Objectives: To study mortality in African children born to HIV-1-infected mothers exposed peripartum to zidovudine.
Methods: A randomized placebo-controlled trial in Abidjan and Bobo-Dioulasso. Pregnant women received either 300 mg zidovudine twice daily from 36–38 weeks’ gestation, 600 mg during labour, and 300 mg twice daily for 7 days post-partum or a matching placebo. Determinants of mortality were studied up to 18 months, overall and among the infected children: treatment, centre, timing of infection, mother and child HIV disease.
Results: There were 75 infant deaths among 407 live births. The risk of death at 18 months was 176/1000 in the zidovudine arm and 221 for placebo. Relative hazard (RH, zidovudine versus placebo) was 0.47 [95% confidence interval (CI) 0.2–1.0] up to 230 days of life. Maternal CD4 lymphocyte count < 200/mm3 (RH 2.92; CI 1.4–6.1) and child HIV-1 infection (RH 12.6; CI 6.6–24.3) increased mortality of all children born to HIV-1-infected mothers. There were 101 children infected (40 in the zidovudine group), and 51 died. Their 18 month probability of death was 590/1000 in the zidovudine group and 510 in the placebo group. Among infected children, maternal zidovudine reduced the risk of death on or before day 230 (RH 0.18; CI 0.1–0.5). Maternal CD4 lymphocyte count < 200/mm3 (RH 3.25; CI 1.3–8.4), maternal death (RH 9.65; CI 1.7–56.0), diagnosis of paediatric infection on or before day 12 (RH 18.1; CI 4.8–69.0) and between days 13 and 45 (RH 7.63; CI 2.0–29.5), clinical paediatric AIDS (RH 5.37; CI 2.3–12.7) were risk factors for death in HIV-1-infected children.
Conclusion: Mother-to-child transmission reduction by zidovudine is safe and beneficial to African children. The mortality of HIV-1-infected children is high. Peripartum maternal zidovudine exerts a protective effect for at least 8 months.
From the aUnité INSERM no. 330, ISPED, Université Victor Segalen Bordeaux 2, Bordeaux, France; bCentre Hospitalier Universitaire de Yopougon and PAC-CI Programme, Abidjan, Côte d'Ivoire; cCentre Muraz, Bobo-Dioulasso, Burkina Faso; and dIRD Petit Bassam, Abidjan, Côte d'Ivoire.
Received: 4 August 2000;
revised: 17 November 2000; accepted: 10 January 2001.
Sponsorship: The DITRAME ANRS 049 trial was sponsored by the Agence Nationale de Recherches sur le SIDA (ANRS, Paris, France) and the French Ministry of Foreign Affairs, through the Coordinated Action AC12.
Correspondence and requests for reprints to: Pr François Dabis, Unité INSERM no. 330, Université Victor Segalen Bordeaux 2, 146 rue Léo-Saignat, 33076 Bordeaux Cedex, France. Fax: 22.214.171.124.45.28; e-mail: email@example.com
This work was presented in part at the XIIIth International AIDS Conference, Durban, July 2000 [Abstract MoPpB1024].
Contributors: F. Dabis was the programme coordinator, wrote the protocol, supervised the research and wrote the manuscript. V. Leroy contributed to the design of the trial and was in charge of all statistical aspects of the project. L. Dequae-Merchadou performed the statistical analysis. N. Elenga was in charge of paediatric follow-up in Abidjan. I. Viho was trial monitor in Abidjan. P. Msellati wrote the protocol and was the coordinator of the Abidjan centre. N. Meda wrote the protocol and was the coordinator of the Bobo-Dioulasso centre. I. Sombie was trial monitor in Bobo-Dioulasso.
*For the members of the DITRAME Study Group see Lancet 1999; 353:786–790.
Paediatric infection by HIV-1 has become a threat to childhood mortality in developing countries. Every day, 1600 children become infected with HIV world-wide, predominantly by mother-to-child transmission (MTCT) . Most live in Africa where resources for case management remain very scarce . Paediatric HIV/AIDS may thus erode the gains made over the past three decades through the programmes now merged into the Integrated Management of Childhood Illness strategy of the World Health Organization (WHO) .
Several clinical trials have highlighted the efficacy of short regimens of antiretroviral agents in reducing MTCT in developing countries . In three of them, maternal zidovudine treatment in the peripartum period was evaluated [5–7]. The two African trials [8,9] indicated a sustained reduction in transmission of at least 30% at 12–15 months of age, despite prolonged breast-feeding. Neonatal assessment of the HIV-1 infection status is difficult , and some trials have reported efficacy figures combining infection and mortality data [11,12]. Concern has been expressed that perinatal exposure to nucleoside reverse trancriptase inhibitors such as zidovudine may lead to toxic effects on the mitochondria in infants . However, such effects appear to be extremely rare, and the risk is outweighed by the number of cases of paediatric infection that can be averted . Careful monitoring of the adverse events associated with perinatal exposure to these drugs is essential in developing countries where pilot programmes are being implemented [15,16].
We have explored the mortality patterns in all children born to HIV-1-infected women who received zidovudine in the peripartum period, and for the subset of children who were subsequently diagnosed as HIV-1 infected themselves. Risk factors for death in the first 18 months were investigated, focusing on the contribution of maternal zidovudine exposure.
The project was conducted in two large cities in West Africa, Abidjan, Côte d'Ivoire, and Bobo Dioulasso, Burkina Faso, with good access and coverage of mother and child care services. Infant mortality rate (IMR) was 112 per 1000 in Côte d'Ivoire in 1994–1998  and 134 per 1000 for Burkina Faso in 1993 .The methodology of this randomized double-blind placebo-controlled trial has previously been published, with results on the number of cases of paediatric infection averted at 6 and 15 months of age [6,8].
The oral regimen of zidovudine was a daily pre-partum treatment of 500 mg during phase II and 600 mg during phase III, from 36 to 38 weeks of gestation, a single oral loading dose of 500–600 mg at the beginning of labour, a 7 day post-partum treatment of 500–600 mg per day, and no treatment to the neonate. Clinical follow-up and blood collection from the child were scheduled within one week after birth, then at days 45 and 90, and quarterly until 18 months. Feeding practices were reported at each visit. All prescribed medications, hospital stays and transportation fees were free of charge. The prophylaxis of opportunistic infections and micronutrient supplementation were not provided, in the absence of African guidelines.
The blood sample collected at day 180, or an earlier one when that was not available, were systematically processed by a polymerase chain reaction (PCR) test. PCR was then applied to all the preceding available samples if the first one tested was positive. Non-commercial DNA PCR was used in Abidjan . In Bobo Dioulasso, samples were analysed first by non-commercial DNA PCR and quantitative plasma RNA PCR (Amplicor HIV Monitor version 1.5, Roche Diagnostic Systems Inc., Branchburg, NJ, USA), which gave concordant results, and then by RNA PCR only. The diagnosis of paediatric HIV-1 infection was considered on the basis of one positive PCR . Serum samples collected between 9 and 18 months of age were screened for HIV-1 and HIV-2 antibodies using a commercial enzyme-linked immunosorbent assay (Genelavia Mixt, Diagnostics Pasteur, Paris, France, or Murex ICE 1-0-2; Murex Biotech Ltd, Dartford, UK). Confirmation on the same sample was obtained with a synthetic peptide enzyme-linked immunosorbent assay (Peptilav 1-2, Diagnostics Pasteur). A positive antibody test at 15 months or beyond was also a diagnostic criteria of paediatric infection . Children who had no sample available for PCR and could not be followed beyond 6 months of age were considered to be of indeterminate HIV-1 status. The date of diagnosis of infection was the date of the first positive PCR test for children diagnosed up to day 45. It was estimated to be the mid-point between the dates of the last negative and the first positive tests for those diagnosed after day 45.
The analysis was performed on an intent-to-treat basis. Data were frozen in October 2000. The date of origin for the present study was the date of birth. The endpoint was the date of death or the last available date of follow-up until 18 months. The probability of death at a given age and the probability of breast-feeding were estimated using the Kaplan–Meier technique. Descriptions and comparisons were made first for all children born to HIV-infected mothers, then for the subset of those diagnosed as infected. A Cox univariate proportional hazards model studied determinants of child mortality, followed by a multivariate model with a stepwise descending procedure, fixed and time-dependant variables and terms of interaction. Hazard ratios (HR) are reported with their 95% confidence interval (CI). We verified the proportionality hazards assumption for treatment effect and, whenever necessary, performed analyses by time periods.
This report is based on 407 liveborn infants, 238 in Abidjan and 169 in Bobo Dioulasso, exposed to zidovudine (202) or placebo (205). They were born to 401 HIV-infected mothers, and included seven pairs of twins. The median baseline maternal plasma viral load (N = 186) was 4.1 log [interquartile range (IR) 3.4–4.8], using a quantitative RNA-PCR (Bayer-Chiron, Quantiplex 340, version 3.0, E. Walpole, MA, USA). The median maternal CD4 T lymphocyte count was 541/mm3 (IR 356–741) and 8.8% had less than 200 cells/mm3. Low birthweight (< 2500 g) was recorded in 17.0% of births and prematurity in 7.7% (Finnström score < 37 weeks). Intra-uterine growth retardation, defined by low birthweight in full-term newborns 37 weeks and older, was reported in 13.4%. Neonatal anaemia (haemoglobinemia < 10 g/dl at days 1–8 or < 8 g/dl at day 45) was recorded in 2.9%. Twelve children were artificially fed from birth. The probability of being fully breast-fed at 3, 6, 9, 12, 15 and 18 months was 92.9, 86.6, 63.6, 46.6, 42.1 and 31.6% in the zidovudine group, and 95.9, 91.9, 64.5, 46.6, 40.5 and 33.5%, respectively, in the placebo group (P = 0.62). Eight maternal deaths were recorded, four in each arm.
Seven children in the zidovudine group and three in the placebo group remained of indeterminate infection status (P = 0 . 22). Six died in the first 4 days of life of neonatal asphyxia (three), neonatal sepsis (two) or congenital malformation (one). Three other children were lost to follow-up in the first week of life and the last one at day 85. None of these children had blood samples available.
The cumulative number of HIV-1-infected children by age 18 months was 101, 40 in the zidovudine group and 61 in the placebo group (P = 0.03). Infection was diagnosed at a median age of 11 days (IR 7–45 days) for the 72 children diagnosed up to day 45. Diagnosis was estimated at a median age of 179 days (IR 92–321 days) for the 29 other children.
Overall, 75 children deaths were recorded, 33 in the zidovudine group and 42 in the placebo group: nine deaths occurred in the early neonatal period (first week of life), six of them among children of indeterminate HIV-1 status, two between days 8 and 28 (late neonatal period) and 64 up to 18 months (Table 1). The 13 twin live births accounted for five deaths. The 18 month mortality rate in children born to HIV-infected mothers was 176 per 1000 in the zidovudine group (CI 122–231) and 221 (CI 162–281) in the placebo group. Mortality curves crossed after 3 months of life (Fig. 1), and hazard functions were reversed by day 230 (8 months), prohibiting an overall statistical comparison. The univariate analysis of mortality determinants is summarized in Table 2. Neonatal anaemia, prematurity, paediatric HIV-1 infection, indeterminate HIV-1 status, maternal plasma viral load at baseline, CD4 lymphocyte count less than 350/mm3 and maternal death were associated with an increased risk of death. In multivariate analysis, three factors remained associated with the risk of death: maternal zidovudine as a protective factor in the first 8 months (HR 0.47 ≤ day 230; CI 0.2–1.0; P = 0.05); maternal CD4 lymphocyte count less than 200/mm3(HR 2.92 versus CD4 cell count > 500/mm3; CI 1.4–6.1; P = 0.004); and a diagnosis of paediatric HIV-1 infection as a time-dependent variable (HR 12.6; CI 6.6–24.3; P = 10−4). There was no statistical interaction between maternal zidovudine and child infection when studying the risk of infant death (P = 0.34).
Mortality of HIV-1-infected children
There were 51 deaths in the first 18 months of life among the 101 HIV-1-infected children, 21 out of 40 in the zidovudine group and 30 out of 61 in the placebo group. No death was recorded in the early neonatal period, one in the late neonatal period and 50 up to 18 months (Table 1). Twenty-four children developed clinical AIDS before 18 months of age (1985 WHO definition ), at a median age of 107 days (IR 65–280 days), of whom 17 died. The 18 month mortality rate in these HIV-1-infected children was 590 per 1000 in the zidovudine group (CI 427–753) and 510 per 1000 (CI 381–638) in the placebo group (Fig. 2). In univariate analysis, maternal peripartum zidovudine had no effect on mortality up to day 230, but a negative effect beyond 8 months of age (Table 3). Neonatal anaemia, a diagnosis of HIV-1 infection on or before day 12 and between days 13 and 45, paediatric AIDS, a maternal CD4 lymphocyte count of less than 200/mm3, and a high maternal plasma viral load were risk factors for child death. Six factors remained significantly associated with the risk of child death in the final multivariate model (N = 75): maternal zidovudine as a protective factor up to 230 days of life (HR 0.18 ≤ 230 days; CI 0.1–0.5; P = 0.0024); maternal CD4 lymphocyte count of less than 200/mm3(HR 3.25 compared with CD4 cell count greater than 500/mm3; CI 1.3–8.4; P = 0.015); maternal death as a time-dependent variable (HR 9.65; CI 1.7–56.0; P = 0.012); diagnosis of paediatric HIV-1 infection on or before day 12 (HR 18.1; CI 4.8–69.0; P = 10−4) and between days 13 and 45 (HR 7.63; CI 2.0–29.5; P = 0.032) compared with diagnosis after day 45; and diagnosis of clinical paediatric AIDS as a time-dependent variable (HR 5.37; CI 2.3–12.7; P = 10−4).
Mortality of HIV-1-uninfected children
There were 18 deaths in the first 18 months of life among the 296 HIV-uninfected children, eight out of 155 in the zidovudine group and 10 out of 141 in the placebo group. Three deaths were recorded in the first week of life, one between days 8 and 28, and 14 between days 29 and 18 months. The 18 month mortality rate in these HIV-uninfected children was 53 per 1000 in the zidovudine group (CI 17–89) and 78 per 1000 (CI 31–125) in the placebo group (P = 0.46).
Causes of death
All but one of the 51 deaths among the HIV-1-infected children occurred beyond the neonatal period (Table 4). The three main causes of death were pneumonia (19), diarrhoea and malnutrition (14) and septicaemia (seven). Altogether, 11 of the 51 deaths of the HIV-1-infected children were attributed to a cause belonging to the AIDS clinical syndrome. Pneumonia accounted for five out of the 18 deaths of uninfected children. Two deaths were attributed to neurological disorders in uninfected children exposed to zidovudine, one died of meningitis and the other of cerebral malaria.
This randomized trial allowed a thorough assessment of infant mortality in African children born to HIV-infected mothers, and perinatally exposed to zidovudine. Only 11% of the potential years of follow-up of the cohort could not be ascertained, and only 2.5% of the live births remained of indeterminate HIV-1 status. Mortality in the first 18 months of life was high overall, exceeding the IMR in the general population [17,18]. Deaths were primarily attributable to infectious causes, and most of them occurred in the post-neonatal period. There is limited information on mortality patterns of children born to HIV-infected women in Africa . Routinely collected data do not capture the full scope of HIV-1-related deaths, especially in young children . Observational cohort studies have provided IMR estimates in the range of 100–200 per 1000 live births of HIV-infected mothers [23,24] and we confirm these findings.
There was no excess mortality in the zidovudine-exposed group compared with the placebo group. Serious adverse effects of nucleoside analogues have recently been reported in France , although not confirmed in other cohorts [25,26], and their occurrence is probably rare. All MTCT randomized trials in Africa should report IMR, as this question will frequently be raised when implementing MTCT intervention programmes. The trial evaluating artificial feeding to reduce MTCT in Kenya had an IMR of 167 per 1000 live births among breast-feeders, compatible with our observation .
HIV-1 infection was the main contributor to death in children born to HIV-infected mothers. Intra-uterine growth retardation and prematurity did not contribute in the final model. Although the background IMR was not the same in the two centres, there was no difference in mortality between the study sites where case management was similar. We were not able to document as in the US studies the lack of excess in fatal neoplasia and other serious outcomes [28,29], as a result of the limited diagnostic facilities, the preponderance of infectious causes of death and the 1imited length of follow-up. Mortality in uninfected children was approximately 50 per 1000 live births by the age of 12 months, two times lower than national estimates of IMR [17,18], and strictly comparable between the two treatment groups. This favours the lack of a deleterious effect of in-utero exposure to zidovudine on infant mortality . The absence of unexplained deaths from neurological causes among uninfected children exposed peripartum to zidovudine does not favour severe mitochondrial toxicity [14,31].
Half of the HIV-1-infected children died before their first birthday. This figure is among the highest ever reported [23,32]. Determinants of mortality in these African infected children are compatible with current knowledge in industrialized countries: advanced maternal HIV disease, early acquisition of paediatric HIV-1 infection and the occurrence of AIDS [33–35]. Zidovudine was protective against death among infected children for at least the first 8 months in the final model. Furthermore, we did not confirm the long-term negative effect of zidovudine exposure described in the univariate analysis. Studies in industrialized countries have either found no effect on HIV-1 paediatric disease progression , or more rapid progression after zidovudine perinatal exposure [37,38]. Our findings, to be confirmed, might be partly explained by the reduction in maternal viral load and the host response (avoidance of HIV-1 by children of unknown characteristics).
There are policy implications to our findings. As zidovudine safety is further documented, strengthening its use for peripartum prophylaxis indications is highly desirable in Africa, and reinforces current WHO recommendations [15,16]. One should also bear in mind that nevirapine now offers another option of validated short-term efficacy [12,39]. As well as reducing the number of cases of paediatric HIV-1 infection, antiretroviral agents may have a measurable impact on infant mortality. In Abidjan, the IMR is currently 112 per 1000 live births, with 80 000 births per year . With an average maternal HIV-1 seroprevalence of 14%, 11 200 children are born each year to HIV-infected mothers. Without intervention, assuming a transmission rate of 30% , 3360 children acquire HIV-1 infection from their mother and 1717 of them die before their first birthday, one out of five infant deaths overall. If maternal zidovudine reduces transmission in the first year to 20% , and then among HIV-1-infected children mortality by approximately sixfold (82%) in the first 8 months of life (HR 0.18), and assuming an 80% coverage of the zidovudine peripartum intervention, 951 HIV-1 infant deaths will be averted. The IMR in the general population will thus be lowered from 112 to 99 per 1000, a marked reduction of 12%.
Besides the prevention of MTCT by antiretroviral agents, early case management of children born to HIV-infected infected mothers is necessary to reduce HIV-1-related infant mortality in Africa. The fact that in our cohort, most deaths occurred in the post-neonatal period and were attributed to infectious causes such as pneumonia, particularly in the placebo arm, strongly suggests the important contribution of preventable bacterial and opportunistic infections to infant mortality in children born to HIV-infected mothers . Primary prophylaxis by cotrimoxazole should thus be widely prescribed, even in the absence of early paediatric HIV-1 diagnosis, as recently endorsed by WHO .
Peripartum exposure to zidovudine is safe and highly beneficial to African children, whether or not they are infected. Reducing child mortality may be an achievable goal and an indicator of the success of such programmes. This is one more reason to translate the recent research findings of MTCT prevention into public health practice . In addition, more emphasis should be put on the early identification and appropriate care of children born to HIV-infected mothers .
The authors wish to acknowledge the support obtained from the Agence Nationale de Recherches sur le SIDA (ANRS), especially Prs J-P. Levy and J. Dormont, Mrs F. Agid, B. Bazin, C. Canon, M-J. Commoy and H. Pollard, Mr J-L. Chassaing and from the French Ministry of Cooperation (Dr C. Marchal in Paris, Drs B. Floury and JP. Louis in Abidjan). The trial would never have taken place without their permanent encouragement, as well as those of the National AIDS authorities in Côte d'Ivoire (Dr I.M. Coulibaly) and Burkina Faso (Drs J.G. Ouango, M. Ouedraogo and A. Seye). Special thanks to Ahmadou Alioum for his statistical comments in the preparation of the manuscript.
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Keywords:© 2001 Lippincott Williams & Wilkins, Inc.
Africa; child mortality; HIV-1; zidovudine