18-Month mortality and perinatal exposure to zidovudine in West Africa

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18-Month mortality and perinatal exposure to zidovudine in West Africa

FrancËois Dabisa, Narcisse Elengab, Nicolas Medac, ValeÂriane Leroya, Ida Vihob, Olivier Manigartc, Laurence Dequae-Merchadoua,

Philippe Msellatid and Issiaka Sombiec, for the DITRAME Study Group

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% con®dence 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 bene-

®cial to African children. The mortality of HIV-1-infected children is high. Peripartum maternal zidovudine exerts a protective effect for at least 8 months.

&2001 Lippincott Williams & Wilkins

AIDS 2001,15:771±779

Keywords: Africa, child mortality, HIV-1, zidovudine


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) [1]. Most live in Africa where resources for case management remain very scarce [2]. Paediatric

From theaUnite INSERM no. 330, ISPED, Universite Victor Segalen Bordeaux 2, Bordeaux, France;bCentre Hospitalier Universitaire de Yopougon and PAC-CI Programme, Abidjan, CoÃte d'Ivoire;cCentre Muraz, Bobo-Dioulasso, Burkina Faso; and

dIRD Petit Bassam, Abidjan, CoÃte d'Ivoire.

Correspondence and requests for reprints to: Pr FrancËois Dabis, Unite INSERM no. 330, Universite Victor Segalen Bordeaux 2, 146 rue LeÂo-Saignat, 33076 Bordeaux Cedex, France.

Fax:; e-mail: francois.dabis@isped.u-bordeaux2.fr

Received: 4 August 2000; revised: 17 November 2000; accepted: 10 January 2001.

ISSN 0269-9370&2001 Lippincott Williams & Wilkins 771


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) [3].

Several clinical trials have highlighted the ef®cacy of short regimens of antiretroviral agents in reducing MTCT in developing countries [4]. In three of them, maternal zidovudine treatment in the peripartum peri- od 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 dif®cult [10], and some trials have reported ef®cacy ®gures combining infection and mor- tality 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 [13]. 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 [14]. 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 zidovu- dine 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 ®rst 18 months were investigated, focusing on the contribu- tion of maternal zidovudine exposure.


The project was conducted in two large cities in West Africa, Abidjan, CoÃte 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 CoÃte d'Ivoire in 1994±1998 [17] and 134 per 1000 for Burkina Faso in 1993 [18].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 begin- ning 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 infec- tions 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 ®rst one tested was positive. Non- commercial DNA PCR was used in Abidjan [6]. In Bobo Dioulasso, samples were analysed ®rst 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 con- sidered on the basis of one positive PCR [19]. 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).

Con®rmation 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 [10]. 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 ®rst 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 ®rst 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 ®rst for all children born to HIV-infected mothers, then for the subset of those diagnosed as infected. A Cox univariate proportional hazards mod- el studied determinants of child mortality, followed by a multivariate model with a stepwise descending procedure, ®xed and time-dependant variables and terms of interaction. Hazard ratios (HR) are reported with their 95% con®dence interval (CI). We veri®ed 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 (Nˆ186) 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% (FinnstroÈm score ,37 weeks). Intra-uterine growth retardation, de®ned 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 arti®cially fed from birth. The probabil- ity 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 (Pˆ0.62). 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 (Pˆ0.22). Six died in the ®rst 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 ®rst 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 (Pˆ0.03). 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 mortality

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 (®rst 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 ®ve 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 sta- tus, 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 asso- ciated with the risk of death: maternal zidovudine as a

Table 1. Probability of dying in the ®rst 18 months of life by maternal zidovudine prophylactic treatment and paediatric HIV-1 infection status.

DITRAME ANRS 049a trial, Abidjan and Bobo-Dioulasso, 1995±1999.

Age (days) 0 7 28 90 180 365 450 540

Children born to HIV-1-infected mothers

Children at risk ZDV 202 194 192 182 174 152 143 133

Placebo 205 200 198 181 165 138 135 119

Cumulative deaths ZDV ± 6 7 11 17 28 30 33

Placebo ± 3 4 15 28 38 40 42

Probability of death ZDV ± 30 35 55 86 147 158 176

(CI) (±) (6±53) (9±60) (23±87) (47±126) (96±197) (106±210) (122±231)

Placebo ± 15 20 75 142 197 209 221

(±) (0±31) (1±39) (38±112) (93±191) (141±254) (151±266) (162±281) HIV-1-infected children

Children at risk ZDV 40 40 40 38 32 18 16 14

Placebo 61 61 60 52 40 30 27 26

Cumulative deaths ZDV ± 0 0 1 6 17 19 21

Placebo ± 0 1 8 19 28 30 30

Probability of death ZDV ± ± ± 25 157 473 532 590

(CI) (±) (±) (±) (0±73) (42±272) (308±638) (366±697) (427±753)

Placebo ± ± 16 133 320 475 510 510

(±) (±) (0±48) (47±219) (201±439) (347±602) (381±638) (381±638) Probability of death (per 1000).

CI, 95% con®dence interval; ZDV, zidovudine.








0 3 6 9 12 15 18

Time (months)

Probability (%)

Fig. 1. Probability of survival in the ®rst 18 months of life in children born to HIV-1-infected mothers by maternal treatment group: 202 zidovudine (ÐÐ) and 205 placebo (- - - -). Univariate model, Pˆ0.066 on or before day 230 and Pˆ0.54 thereafter. From the DITRAME ANRS 049a trial, Abidjan and Bobo-Dioulasso, 1995±1999.

Table 2. Univariate analysis of risk factors of 18 month mortality in children born to HIV-1- infected mothers (75 deaths among 407 live births). DITRAME ANRS 049a trial, Abidjan and Bobo-Dioulasso, 1995±1999.

Factor Cumulative death

rate (%) Hazard ratioy

(95% CI) Pvalue

Zidovudine 33/202 (16.4) 0.58 (0.3±1.0) (a) 0.066

1.27 (0.6±2.8) (b) 0.54

versus placebo 42/205 (20.5) 1.0 ±

Abidjan 40/238 (16.8) 0.77 (0.5±1.2) 0.26

versus Bobo-Dioulasso 35/169 (20.7) 1.0 ±

Twins 5/13 (38.5) 2.41 (1.0±6.0) 0.058

versus singletons 70/394 (17.8) 1.0 ±

Males 36/215 (16.7) 0.80 (0.5±1.3) 0.33

versus females 39/191 (20.4) 1.0 ±

Intrauterine growth retardation 13/47 (27.7) 1.74 (0.9±3.2) 0.074

versus no retardation 50/304 (16.5) 1.0 ±

Prematurity 9/27 (33.3) 2.16 (1.1±4.4) 0.032

versus full-term birth 54/324 (16.7) 1.0 ±

Neonatal anaemia 4/10 (40.0) 3.00 (1.1±8.2) 0.035

versus no anaemia 57/340 (16.8) 1.0 ±

Maternal death<1 year (c) 3/8 (37.5) 4.13 (1.3±13.1) 0.017

versus no death 72/399 (18.1) 1.0 ±

Maternal CD4 cell count,200/mm3 14/35 (40.0) 3.77 (2.0±7.1) 0.0001 200<CD4 cell count,350 17/59 (18.8) 2.37 (1.3±4.3) 0.0047 350<CD4 cell count,500 13/81 (16.1) 1.28 (0.7±2.5) 0.46

versus CD4 cell count>500 29/224 (13.0) 1.0 ±

Maternal plasma viral load (d) ± 4.69 (2.6±8.4) 0.0001

Infected child (c) 51/101 (50.5) 16.89 (9.7±29.3) 0.0001 Indeterminate HIV-1 status 6/10 (60.0) 109.89 (34.4±351.2) 0.0001

versus uninfected child 18/296 (6.1) 1.0 ±

yUnivariate Cox model (a) until day 230; (b) after day 230; (c) time-dependent variable; (d) for

‡1 log (Nˆ186);included in ®nal multivariate model.


protective factor in the ®rst 8 months (HR 0.47<day 230; CI 0.2±1.0; Pˆ0.05); maternal CD4 lymphocyte count less than 200/mm3(HR 2.92 versus CD4 cell count .500/mm3; CI 1.4±6.1; Pˆ0.004); and a diagnosis of paediatric HIV-1 infection as a time- dependent variable (HR 12.6; CI 6.6±24.3; Pˆ10ÿ4).

There was no statistical interaction between maternal zidovudine and child infection when studying the risk of infant death (Pˆ0.34).

Mortality of HIV-1-infected children

There were 51 deaths in the ®rst 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 de®nition [20]), 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 peripar- tum 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 signi®cantly associated with the risk of child death in the ®nal multivariate model (Nˆ75):

maternal zidovudine as a protective factor up to 230 days of life (HR 0.18 <230 days; CI 0.1±0.5;

Pˆ0.0024); 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; Pˆ0.015);

maternal death as a time-dependent variable (HR 9.65;

CI 1.7±56.0; Pˆ0.012); diagnosis of paediatric HIV- 1 infection on or before day 12 (HR 18.1; CI 4.8±

69.0; Pˆ10ÿ4) and between days 13 and 45 (HR 7.63; CI 2.0±29.5; Pˆ0.032) compared with diag- nosis after day 45; and diagnosis of clinical paediatric AIDS as a time-dependent variable (HR 5.37; CI 2.3±


Mortality of HIV-1-uninfected children

There were 18 deaths in the ®rst 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 ®rst 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







0 3 6 9 12 15 18

Time (months)

Probability (%)

Fig. 2.Probability of survival in the ®rst 18 months of life in HIV-1-infected children by maternal treatment group: 40 zidovudine (ÐÐ) and 61 placebo(- - - -).Univariate model,Pˆ0.082 on or before day 230 andPˆ0.033 thereafter. From the DITRAME ANRS 049a trial, Abidjan and Bobo-Dioulasso, 1995±1999.


Table 3. Univariate analysis of risk factors of 18 month mortality in HIV-1-infected children born to infected mothers (51 deaths among 101 children). DITRAME ANRS 049a trial, Abidjan and Bobo-Dioulasso, 1995±1999.

Factor Cumulative

death rate (%) Hazard ratioy

(95% CI) Pvalue

Zidovudine 21/40 (52.5) 0.47 (0.2±1.1) (a) 0.082

2.49 (1.1±5.8) (b) 0.033

versus placebo 30/61 (49.2) 1.0 ±

Abidjan 27/53 (50.9) 0.95 (0.5±1.7) 0.86

versus Bobo-Dioulasso 24/48 (50.0) 1.0 ±

Twins 3/5 (60.0) 1.55 (0.5±5.0) 0.46

versus singletons 48/96 (50.0) 1.0 ±

Males 23/49 (46.9) 0.76 (0.4±1.3) 0.32

versus females 28/52 (53.9) 1.0 ±

Intrauterine growth retardation 10/15 (66.7) 1.72 (0.8±3.5) 0.13

versus no retardation 33/72 (45.8) 1.0 ±

Prematurity 6/9 (66.7) 1.48 (0.6±3.5) 0.38

versus full-term birth 37/78 (47.4) 1.0 ±

Neonatal anaemia 4/4 (100.0) 3.34 (1.2±9.4) 0.023

versus no anaemia 42/86 (48.8) 1.0 ±

Maternal death<1 year (c) 2/3 (66.7) 3.47 (0.8±14.5) 0.087

versus no death 49/98 (50.0) 1.0 ±

Maternal CD4 cell count,200/mm3 13/20 (65.0) 2.25 (1.1±4.7) 0.031 200<CD4 cell count,350 13/28 (46.4) 1.05 (0.5±2.2) 0.89 350<CD4 cell count,500 8/16 (50.0) 1.34 (0.6±3.1) 0.50

versus CD4 cell count>500 16/35 (45.7) 1.0 ±

Maternal plasma viral load (d) ± 3.10 (1.5±6.6) 0.0033

Infection<day 12 28/38 (73.7) 5.67 (2.3±13.7) 0.0001 Infection days 13±45 17/34 (50.0) 3.46 (1.4±8.8) 0.009

versus infection.day 45 6/29 (20.7) 1.0 ±

Pediatric AIDS (c) 17/24 (70.8) 3.77 (2.1±6.8) 0.0001

versus no AIDS 34/77 (44.2) 1.0 ±

yCox model (a) until day 230; (b) after day 230; (c) time-dependent variable; (d) for‡1 log (Nˆ65).

Included in ®nal multivariate analysis.

Table 4.Primary cause of death in the ®rst 18 months of life in children born to HIV-1-infected mothers by child HIV-1 infection status and treatment group. DITRAME ANRS 049a trial, Abidjan and Bobo-Dioulasso, 1995±1999.

Group Causes <7 days 8±28 days 29±540 days

Infected children (Nˆ101) ZDV Placebo ZDV Placebo ZDV Placebo

Pneumonia (19) (4)a ± ± ± ± 3 (1)a 16 (3)a

Diarrhoea, malnutrition (14) (4)a ± ± ± ± 8 (3)a 6 (1)a

Septicaemia (7) (3)a 1 3 (1)a 3 (2)a

Neurological disorders (4) ± ± ± ± 1 3

Others (4)b ± ± ± ± 3 1

Unknown (3) ± ± ± ± 3 0

Total (51) 0 0 0 1 21 29

Uninfected children (Nˆ296) ZDV Placebo ZDV Placebo ZDV Placebo

Neonatal asphyxia (2) 1 1 ± ± ± ±

Neonatal infection (2) 1 ± 1 ± ± ±

Pneumonia (5) ± ± ± ± 3 2

Neurological disorders (4) ± ± ± ± 2 2

Diarrhea, malnutrition (4) ± ± ± ± ± 4

Cardiac malformation (1) ± ± ± ± ± 1

Total (18) 2 1 1 0 5 9

Children of indeterminate HIV-1 status (Nˆ10)

Neonatal asphyxia (3) 3 ± ± ± ± ±

Neonatal infection (2) 1 1 ± ± ± ±

Congenital malformation (1) ± 1 ± ± ± ±

Total (6) 4 2 0 0 0 0

All deaths (75/407 children) 6 3 1 1 26 38

aDisease condition included in de®nition of AIDS syndrome.

bMeasles (1), anaemia (1), fever (1) and peritonitis (1).

ZDV, Zidovudine.


per 1000 (CI 31±125) in the placebo group (Pˆ 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 ®ve 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 zidovu- dine. 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 ®rst 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 [21].

Routinely collected data do not capture the full scope of HIV-1-related deaths, especially in young children [22]. 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 con®rm these


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 [13], although not con®rmed in other cohorts [25,26], and their occur- rence is probably rare. All MTCT randomized trials in Africa should report IMR, as this question will fre- quently be raised when implementing MTCT inter- vention programmes. The trial evaluating arti®cial feeding to reduce MTCT in Kenya had an IMR of 167 per 1000 live births among breast-feeders, compa- tible with our observation [27].

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 ®nal 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 preponder- ance 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 [30]. 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

®rst birthday. This ®gure 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 mater- nal HIV disease, early acquisition of paediatric HIV-1 infection and the occurrence of AIDS [33±35]. Zido- vudine was protective against death among infected children for at least the ®rst 8 months in the ®nal model. Furthermore, we did not con®rm 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 [36], or more rapid progression after zidovudine perinatal exposure [37,38].

Our ®ndings, to be con®rmed, might be partly ex- plained 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 ®ndings. 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 ef®cacy [12,39]. As well as redu- cing 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 [17].

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% [8], 3360 children acquire HIV-1 infection from their mother and 1717 of them die before their ®rst birthday, one out of ®ve infant deaths overall. If maternal zidovudine reduces transmis- sion in the ®rst year to 20% [8], and then among HIV- 1-infected children mortality by approximately sixfold (82%) in the ®rst 8 months of life (HR 0.18), and assuming an 80% coverage of the zidovudine peripar-


tum 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 preven- table bacterial and opportunistic infections to infant mortality in children born to HIV-infected mothers [40]. Primary prophylaxis by cotrimoxazole should thus be widely prescribed, even in the absence of early paediatric HIV-1 diagnosis, as recently endorsed by WHO [41].


Peripartum exposure to zidovudine is safe and highly bene®cial to African children, whether or not they are infected. Reducing child mortality may be an achiev- able goal and an indicator of the success of such programmes. This is one more reason to translate the recent research ®ndings of MTCT prevention into public health practice [42]. In addition, more emphasis should be put on the early identi®cation and appro- priate care of children born to HIV-infected mothers [3].


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 en- couragement, as well as those of the National AIDS authorities in CoÃte 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 manu- script.

Sponsorship: The DITRAME ANRS 049 trial was spon- sored by the Agence Nationale de Recherches sur le SIDA (ANRS, Paris, France) and the French Ministry of Foreign Affairs, through the Coordinated Action AC12.

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 Lancet1999;353:786±790.


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