Editorial
Protecting the Next Generation — Eliminating Perinatal HIV-1 Infection
N Engl J Med 2010; 362:2316-2318June 17, 2010
- Article
More than 90% of the 430,000 human immunodeficiency virus type 1 (HIV-1) infections in children each year occur in sub-Saharan Africa, where HIV-1 acquisition through breast milk accounts for more than 40% of infections. However, in Africa, breast-feeding is a cornerstone of child survival. Two randomized trials reported in this issue of the Journal 1,2 show that antiretroviral regimens in breast-feeding infants or lactating mothers significantly decrease postnatal acquisition of HIV-1. It should be possible to eliminate new perinatal HIV-1 infections globally with the use of antiretroviral therapy when needed for maternal health and, when treatment is not otherwise required for the mother's health, by adding postpartum prophylaxis to antepartum and intrapartum prophylaxis.
A key determination in choosing an antiretroviral regimen for a pregnant or lactating woman with HIV-1 infection is whether she requires treatment. The revised World Health Organization (WHO) treatment criteria (WHO stage 3 or 4 disease or CD4+ lymphocyte count of <350 cells per cubic millimeter) are particularly important for these women, since treatment affects both maternal and child outcomes. The Zambia Exclusive Breastfeeding Study (ClinicalTrials.gov number, NCT00310726) enrolled 1025 pregnant women infected with HIV-1 before the availability of widespread treatment; 92% of deaths and 88% of perinatal or postnatal transmissions occurred among the 68% of women who would have met the new WHO criteria for HIV treatment.3 The intervention that would have the most substantial impact on HIV-1−related maternal deaths and perinatal infections throughout the world is the initiation of lifelong antiretroviral therapy in pregnant and lactating women infected with HIV-1 who meet the treatment criteria. When antiretroviral drugs are provided solely for prophylaxis and discontinued when the risk of transmission ceases, a three-drug regimen in mothers and antiretroviral prophylaxis in infants appear to have similar efficacy in the prevention of postnatal infection.
The Mma Bana Study reported on by Shapiro et al.1 randomly assigned 560 pregnant women with CD4+ lymphocyte counts of 200 cells per cubic millimeter or more to receive one of two prophylaxis regimens, starting at 26 to 34 weeks' gestation through planned weaning by 6 months post partum. There were no significant differences in viral suppression or transmission between the regimens, and overall (1.3%) and postnatal (0.4%) transmission in the two randomized groups was among the lowest ever reported in Africa. The lack of an infant-prophylaxis group prevented a direct comparison of the interventions.
The Breastfeeding, Antiretrovirals, and Nutrition (BAN) study reported on by Chasela et al.2 enrolled 2369 mothers with CD4+ lymphocyte counts of at least 250 cells per cubic millimeter; based on the standard of care at the time, no antepartum regimen was given. The study was designed to determine whether a 6-month infant or maternal regimen was superior to intrapartum single-dose nevirapine combined with 1 week of zidovudine−lamivudine in preventing postnatal infection. Both were effective. At 6 months, as compared with a 5.7% rate of postnatal infection among infants who received the control regimen, postnatal infections were reduced by 70.2% among infants who received the nevirapine regimen, to 1.7%, and postnatal infections were reduced by 49.1% among infants of women who received the maternal triple-drug regimen, to 2.9%. The study was not powered to address the comparative efficacy of infant versus maternal regimens.
Although the trials cannot be directly compared, some important lessons can be gleaned. To maximally reduce transmission, antiretroviral regimens must start during pregnancy. In the BAN study, which did not include an antepartum regimen, in utero transmission was 5.0% as compared with 0.9% in the Mma Bana Study. In the BAN control group, the risk of postnatal infection was highest between 2 and 12 weeks of age; infection rates were 0.5% per week between 2 and 6 weeks, 0.3% per week between 6 and 12 weeks, and 0.1% per week thereafter. During this early high-risk period, the infant regimen reduced postnatal transmission by 86.1% (from 3.6% in the control group to 0.5%), while the maternal regimen reduced transmission by 52.8% (from 3.6% in the control group to 1.7%). After 18 weeks of age, the incremental risk of infection was similar (1.2% and 1.0%, respectively). This early difference in efficacy probably reflected the time required for the triple-drug regimen to suppress the maternal viral load. Therefore, in women presenting late or during labor, the use of nevirapine in infants may be particularly critical to prevent early postnatal infection.
The safety of nevirapine prophylaxis in more than 2800 infants in the Six-Week Extended-Dose Nevirapine study involving three trials (NCT00074399, NCT00061321, and NCT00639938), the Post-Exposure Prophylaxis of Infants study (NCT00115648), and the BAN trial was comparable to that of control interventions, with the exception of more nevirapine-associated rashes in infants in the BAN trial (in <2%).2,4,5 The safety of a maternal triple-drug regimen in more than 1800 mother−infant pairs in the Mma Bana, BAN, and Kesho Bora (Current Controlled Trials number, ISRCTN71468401) trials was also comparable to that of control interventions.1,2,6 Investigators in the BAN study reported more neutropenia in women who received the antiretroviral regimen than in women in the other study groups. In the Mma Bana Study, there was a troubling increase in preterm delivery in mothers receiving lopinavir−ritonavir. As maternal triple-drug use increases, it is critical to enhance surveillance for complications in pregnancy and long-term outcomes in infants.
The use of antiretroviral drugs in both infants and mothers is associated with infection with drug-resistant virus in the few infants who are infected despite postnatal prophylaxis. High rates of resistance to nonnucleoside reverse-transcriptase inhibitors among infants infected despite nevirapine prophylaxis have been reported.7 Three studies have shown multiclass drug resistance in breast-feeding infants who were infected despite the use of maternal triple-drug regimens.8-10
The WHO recommends two prophylaxis options for women who do not otherwise require therapy: antepartum zidovudine plus single-dose nevirapine with 1 week of zidovudine−lamivudine combined with infant nevirapine prophylaxis, or antepartum and postpartum maternal triple-drug prophylaxis; both regimens continue until the cessation of breast-feeding. Although BAN lacked an antepartum component, the Kesho Bora trial provided a direct comparison of the two antepartum options. In women with CD4+ lymphocyte counts of 200 to 500 cells per cubic millimeter who were randomly assigned to receive antepartum and intrapartum zidovudine plus single-dose nevirapine with 1 week of postpartum zidovudine−lamivudine or a maternal triple-drug regimen during pregnancy and breast-feeding, rates of infection at birth, reflecting in utero transmission, were 2.2% and 1.8%, respectively — these rates were not significantly different.6
Given two similarly effective interventions, the choice of prophylaxis involves several considerations, including relative costs, feasibility, and risks and benefits. The cost-effectiveness of the two interventions has not been determined. Infant prophylaxis combined with antepartum zidovudine plus single-dose nevirapine plus 1 week of zidovudine−lamivudine is less expensive than a maternal triple-drug regimen, but it may be more difficult to implement. With maternal triple-drug prophylaxis, the risks of drug toxicity in women, possible adverse pregnancy outcomes, treatment interruption after prolonged exposure during pregnancy and breast-feeding, and fetal exposure to multiple drugs need to be weighed against whether there might be some incremental benefit in preventing transmission as compared with less expensive regimens in women who do not otherwise require treatment. Although an ongoing trial (NCT01061151) is designed to address the comparative efficacy and safety of these two prophylaxis options, data will not be available for several years.
Debate about which intervention is optimal and most effective should not be used to justify inaction. Success will be tied less to what regimen is provided than to the integration of services for the identification, care, and treatment of women with HIV-1 infection and their infants. The implementation of these new options for the perinatal prevention of HIV-1 infection in resource-limited countries offers a unique opportunity to link prevention and treatment efforts, rather than view these as competing efforts. We now have the tools to make a considerable difference in controlling the pediatric HIV-1 epidemic. A generation of children awaits our actions.
The conclusions and opinions expressed in this article are those of the author and do not necessarily reflect those of the National Institutes of Health or the Department of Health and Human Services.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
Source Information
From the Pediatric, Adolescent and Maternal AIDS Branch, Center for Research for Mothers and Children, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD.
- References
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1
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Regina Célia de Souza Campos Fernandes, Thais Louvain de Souza, Enrique Medina-Acosta. (2011) Role of maternal, transplacentally acquired HIV-1-specific neutralizing antibodies in protecting the uninfected offspring against HIV-1 transmission via breast milk. Future Virology 6:9, 1029-1034
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Taha E Taha, Qing Li, Donald R Hoover, Linda Mipando, Kondwani Nkanaunena, Michael C Thigpen, Allan Taylor, Johnstone Kumwenda, Mary Glenn Fowler, Lynne M Mofenson, Newton I Kumwenda. (2011) Postexposure Prophylaxis of Breastfeeding HIV-Exposed Infants With Antiretroviral Drugs to Age 14 Weeks: Updated Efficacy Results of the PEPI-Malawi Trial. JAIDS Journal of Acquired Immune Deficiency Syndromes 57:4, 319-325
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Mary A. Vogler, Harjot Singh, Rodney Wright. (2011) Complex Decisions in Managing HIV Infection During Pregnancy. Current HIV/AIDS Reports 8:2, 122-131
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J. Fogel, Q. Li, T. E. Taha, D. R. Hoover, N. I. Kumwenda, L. M. Mofenson, J. J. Kumwenda, M. G. Fowler, M. C. Thigpen, S. H. Eshleman. (2011) Initiation of Antiretroviral Treatment in Women After Delivery Can Induce Multiclass Drug Resistance in Breastfeeding HIV-Infected Infants. Clinical Infectious Diseases 52:8, 1069-1076
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(2010) Maternal or Infant Antiretroviral Drugs to Reduce HIV-1 Transmission. New England Journal of Medicine 363:20, 1968-1970
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Lallemant, Marc, Jourdain, Gonzague, . (2010) Preventing Mother-to-Child Transmission of HIV — Protecting This Generation and the Next. New England Journal of Medicine 363:16, 1570-1572
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Myron S Cohen. (2010) HIV Treatment as Prevention: To be or not to be?. JAIDS Journal of Acquired Immune Deficiency Syndromes 55:2, 137-138
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