Further evidence indicating immunological immaturity in neonates has been shown for nef-deleted SIV infection, which, while not virulent in adult macaques, is highly pathogenic in neonatal macaques . Factors permitting high viral replication in infants include a larger pool of CD4+ T-cells, a large thymus, delayed development of cytotoxic lymphocyte activity, and antibody-dependent cytotoxicity . Infants cannot suppress HIV replication as effectively as adults. In a prospective study comparing newly infected Kenyan adults and infants, the mean peak HIV-1 RNA was significantly higher in infants than adults, as was the mean set point level, indicating poorer ability to control HIV replication in infants. Further evidence is that the viral set point in infants infected later in life through breastfeeding was far lower than that in infants infected earlier . Evidence that early initiation of ARV therapy (by 6 weeks of age) reduces mortality by 75% compared with waiting for immunological markers to be below threshold values  corroborates the interpretation from this study that infants born infected with HIV are at particular risk of dying a few months after birth.
By contrast, acquisition of HIV infection from breast milk is likely to take place over an extended period of time, as will the manifestation of the sequelae of infection leading to death. We hypothesize that this particular mechanism will not lead to a sharp peak of mortality, but is more likely to lead to an extended tail of mortality beyond the peak described here.
D.B. is in receipt of a self-initiated research grant from the SA Medical Research Council. The University of Cape Town health sciences faculty also provided partial support, as did the Burden of Disease research project of the Western Cape Department of Health. We thank Dr Heston Philips of Statistics South Africa for producing the special tabulations for 1997–2002, Dr Marie-Louise Newell from the Africa Centre for sharing data on cumulative mortality, and Dr A Boulle for useful comments. We are appreciative of helpful comments from two anonymous reviewers.
D.B. is the primary author who conceived and designed the study, directed its implementation, and carried out preliminary analyses with L.B. and R.L. L.B., an MPH student, was also responsible for data management. M.L.T. provided biostatistical consultation, devised and conducted advanced statistical analyses, and provided critical review. B.D. and F.A. contributed to the health systems, M.C. to the clinical and J.M. to the epidemiological aspects of the interpretation of findings. All authors collectively contributed to drafting and editing of the article.
Ethics approval was obtained from the University of Cape Town Research Ethics Committee REC/REF 071/2008. There are no conflicts of interest.
1. Department of Health, Medical Research Council, Measure DHS+. South Africa Demographic and Health Survey 1998. Full Report
. Pretoria: Department of Health; 2002.
2. Department of Health. National HIV and syphilis antenatal seroprevalence survey in South Africa 2006
. Pretoria: Department of Health; 2007.
3. Doherty T, Besser M, Donohue S, Kamoga N, Stoops N, Williamson L, Visser R. Case Study Reports on Implementation and Expansion of the PMTCT Programme in the Nine Provinces of South Africa
. Durban: Health Systems Trust; 2003.
4. Abdullah MF, Young T, Bitalo L, Coetzee N, Myers JE. Public health lessons from a pilot programme to reduce mother-to-child transmission of HIV-1 in Khayalitsha. S Afr Med J 2001; 81:579–583.
5. Eley B. Addressing the paediatric HIV epidemic: a perspective from the Western Cape Region of South Africa
. Trans R Soc Trop Med Hyg 2006; 100:19–23.
6. The Working Group on Mother-to-Child Transmission of HIV. Rates of mother-to-child transmission of HIV-1 in Africa, America and Europe: results from 13 perinatal studies
. J Acquir Immune Defic Syndr Hum Retrovirol
7. Bobat R, Coovadia H, Coutsoudis A, Moodley D. Determinants of mother-to-child transmission of human immunodeficiency virus type 1 infection in a cohort from Durban, South Africa
. Pediatr Infect Dis J 1996; 15:604–610.
8. Magder LS, Mofenson L, Paul ME, Zorrilla CD, Blattner WA, Tuomala RE, et al
. Risk factors for in utero and intrapartum transmission of HIV. J Acquir Immune Defic Syndr 2005; 38:87–95.
9. WHO. International statistical classification of diseases and health related problems
. Tenth revision. Geneva: World Health Organization; 1992.
10. Brody LL. Infant and child mortality in South Africa in the context of a high HIV prevalence: an investigation into changing mortality patterns at a fine age resolution
. MPH Thesis. University of Cape Town; 2007.
11. Groenewald P, Nannan N, Bourne D, Laubscher R, Bradshaw D. Identifying deaths from AIDS in South Africa
. AIDS 2005; 19:193–201.
12. Statistics South Africa
. Mortality and causes of death in South Africa, 2005: findings from death notification. Statistical release P0309.3
. Pretoria: Statistics South Africa
13. Moultrie TA, Dorrington R. Estimation of fertility from the 2001 South Africa Census data. CARe Monograph no. 12
. Centre for Actuarial Research University of Cape Town; 2004.
14. McCullagh P, Nelder JA. Generalized linear models. London: Chapman and Hall; 1989.
15. Williams RL. A note on robust variance estimation for cluster-correlated data. Biometrics 2000; 56:645–646.
16. Stata Corp. Stata Statistical Software, Release 9.1
. College Station, TX: Stata Corporation; 2005.
17. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality
of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 2004; 364:1236–1243.
18. Setel PW, Macfarlane SB, Szreter S, Mikkelsen L, Jha P, Stout S, et al
. A scandal of invisibility: making everyone count by counting everyone. Lancet 2007; 370:1569–1577.
19. McIntyre J. Preventing mother-to-child transmission of HIV: successes and challenges. BJOG 2005; 112:1196–1203.
20. Luzuriaga K, Sullivan JL. Viral and immunopathogenesis of vertical HIV-1 infection. Pediatr Clin North Am 2000; 47:65–78.
21. Zinkernagel RM. Maternal antibodies, childhood infections, and autoimmune diseases: advances in immunology. N Engl J Med 2001; 345:1331–1335.
22. de Moraes-Pinto MI, Farhat CK, Carbonare SB, Curti SP, Otsubo ME, Lazarotti DS, et al
. Maternally acquired immunity in newborns from women infected by the human immunodeficiency virus. Acta Paediatr 1993; 82:1034–1038.
23. de Moraes-Pinto MI, Almeida AC, Kenj G, Filgueiras TE, Tobias W, Santos AM, et al
. Placental transfer and maternally acquired neonatal IgG immunity in human immunodeficiency virus infection. J Infect Dis 1996; 173:1077–1084.
24. Kuhn L, Kasonde P, Sinkala M, Kankasa C, Semrau K, Scott N, et al
. Does severity of HIV disease in HIV-infected mothers affect mortality
and morbidity among their uninfected infants? Clin Infect Dis 2005; 41:1654–1661.
25. Chougnet C, Kovacs A, Baker R, Mueller B, Luban N, Liewehr D, et al
. Influence of human immuno-deficiency virus-infected maternal environment on development of infant interleukin-12 production. J Infect Dis 2000; 181:1590–1597.
26. Clerici M, Saresella M, Colombo F, Fossati S, Sala N, Bricalli D, et al
. T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV. Blood 2000; 96:3866–3871.
27. Graham SM, Gibb DM. HIV disease and respiratory infection in children. British Medical Bulletin 2002; 61:133–150.
28. Baba TW, Jeong YS, Pennick D, Bronson R, Greene MF, Ruprecht RM. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 1995; 267:1820–1825.
29. Richardson BA, Mbori-Ngacha D, Lavreys L, John-Stewart GC, Nduati R, Panteleeff DD, et al
. Comparison of human immunodeficiency virus type 1 viral loads in Kenyan women, men, and infants during primary and early infection. J Virol 2003; 77:7120–7123.
30. Spira R, Lepage P, Msellati P, Van De Perre P, Leroy V, Simonon A, et al
. Natural history of human immunodeficiency virus type 1 infection in children: a five-year prospective study in Rwanda. Pediatrics 1999; 104:e56.
31. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn M, Madhi SA, et al
. Early Antiretroviral Therapy and Mortality
among HIV-Infected Infants. N Engl J Med 2008; 359:2233–2244.
32. Richardson BA, Nduati N, Mbori-Ngacha D, Overbaugh J, John-Stewart GC. Acute HIV infection among Kenyan infants. Clin Infect Dis 2008; 46:289–295.