine–nevirapine group of 1.1 percent.3 This percentage cannot be explained by a lack of sensitivity of DNA PCR. Rather, it suggests that nevirapine prevented transmissions that would have occurred at the beginning of labor, and that would be detectable at birth.
Resistance mutations to nevirapine are also a concern for the children.4 However, we found that in mothers, the results of genotyping 10 days after exposure were very poor predictors of treatment failure, and the clinical significance of resistance mutations will be even more difficult to evaluate in the small number of children infected in our study of shortened zidovudine regimens. More generally, we feel that the dilemma posed by Herzmann and Karcher cannot be framed as impairing the health of one patient to help another. The two patients are closely related, and a mother may decide to give her unborn child the best 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 lower chance to achieve an undetectable viral load at the 50-copies threshold after six months of NNRTI-based therapy while other treatment options are available, as discussed in our report. Moreover, the risks for both mother and child associated with alternative interventions, such as triple antiretroviral combinations during pregnancy, regardless of the mother's immune status, are not yet fully documented, and no data from a comparative study 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.
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.
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.
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.
With the use of zidovudine monotherapy in 1000 HIV-1–positive women, 63 infected babies will be delivered. If nevirapine is added to their treatment, 320 of the 1000 will have NNRTI resistance mutations, 24 infected infants will be born, and possibly 11 of them will harbor NNRTI resistance mutations. Thus, adding single-dose nevirapine to zidovudine prophylaxis will prevent 39 transmissions but may leave 11 babies and 320 mothers with NNRTI resistance mutations. These mutations may reduce their treatment options and worsen their prognosis.5 This risk must be considered when giving additional nevirapine during labor. Infected children should be tested for resistance mutations to allow for optimal future care.
Christian Herzmann, M.D.
Royal Free Hospital
London NW3 2QG, United Kingdom
christian.herzmann@web.de
Heiko Karcher, M.D.
German Agency for International Development and 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.
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.
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.
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.
Clavel F, Hance AJ. HIV drug resistance. N Engl J Med 2004;350:1023-1035.
To the Editor: The study by Lallemant and colleagues unexpectedly suggested that the rate of mother-to-child transmission of HIV in utero was significantly reduced by the addition of a dose of nevirapine at delivery to the antiretroviral drug therapy the pregnant women were receiving. Twenty-seven percent of the cases of HIV detected at the first interim analysis in the nevirapine groups represented in utero transmission. In contrast, in the HIV Network for Prevention Trials (HIVNET) 012 study in Uganda,1 and in our study in Durban, South Africa, 73 to 78 percent of the infected infants had HIV at birth after perinatal administration of nevirapine. These discrepancies may relate to the method of detection of in utero infection. In the HIVNET 012 study, 50-μl peripheral-blood samples obtained by finger prick were used; in our study, we used a quantitative reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay with a 500-μl plasma sample. On the basis of our data (Figure 1), approximately 50 percent of infections transmitted in utero would go undetected with the use of the finger-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 sensitive than testing with RNA PCR,3 might lessen artifactual reduction in mother-to-child transmission. However, most viral DNA is unintegrated and labile. The decline in viral DNA tracks with the level of viremia.4 These data are important in the early diagnosis of pediatric HIV infection and in the interpretation of the action of nevirapine as a prophylactic agent against mother-to-child transmission.
Philip J.R. Goulder, M.D., D.Phil.
Oxford University
Oxford OX1 3SY, United Kingdom
philip.goulder@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.
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.
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.
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.
The authors reply: The proportion of infants in whom HIV infection is diagnosed at birth is primarily influenced by the antiretroviral prophylaxis provided to the mother during pregnancy. In the HIVNET 012 study without zidovudine prophylaxis, the proportion of infants with HIV infection at birth was 8.2 percent, whereas in the Perinatal HIV Prevention Trial 1 (PHPT-1), which used the same diagnostic methods as those used in the Perinatal HIV Prevention Trial 2 (PHPT-2), the proportion was 5.1 percent with zidovudine prophylaxis initiated at 35 weeks of pregnancy and 1.5 percent with zidovudine prophylaxis initiated at 28 weeks.1,2 It is still possible, as Goulder et al. suggest, that the DNA PCR assay with 50 μl of blood, used in PHPT-2, was less sensitive than the quantitative RT-PCR assay with 500 μl of plasma, used in the HIVNET 012 study. However, the proportion of children with HIV infection at birth in the PHPT-2 placebo group was surprisingly high, at 3.1 percent, as compared with the overall transmission rate in the nevirapine–nevirapine group of 1.1 percent.3 This percentage cannot be explained by a lack of sensitivity of DNA PCR. Rather, it suggests that nevirapine prevented transmissions that would have occurred at the beginning of labor, and that would be detectable at birth.
Resistance mutations to nevirapine are also a concern for the children.4 However, we found that in mothers, the results of genotyping 10 days after exposure were very poor predictors of treatment failure, and the clinical significance of resistance mutations will be even more difficult to evaluate in the small number of children infected in our study of shortened zidovudine regimens. More generally, we feel that the dilemma posed by Herzmann and Karcher cannot be framed as impairing the health of one patient to help another. The two patients are closely related, and a mother may decide to give her unborn child the best 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 lower chance to achieve an undetectable viral load at the 50-copies threshold after six months of NNRTI-based therapy while other treatment options are available, as discussed in our report. Moreover, the risks for both mother and child associated with alternative interventions, such as triple antiretroviral combinations during pregnancy, regardless of the mother's immune status, are not yet fully documented, and no data from a comparative study 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.
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.
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.
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.