From the University of California San Diego, La Jolla, California, USA.
Received 4 October, 2005
Accepted 25 October, 2005
Correspondence to Davey M. Smith, University of California San Diego, 9500 Gilman Drive 0679, La Jolla, CA 92093, USA. E-mail: firstname.lastname@example.org
The efficacy of antiretroviral therapy to prevent mother-to-child HIV transmission (MTCT) was first established in 1994. In that study by Connor and colleagues (PACTG 076) both mother and infant were treated with long courses of zidovudine, which reduced HIV transmission from 25 to 8% . Since then, improved interventions in industrialized nations have further reduced MTCT rates to less than 2% through access to HAART, caesarian deliveries when indicated and formula feeding [2–4]. In developing nations, however, full access to HAART is not yet a reality and MTCT rates remain high . An ideal method would be one that is convenient to administer, safe for both mother and infant, inexpensive and offering complete protection from transmission.
Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor (NNRTI), has become an especially attractive option to decrease MTCT because it is lipophilic and easily absorbed . It achieves high blood concentrations with a single oral 200 mg dose, often reaching plasma concentrations 10 times that needed to inhibit viral replication by 50% (IC50). Nevirapine also penetrates well into breast milk and readily crosses the placenta [6,7]. Taken together, these characteristics of NVP explain the success of the HIVNET 012 study in Uganda, which demonstrated that a single 200 mg dose of NVP taken by an HIV-infected mother at the onset of labor and a 2 mg/kg dose of NVP given to the infant within 72 h of birth could reduce the MTCT rate by 42% at 6 weeks of the infant's life [8,9].
In this issue of AIDS, Jackson and colleagues report a sub-study of HIVNET 012. They correlated the concentration of NVP in the cord blood of infants, self-reported administration of the maternal NVP dose and HIV transmission to better define the optimal timing of maternal dosing . When and how to administer the maternal NVP dose is important because previous studies have reported higher transmission rates if the maternal dose was taken less than 2 h before delivery . Jackson and colleagues confirmed previous reports  that NVP levels in cord blood are high, especially for women who reported taking the dose more than 1 h prior to delivery and that HIV transmission risk is increased if the dosing occurred within 2 h of delivery . Their data further support the feasibility of NVP self-administration by the mother before delivery to increase the duration of NVP protection to the infant.
Despite the demonstrated efficacy of reducing MTCT rates, single-dose NVP regimens are temporizing at best. The half-life of NVP is very long with detectable levels in maternal blood and breast milk for up to 3 weeks after a single 200 mg dose . This may explain why single dose NVP was shown to be more effective than zidovudine in HIVNET 012 , since 30–50% of MTCT occurs through breast feeding [14,15]. However, this amounts to protracted monotherapy, which readily selects for NNRTI resistance in 15–40% of post-partum women [16–18] and 23% of the infants where transmission does occur . More sensitive techniques, such as allele-specific polymerase chain reaction, has identified NNRTI drug-resistant rates as high as 75% in mothers receiving a single dose of NVP  and 78% of infants in which the NVP regimen failed . Selection for NNRTI resistance in the mother has been shown to decrease the effectiveness of subsequent antiretroviral therapy, especially since NNRTI-based antiretroviral regimens are recommended first-line treatments in resource-limited settings . This is especially poignant in Africa where maternal death is associated with an increase in infant death by three to fourfold independent of maternal HIV status, child birth weight, socio-economic status, and maternal age and parity . Furthermore, the development of NNRTI resistance may lessen the protection of NVP for future pregnancies .
Today, one infant will be born infected with HIV in either the United States or Europe, which sharply contrasts with the 1900 infants who will be born infected with HIV in Africa . This study by Jackson and colleagues, in conjunction with HIVNET 012, has shown that NVP can be a convenient and inexpensive method to decrease MTCT in these resource-limited settings [8,10]. However, the single dose NVP is not a permanent solution. Although no significant short-term toxicities have been documented with the single dose regimen [7,13], the real price is paid with the development of NNRTI resistance, which decreases the effectiveness of this class of antiretroviral drugs . The selection for HIV drug resistance may not only have detrimental effects on the mother or infant treated with NVP, but also on the HIV-infected population as a whole, as NNRTI resistance has been shown to be relatively transmissible . This is disappointing since we know that improving access to HAART will further reduce MTCT and increase the life span of the mother through HAART. Although we currently lack the resources, universal access to HAART would probably decrease all transmissions, both horizontal and vertical, while improving the quantity and quality of life all those affected . However, this remains hopelessly optimistic as fewer than 10% of all pregnant women in Africa have access to NVP prophylaxis . More than a decade has passed since zidovudine was found to reduce MTCT rates, and we still grapple with preventing MTCT in resource-limited settings. Although NVP regimens offer considerable benefits, they remain only a temporary and imperfect solution to a long-term crisis.
I would like to thank Terry Albritton and Susan Little for their editorial assistance.
1. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, et al
. The Pediatric AIDS Clinical Trials Group. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331:1173–1180.
2. Coovadia H. Antiretroviral agents – how best to protect infants from HIV and save their mothers from AIDS. N Engl J Med 2004; 351:289–292.
3. Mofenson LM, McIntyre JA. Advances and research directions in the prevention of mother-to-child HIV-1 transmission. Lancet 2000; 355:2237–2244.
4. McIntyre JA, Martinson N, Gray GE, Hall DB, Boltz V, Palmer S, et al
. Single dose nevirapine combined with short course of combivir for prevention of mother to child transmission of HIV-1 can significantly decrease the subsequent development of maternal and infant resistant virus [abstract]. Antiviral Ther 2005; 10:S.
5. Dabis F, Ekpini ER. HIV-1/AIDS and maternal and child health in Africa. Lancet 2002; 359:2097–2104.
6. Mirochnick M, Fenton T, Gagnier P, Pav J, Gwynne M, Siminski S, et al
. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis 1998; 178:368–374.
7. Musoke P, Guay LA, Bagenda D, Mirochnick M, Nakabiito C, Fleming T, et al
. A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1-infected pregnant Ugandan women and their neonates (HIVNET 006). AIDS 1999; 13:479–486.
8. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, 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.
9. Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, et al
. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 2003; 362:859–868.
10. Jackson JB, Parsons T, Musoke P, Nakabiito C, Donnell D, Fleming T, et al
. Association of cord blood nevirapine concentration with reported timing of dose and HIV-1 transmission. AIDS 2005; 20:217–222.
11. Moodley D, Moodley J, Coovadia H, Gray G, McIntyre J, Hofmyer J, et al
. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus type 1. J Infect Dis 2003; 187:725–735.
12. Mirochnick M, Dorenbaum A, Blanchard S, Cunningham CK, Gelber RD, Mofenson L, et al
. Predose infant nevirapine concentration with the two-dose intrapartum neonatal nevirapine regimen: Association with timing of maternal intrapartum nevirapine dose. J Acquir Immune Defic Syndr 2003; 33:153–156.
13. Chung MH, Kiarie JN, Richardson BA, Lehman DA, Overbaugh J, John-Stewart GC. Breast milk HIV-1 suppression and decreased transmission: a randomized trial comparing HIVNET 012 nevirapine versus short-course zidovudine. AIDS 2005; 19:1415–1422.
14. Miotti PG, Taha TET, Kumwenda NI, Broadhead R, Mtimavalye LAR, Van der Hoeven L, et al
. HIV transmission through breastfeeding: a study in Malawi. JAMA 1999; 282:744–749.
15. Eshleman SH, Guay LA, Mwatha A, Brown E, Musoke P, Mmiro F, et al
. Comparison of mother-to-child transmission rates in Ugandan women with subtype A versus D HIV-1 who received single-dose nevirapine prophylaxis - HIV Network for Prevention Trials 012. J Acquir Immune Defic Syndr 2005; 39:593–597.
16. Jackson JB, Becker-Pergola G, Guay LA, Musoke P, Mracna M, Fowler MG, et al
. Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission. AIDS 2000; 14:F111–F115.
17. Eshleman SH, Mracna M, Guay LA, Deseyve M, Cunningham S, Mirochnick M, 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.
18. Cunningham CK, Chaix ML, Rekacewicz C, Britto P, Rouzioux C, Gelber RD, et al
. Development of resistance mutations in women receiving standard antiretroviral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: A substudy of Pediatric AIDS Clinical Trials Group protocol 316. J Infect Dis 2002; 186:181–188.
19. Dabis F, Bequet L, Ekouevi DK, Viho I, Rouet F, Horo A, et al
. Field efficacy of zidovudine, lamivudine and single-dose nevirapine to prevent peripartum HIV transmission. AIDS 2005; 19:309–318.
20. Palmer S, Boltz V, Maldarelli, Martinson N, McIntyre J, Gray G, et al
. Short-course combivir (CBV) single dose nevirapine reduces but does not eliminate the selection of nevirapine-resistant HIV-1: improved detection by allele-specific PCR [abstract]
. Antiviral Ther
21. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, Bowonwatanuwong C, Kantipong P, Leechanachai P, et al
. the Perinatal HIV Prevention Trial Group. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004; 351:229–240.
22. Taha TET, Miotti P, Liomba G, Dallabetta G, Chiphangwi J. HIV, maternal death and child survival in Africa. AIDS 1996; 10:111–112.
23. Richman D, Shih CK, Lowy I, Rose J, Prodanovich P, Goff S, et al
. Human-immunodeficiency-virus type-1 mutants resistant to nonnucleoside inhibitors of reverse-transcriptase arise in tissue-culture. Proc Natl Acad Sci USA 1991; 88:11241–11245.
24. Brown AJL, Frost SDW, Mathews WC, Dawson K, Hellmann NS, Daar ES, et al
. Transmission fitness of drug-resistant human immunodeficiency virus and the prevalence of resistance in the antiretroviral-treated population. J Infect Dis 2003; 187:683–686.
25. Mofenson LM. Tale of two epidemics – the continuing challenge of preventing mother-to-child transmission of human immunodeficiency virus. J Infect Dis 2003; 187:721–724.
26. Joint United Nations Programme on HIV/AIDS (UNAIDS); World Health Organization (WHO). AIDS Epidemic Update 2004
. Geneva: UNAIDS/WHO; 2004.