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AIDS. Author manuscript; available in PMC Jul 18, 2008.
Published in final edited form as:
PMCID: PMC2474891
HALMSID: HALMS193079
INSERM Subrepository
Field efficacy of zidovudine, lamivudine and single-dose nevirapine to prevent peripartum HIV transmission
François Dabis,1,2* Laurence Bequet,3 Didier Koumavi Ekouevi,3 Ida Viho,3 François Rouet,4 Apollinaire Horo,5 Charlotte Sakarovitch,1,6 Renaud Becquet,1,2 Patricia Fassinou,7 Laurence Dequae-Merchadou,1,2 Christiane Welffens-Ekra,5 Chrisitine Rouzioux,8 and Valériane Leroy1,2
1Epidémiologie, santé publique et développement INSERM : U593, IFR99, Université Victor Segalen - Bordeaux II, ISPED, Universite Victor Segalen
146, Rue Leo Saignat
33076 BORDEAUX CEDEX,FR
2ISPED, Institut de Santé Publique, d'Epidémiologie et de Développement Université Victor Segalen - Bordeaux II, 146 rue Léo Signat
33076 Bordeaux Cedex,FR
3ANRS 1201/1202, Ditrame Plus, Programme PACCI ANRS, CHU Treichville, Abidjan,CI
4CeDreS, Centre de recherche et de Diagnostic sur le Sida CHU Treichville, CI
5Service de gynécologie - obstétrique CHU de Yopougon, Abidjan,CI
6Equipe de Biostatistique INSERM : E0338, IFR99, Université Victor Segalen - Bordeaux II, ISPED, Universite Victor Segalen
146, Rue Leo Saignat
33076 BORDEAUX CEDEX,FR
7Service de pédiatrie CHU Yopougon, Abidjan,CI
8Laboratoire de Virologie AP-HP, Hôpital Necker - Enfants Malades, Université Paris Descartes - Paris V, FR
* Correspondence should be adressed to: François Dabis ; francois.dabis/at/gmail.com
Objectives
In Africa, single-dose nevirapine (NVPsd), short regimens of zidovudine (ZDV) or ZDV+lamivudine (3TC) are recommended to prevent peripartum mother-to-child HIV transmission (PMTCT). We evaluated the six-week field efficacy of two more PMTCT drug combinations.
Design
An open-label intervention cohort in Abidjan.
Methods
In 2001–2002, consenting women started oral ZDV 300mg bid at ≥36 weeks of gestation, with 600mg of ZDV + 200mg NVPsd orally at beginning of labour. In 2002–2003, the antepartum regimen at ≥32weeks comprised ZDV as previously + 3TC 150mg bid; the labour dose comprised ZDV+NVPsd as previously + 300mg 3TC orally. Neonates received ZDV syrup (2 mg/kg/6 hours) for 7 days + NVPsd syrup (2mg/kg) on Day 2 in both periods. Each woman was assisted to either use breast milk substitutes or breastfeed exclusively. Paediatric HIV infection was diagnosed by plasma HIV RNA viral load at 4 weeks, confirmed at 6 weeks. The reference group was a cohort receiving a short regimen of ZDV ≥36–38 weeks in 1995–2000 in the same population.
Results
1144 HIV-infected pregnant women were included: 351 with ZDV, 420 with ZDV+NVPsd and 373 with ZDV+3TC+NVPsd; 1010 livebirths were eligible for analysis; 79 children were HIV-infected peripartum. Six-week transmission probability was 6.5% (95% confidence interval 3.9–9.1%) with ZDV+NVPsd, a 72% reduction compared to ZDV alone (52–88%; p=0.0002 adjusted on maternal CD4, clinical stage and breastfeeding). It was 4.7% (2.4–7.0%) with ZDV+3TC+NVPsd (p=0.34 compared to ZDV+NVPsd).
Conclusions
A short-course of ZDV+NVPsd prevents most peripartum HIV transmission in Africa. This regimen could be added to international guidelines.
Keywords: Adult, Anti-HIV Agents, therapeutic use, Cote d'Ivoire, Developing Countries, Disease Transmission, Vertical, prevention & control, Drug Therapy, Combination, Female, HIV Infections, prevention & control, transmission, virology, HIV-1, Humans, Infant, Newborn, Lamivudine, therapeutic use, Nevirapine, therapeutic use, Perinatal Care, methods, Pregnancy, Pregnancy Complications, Infectious, drug therapy, Prenatal Care, methods, RNA, Viral, analysis, Reverse Transcriptase Inhibitors, therapeutic use, Treatment Outcome, Viral Load, Zidovudine, therapeutic use
Mother-to-child transmission (MTCT) of HIV type 1 accounts for most of the 2000 newly acquired paediatric HIV infections in Africa each day (1). Several antiretroviral (ARV) regimens to prevent MTCT have been successfully evaluated and are recommended by the World Health Organization (WHO) since 2000 (2). Two ARV drugs are thus used in monotherapy: zidovudine (ZDV) and nevirapine (NVP).
ZDV given for the last four weeks of pregnancy plus the labour/delivery period has been evaluated in two placebo-controlled randomized trials in West Africa (3, 4). Transmission risk was 14.7% at six weeks compared to 24.8% with placebo, despite predominant breastfeeding exposure allowing for early HIV postnatal transmission (5). Open-label cohort studies confirmed the field efficacy or effectiveness of this ZDV regimen (6). The efficacy of maternal and neonatal NVP single dose (NVPsd) prophylaxis has been demonstrated first in a randomized controlled trial in Uganda with a six-week transmission rate of 11.8% (7). Another trial in South Africa demonstrated the statistical equivalence at six weeks of a NVP regimen, adding a second postpartum maternal NVP dose to the previous regimen, compared to a dual regimen of ZDV+lamivudine (3TC), 12% versus 9% (8).
Combinations of ARVs may further reduce MTCT in Africa as in Europe and in the USA (9). Although succesufully evaluated in South Africa (8), in a multi-country African trial (10) and in France (11), the ZDV+3TC combination may induce neonatal anemia and viral resistance after ≥2 months of use and thus remains infrequently used.
We conducted a cohort study in Abidjan, Côte d’lvoire to evaluate the acceptability, tolerance and effectiveness of: 1) a short-course peripartum ZDV regimen combined with NVPsd during labour (ZDV+NVPsd) and followed by a very short neonatal prophylaxis of ZDV+NVPsd; 2) the same regimen with the addition of a maternal short-course of 3TC (ZDV+3TC+NVPsd).
Study setting
The ANRS 1201/1202 DITRAME PLUS project was conducted in two districts of Abidjan. HIV counselling and testing services were set up within the antenatal clinics of the Yopougon University Hospital and six community-run health facilities. Two sites served for enrolment and follow-up.
Study design
The study was an open-label intervention cohort. The study protocol was approved by the National Ethical Committee in Côte d’lvoire and the French Agence Nationale de Recherches sur le SIDA (ANRS). The pooled data of two consecutive series of mother-infant pairs, receiving ZDVin the ANRS 049a trial in 1995–1998 (4) or in a cohort on the same sites in 1999–2000 (6), were used for comparison. This regimen consisted of 300mg ZDV tablets twice a day at ≥36 weeks of gestation, two tablets (600mg) at beginning of labour and one week of maternal ZDV postnatally but no neonatal prophylaxis.
Inclusion procedures
All pregnant women attending the selected clinics were offered pre-test counselling and HIV testing. Those ≥18 years old, at <32 weeks of gestation, living within the city limits and signing an informed consent were eligible. All serum samples were screened on site for HIV antibodies by an immunochromatographic rapid test (Determine ®, Abbott Laboratories, Abbot Park, IL, USA). A negative diagnosis was based on this single test result. Positive samples were immediately confirmed on site by a second rapid test (Genie II ®, Bio-Rad, Marnes-La-Coquette, France). Announcement of the seropositive status was made if both test results were positive. Women who tested positive with the two rapids tests or whose test results needed confirmation in the CeDReS reference laboratory (12) were systematically offered to enter the cohort if haemoglobinaemia was ≥7 g/deciliter (dl). Eligible women were scheduled for enrolment no later than at beginning of labour.
Study medications
The drug combination regimen evaluated in 2001–2002 consisted of a daily antenatal oral regimen of 300mg ZDV tablets twice a day at ≥36 weeks, two tablets (600mg) of ZDV and a single NVP tablet (200 mg) at beginning of labour. The intrapartum package was given at inclusion. Intra-partum treatment was self-initiated by the woman as soon as the labour had started. A second intra-partum dose was given by the study team if women did not deliver within 48 hours of administration of the first labour dose. In 2002–2003, the antenatal regimen was changed to ZDV 300mg and 3TC 150mg tablets twice a day at ≥32 weeks, followed by two tablets of ZDV (600mg) and 3TC (300mg) at beginning of labour plus NVPsd as previously. The ZDV+3TC maternal regimen was continued for three days post-partum. The neonatal prophylaxis was the same in the two periods. At delivery the mother was given a container with ZDV syrup for her neonate with a mono-dose syringe, four times a day (2 mg/kg) for seven days. Mothers were also asked to attend the study clinic 48–72 hours after birth for directly observed administration of 2 mg/kg of NVPsd syrup to their neonate.
Women were advised at inclusion and during subsequent prenatal visits to either choose artificial feeding from birth (13) or exclusive breastfeeding with initiation of weaning as soon as possible ≥4 months of life (14). Women were given support once their choice made, including free provision of equipment and supplies up to nine months postpartum (15).
Follow-up procedures
Demographic, clinical information, maternal CD4 measured by flow cytometry and HIV-1 RNA plasma viral load were processed at entry in the study. Women were given weekly then bi-weekly prepartum appointments for interview, clinical follow-up, drug distribution, verification of drug intake and tolerance. An appointment was given ≤48 hours after delivery, then a week later at the end of the treatment period, and at weeks 4 and 6 postpartum. The clinical follow-up of the child followed the same schedule. Children’s blood samples were obtained for diagnosis of HIV infection and haemoglobin measurement. Medical and psycho-social support was provided between scheduled visits. All prescribed medications, hospital stays and transportation were provided free of charge.
Study outcomes
Diagnosis of paediatric HIV infection
Capillary blood was collected in EDTA microtainer tubes in new-borns at day 2; 1–2 ml of peripheral blood was taken at weeks 4 and 6. All samples collected at week 4 were processed for plasma RNA viral load measurement. The bDNA Versant HIV RNA kit version 3.0 (Bayer Diagnostics, Emeryville, CA, USA) was applied to the ZDV cohort. A real time PCR (quantitative Taqman technology) was applied to cohorts with combination drug regimens. Compared to the bDNA assay, the real time PCR has shown 100% sensitivity and specificity (95% lower bounds of 93.7% and 98.3%, respectively) (16, 18). The same techniques were applied to the preceding available sample(s) and to the six-week sample if the first one tested was positive. Both assays were controlled by the ANRS quality assurance programme. The diagnosis of pasdiatric HIV-1 infection was made on the basis of two positive virology tests (17). All samples with plasma HIV RNA >5000 copies/ml were considered positive (16, 18). The first positive test in the series allowed the estimation of the timing of infection: in utero if the day 1–4 specimen was positive, intrapartum/early postpartum if the day 1–4 specimen was negative but the week 4–6 specimen positive and timing of peripartum infection remained unknown in other instances (17). Absence of infection was defined by a negative test at the last time point an assay was done. Those children who had no sample available for testing and could not be followed >6 weeks were considered of definitive unknown HIV status.
Adverse events
Neonatal severe anaemia was defined by haemoglobinasmia <8 g/dl at week 4. All stillbirths, early neonatal (≤7 days) and neonatal (<28 days) deaths were taken into account. The frequency of maternal and neonatal clinical rash was estimated seven days after delivery/birth.
Statistical analysis
The sample size of the ZDV+NVPsd cohort was calculated to estimate a 6-week MTCT risk of 7.5%, twice lower than with ZDV alone in a predominantly breast-feeding population (5), with a 5% type-I error (two-sided), a 10% type-II error and 10% of ininterpretable observations. This part of the study was terminated when its Scientific Committee after reviewing the available data concluded to the superiority of the ZDV+NVPsd combination compared to ZDV alone. The next regimen, ZDV+3TC+NVPsd, was then evaluated. This part of the study was terminated when highly active antitretroviral combination therapy (HAART) became available on site for the prevention of MTCT. To guarantee statistical independence of observations, we selected the first livebirth when a woman gave multiple livebirths (17). Group comparisons used variance analysis, Student’s t-test or non parametric Mann-Whitney test for quantitative variables, Chi-2 test or Fisher’s exact test for qualitative variables. The 6-week probability of infection was estimated using the Kaplan-Meier survival technique considering age at infection as the mid-point between the last negative and the first positive test results (17). All factors potentially associated with MTCT were studied in univariate then bivariate analyses adjusted on treatment. Cox multivariate proportional hazards model was used to study the relative effectiveness of each treatment, expressed as one minus the hazard ratio (HR). Multivariate analyses of the effect of treatment used as adjustment variables those with p<0.25 in bivariate analyses or p<0.05 in the comparison of the treatment groups. The role of interaction terms was investigated. Point estimates of summary statistics are reported with their 95 percent confidence interval (CI).
Study population
Between September 1995 and July 2003, 1144 pregnant women were enrolled: 351 received ZDV alone, 420 ZDV+NVPsd and 373 ZDV+3TC+NVPsd. There were 1120 maternal records available for analysis, of whom 56 women were lost to follow-up prior to delivery (Table 1). After exclusion of the multiple birth outcomes, the total number of births selected was 1064, including 22 stillbirths. Thirty-two eligible livebirths could not be taken into account in the analysis, without any blood sample available (n=17) and death in the first week of life (n=15). The baseline and follow-up characteristics of the cohorts are summarized in Table 2. The proportion of women eligible for HAART according to the 2003 WHO criteria (clinical stage 4 or clinical stage 3 and CD4<350/mm3 or stage 1–2 and CD4<200/mm3) (19) was 20.8%, including all the women (14.5%) with CD4<200.
Table 1
Table 1
Number of women and children by treatment group in the ANRS 1201/1202 DITRAME PLUS study of prevention of mother-to-child transmission of HIV
Table 2
Table 2
Baseline and follow-up characteristics of pregnant women and children: ANRS 1201/1202 DITRAME PLUS study
Treatment intake
The median length of antenatal treatment was 21 days with ZDV, 29 with ZDV+NVPsd and 50 with ZDV+3TC+NVPsd (Table 2). The proportion of women taking the ARV labour dose increased from 83% with ZDV alone to 93% with the two drug combinations (p<10−4). The postpartum ARV prophylaxis was generally taken. This component could not be compared between the groups as it differed (Table 2). There was no statistical difference between the three groups for place of delivery and frequency of cesaerian section, an infrequent practice (Table 2). The proportion of women who chose to breastfeed from birth was 54–66% in the two groups receiving ARV combinations, whereas it was 97.6% in the ZDV group (Table 2).
Tolerance
Maternal tolerance to the three drug regimens was good (Table 3), with a 0.5% incidence of severe anemia in the first month postpartum. One woman, 32 years old, WHO clinical stage 1, 228 CD4/mm3 and 8.1 g/dL of haemoglobinemia, initiated ZDV+3TC at 32 weeks of gestation but stopped prophylaxis after four weeks with an haemoglobinemia of 3.5 g/dL, corrected by a blood transfusion. Her child was infected in utero. There was no report of grade III or IV rash after the maternal NVPsd intake during labour. Severe neonatal anemia was observed in 20 instances (2.2%), always transient. There was no report of grade III or IV rash after the neonatal NVPsd intake. The frequencies of perinatal deaths (stillbirths and early neonatal deaths) and low birthweight were comparable (p=0.17 and 0.28, respectively, tables 1 and and3).3). All neonatal deaths but two were recorded in the first week of life and their frequency was comparable between the three groups (p=0.74, table 3). All but one remained of indeterminate HIV status, without any relation with infant feeding modality.
Table 3
Table 3
Maternal and neonatal biological tolerance to treatment, and neonatal mortality : ANRS 1201/1202 DITRAME PLUS study
Effectiveness
There were 79/1010 neonates for whom the diagnosis of paediatric HIV infection was made (Table 1). For 29 of them, in utero transmission was considered. In 28 instances, transmission was classified as intrapartum or early postnatal, the 22 other infections remaining of unknown timing. The overall six-week probability of transmission was 6.5% (CI 3.9–9.1%) with ZDV+NVPsd and 4.7% (CI 2.4–7.0%) with ZDV+3TC+NVPsd (p=0.34 after adjustment on maternal CD4 count, plasma HIV-1 RNA, WHO clinical stage, primigravida, duration of prepartum treatment, intrapartum treatment intake, low birthweight and breastfeeding). When using ZDV alone as reference (12.5% transmission at six weeks), the protective effect of the two drug combinations was strong, with an adjusted effectiveness of 72% (45–86%) for ZDV+NVPsd and 76% (52–88%) for ZDV+3TC+NVPsd (p<0.0002 and 0.0001, respectively after adjustment for maternal CD4 count, WHO clinical stage, moderate anemia, age, primigravida, low birthweight, duration of prepartum treatment, intrapartum treatment intake, cesaeerian section and breastfeeding) (Table 4). There was neither an interaction between treatment and maternal CD4 count (p=0.68) nor between treatment and infant feeding (p=0.57). There was no statistical difference in the crude and adjusted risks of transmission at six weeks according to the infant feeding exposure. This adjustment factor never reached statistical significance in multivariate analyses (p=0.10, Table 4). Thus, compared to ZDV alone, the relative effectiveness of the two drug combinations among the 703 breastfed children was 70% for ZDV+NVPsd (p<0.002) and 77% for ZDV+3TC+NVPsd (p<0.003).
Table 4
Table 4
Six-week probability of peripartum infection, bivariate and multivariate Cox proportional hazard model for the risk of mother-to-child transmission of HIV according totreatment group (reference: ZDV): ANRS 1201/1202 DITRAME PLUS study
We stratified the sample according to the 2003 WHO criteria for HAART indication (p=0.65 for the interaction of this variable with treatment). Among the 212 HAART eligible women, the six-week probability of peripartum infection was 23.6% with ZDV alone, 13.6% with ZDV+NVPsd and 9.1% with ZDV+3TC+NVPsd (p=0.28 and 0.10, respectively for the two comparisons using ZDV as reference). Among the 774 women who had no HAART indication, the six week peripartum transmission probability was 10.9% with ZDV alone, 3.6% with ZDV+NVPsd and 3.5% with ZDV+3TC+NVPsd (p<0.03 for both comparisons using ZDV as reference).
We could not investigate the relationship between the ARV regimens and the timing of acquisition of paediatric HIV infection as the majority of cases in the ZDV cohort were HIV RNA positive for the first time at ≥Day 7 (Table 1). Finally, the time period of enrolment was not investigated as the study of each drug regimen followed the previous one without any overlap. We verified however that the transmission rate did not vary by calendar year for each period of enrolment (data not shown).
We conclude to the high effectiveness of ZDV+NVPsd, reducing by 72% peripartum MTCT compared to ZDV alone (36). We cannot demonstrate an additional benefit of adding 3TC to ZDV+NVPsd although starting ZDV+3TC a month earlier than ZDV. It is now internationally recognized that triple drug combinations used together and not sequentially further reduce MTCT, especially for women who need HAART for themselves (20). However, we identified with ZDV+NVPsd a peripartum regimen that is particularly effective when HAART is not indicated, with comparable results to industrialized countries before the HAART era (9, 21). The six-week residual risk was independant of the breastfeeding exposure. The prolonged duration of NVP levels in both the mother and the child over the first weeks of life may have reduced early transmission by breastmilk, an added benefit of NVPsd combined with ZDV or ZDV+3TC. Two-year follow-up is under way to estimate the additional postnatal transmission risk and the cumulative effectiveness of our peripartum and postpartum packages (15).
Comparing directly the different ARV MTCT regimens is difficult. The first African placebo-controlled trials evaluated individual drug regimens (3, 4, 7,10). Then, equivalence trials were designed (8). Three key parameters have varied from trial to trial and impair the direct comparison of published results. The median maternal CD4 count varied between 545/mmm3 in West Africa ZDV studies (5) to 370 with ZDV+NVPsd (Table 2), 461 in the Uganda NVPsd trial (7) and 482 in the ZDV+3TC trial (10). The frequency of cesasrian section was 30% in South Africa (8), 3–6% in our cohort and exceptionnally elective. We introduced alternatives to prolonged and predominant breastfeeding whereas no neonatal intervention had been proposed in the ZDV reference cohort. Our estimate of the six-week transmission risk includes early postnatal transmission, possibly partly controlled by the neonatal ZDV+NVPsd prophylaxis but impaired by other risk factors, low maternal CD4 and low frequency of cesaerian section. These three factors were controlled for in all analyses. In doing so, our ZDV+NVPsd regimen had the lowest estimate of the residual transmission risk compared to ZDV alone (3, 4), NVPsd (7), ZDV+3TC, except its longest regimen with a residual transmission of 5.7% (10).
The DITRAME PLUS regimens were made of several components, each of them selected based on previous evidence. We did not design the study to investigate their respective contribution as recently done in Thailand in a randomized trial (22). Indeed, their results strengthen our approach of adding NVPsd to a short-course ZDV regimen. This trial suggests also that the neonatal ZDV+NVPsd prophylaxis has an added value, with a 2.0% residual transmission versus 2.8% in the absence of neonatal NVPsd, although the difference remained below statistical significance (22). Neonatal NVPsd together with one week of ZDV has recently been shown to prevent more intrapartum transmission than NVPsd in Malawi when no ARV could be given before delivery/birth (23). This was not the case however when maternal NVPsd had been administered prior to delivery (24). Based on these evidences, WHO recommends as first line regimen the combination of a short-course of ZDV for pregnant women at ≥28 weeks and children, for at least one week, with NVPsd for both (20).
We chose a nonrandomized approach to estimate the treatment effect as we considered there was a priori lack of equipoise between ZDV+NVPsd and ZDV alone. Indeed, ethical principles and time constraints can legitimize the use of nonrandomized designs (25). The Thai trial conducted at the same time than our study stopped its ZDV alone arm after its first interim analysis as it was already inferior to the two arms evaluating ZDV+NVPsd combinations (22). We acknowledge that beyond important confounding factors systematically controlled for, e.g. the clinical and immunological stage of HIV disease, the breastfeeding exposure and the duration of the ARV prophylaxis, unconsidered factors could not be taken into account by our design. Of note, the uptake in the cohorts remained constant over time (26).
Viral resistance has not been a concern with short-course ZDV (27). In the Uganda NVPsd trial, the resistance mutations were transiently diagnosed in 19% of the mothers but were not associated with transmission (28, 29). The acquisition of different patterns of transient resistance by 46% of the infected children in this trial was considered due to the neonatal NVPsd rather than to the transmission of resistant virus (29). Using NVPsd in combination with other drugs, the incidence of viral mutations at six-week postpartum was 15% in industrialized countries (30). Early results of resistance studies within our cohort confirm that NVP resistance occurs at a high frequency among mothers (33%) and children (23%) despite the use of ZDV+NVPsd instead of NVPsd (31). Further studies will determine whether resistance to 3TC has been added to resistance to NVPsd (11, 32) and conversely, if the three-day maternal postpartum ZDV+3TC regimen has influenced or not the occurrence of maternal NVP resistance (33). The consequences of viral resistance after NVPsd exposure on the subsequent response to HAART in women and children should be urgently investigated in Africa like in the Thai trial (34) considering the possible large-scale adverse effect on subsequent treatment options.
The ZDV+3TC+NVPsd regimen we evaluated was selected at a time access to HAART was too limited in Côte d’lvoire to be considered during pregnancy. Our choice was based on the demonstrated efficacy of short-courses of ZDV+3TC in the ANRS 075 cohort in France (11) and in the PETRA trial in Africa (10). We did not demonstrate an enhanced effectiveness of this regimen compared to ZDV+NVPsd, although our study had limited statistical power, an uneven distribution of confounding variables between the two groups (controlled for in the analysis) and was terminated mid-2003 as soon as HAART became available on site.
The ZDV+NVPsd MTCT prophylactic regimen we evaluated is now part of the list of internationally recommended drug regimens by WHO (20). Once the benefit (effectiveness)/risk (resistance) ratio of the ZDV+3TC+NVPsd combination is known, this regimen may also be considered. Four areas now require further research consideration. First, the uptake of ARV peripartum interventions is critical to obtain a public health impact. ZDV and NVPsd are not easy to use in Africa (3537). Their combined use will not be necessarily more complex but the challenge is to improve coverage (26). Second, the reduction of the risk of postnatal transmission should be adressed, either with infant feeding strategies (15) or with ARV-based approaches (38). Third, alternatives to NVPsd containing regimens should be investigated as viral resistance and impaired response to subsequent ARV treatment is a serious concern. Finally, the residual transmission we observed with ZDV+NVPsd cannot be considered fully satisfactory. HAART is now universally recommended for pregnant women who fulfill this indication for themselves (20). We demonstrate in a large African cohort, like in a randomized trial in Thailand, that a short-course peripartum ZDV regimen combined with NVPsd is more effective than previously used single drug regimens and will greatly contribute to the prevention of paediatric HIV infection if rapidly and widely used.
Acknowledgments
The primary sponsor of the DITRAME PLUS project was the French Agence Nationale de Recherches sur le Sida (ANRS), France. Laurence Bequet and Fraiçois Rouet were supported by the French Ministry of Foreign Affairs. Didier K. Ekouevi was a fellow of the French Charity Ensemble contre le Sida. Renaud Becquet was a fellow of the French Ministry of Education, Research and Technology. The authors wish to acknowledge the support of the Developing Country Unit of the ANRS, particularly Drs Brigitte Bazin and Séverine Blesson, and Mrs Chantal Canon and Névada Mendes. Zidovudine and lamivudine were provided by Glaxo Smith Kline International. Dr Guillaume Walckenaer and Mrs Cecile Thiaux (Glaxo Smith Kline France) facilitated the zidovudine and lamivudine drug supply throughout the study. Pr Marie-Claude Saux, Mrs Dominique Breilh and Mr Bruno Fallour (Pharmacie Centrale, Hôpital du Haut-Lévêque, Pessac, France) were in charge of drug packaging. Euclidis (Pessac, France) ensured quality control of the study drug preparation and was responsible of shipment from France to Côte d’lvoire. The Board of the Formations Sanitaires Urbaines Communautaires participating as study sites supported actively the project. Special thanks to Marie-Pierre Martin, Isabelle Bely, Bertin Kouadio and Philippe Lepère for the administrative management of the study. Finally, we would like to thank Drs Philippe Msellati and Nicolas Meda for their contribution to the ANRS 049 DITRAME reference study and the women and children who accepted to participate to the DITRAME PLUS project.
APPENDIX
Composition of the ANRS 1201/1202 DITRAME PLUS Study Group
Writing Committee: Francois DABIS, Laurence BEQUET, Didier Koumavi EKOUEVI, Ida VIHO, François ROUET,, Apollinaire HORO, Charlotte SAKAROVITCH, Renaud BECQUET, Patricia FASSINOU, Laurence DEQUAE-MERCHADOU, Christiane WELFFENS-EKRA, Christine ROUZIOUX, Valériane LEROY.
Principal Investigators: François Dabis, Valériane Leroy, Marguerite Timite-Konan, Christiane Welffens-Ekra
Coordination in Abidjan: Laurence Bequet, Didier Koumavi Ekouévi, Besigin Tonwe-Gold, IdaViho
Clinical team: Clarisse Amani-Bosse, Ignace Ayekoe, Gédéon Bédikou, Nacoumba
Coulibaly, Christine Danel, Patricia Fassinou, Apollinaire Horo, Ruffin Likikouet, HassanToure
Laboratory team: Dominique Bonard, André Inwoley, Crépin Montcho, François Rouet, Ramata Touré
Biostatistics and data management: Gérard Allou, Renaud Becquet, Katia Castetbon, Laurence Dequae-Merchadou, Charlotte Sakarovitch, Dominique Touchard
Psycho-social team: Hortense Aka-Dago, Herman Brou, Annabel Desgrées du Loû, Alphonse
Sihé, Benjamin Zanou
Scientific Committee: Stéphane Blanche, Jean-Francois Delfraissy, Philippe Lepage, Laurent
Mandelbrot, Christine Rouzioux, Roger Salamon
Footnotes
This study was presented in part at the 14th International AIDS Conference, July 7-12 2002 (Barcelona, Spain), abstract ThOrD1428, the 10th Conference on Retroviruses and Opportunistic Infections, Boston, MA (USA), 10-14 February 2003, abstract 854 and the 2nd IAS Conference on HIV Pathogenesis and Treatment, Paris (France), 13-17 July 2003, abstract 219.
CONTRIBUTORS
François DABIS was the director and co-primary investigator of the entire project, supervised the epidemiological aspects of the study, wrote the manuscript. Laurence BEQUET was the study coordinator of all aspects of the project on site. Didier Koumavi EKOUEVI was the chief data manager and participated to data analysis and manuscript writing. Ida VIHO was the clinical director and monitored the entire study. François ROUET was responsible for all laboratory aspects of the project on site and contributed to the writing of the manuscript. Charlotte SAKAROVITCH and Laurence DEQUAE-MERCHADOU prepared and conducted data analysis. Apollinaire HORO supervised clinically the antenatal and obstetrical phases of the study. Renaud BECQUET contributed to data monitoring and was particularly in charge of surveillance of adverse events. Patricia FASSINOU supervised clinically the paediatric phase of the project. Christiane WELFFENS-EKRA was the obstetrician primary investigator of the project. Christine ROUZIOUX supervised the laboratory component of the project and ensured quality control. Valériane LEROY was the co-primary investigator of the project, was reponsible for evaluation of postpartum interventions, participated to manuscript writing.
1. Dabis F, Ekpini RE. HIV-1/AIDS and maternal and child health in Africa. Lancet. 2002;359:2097–2104. [PubMed]
2. WHO. New data on the prevention of mother-to-child transmission of HIV and their policy implications. Technical consultation. UNFPA/UNICEF/WHO/UNAIDS Inter-Agency Team on mother-to-child transmission of HIV; Geneva. 11–13 October 2000; Geneva: World Health Organization; 2001. WHO/RHR/01.28.
3. Wiktor S, Ekpini E, Karon J, Nkengasong J, Maurice C, Severin S, et al. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Côte d’lvoire: a randomized trial. Lancet. 1999;353:781–785. [PubMed]
4. Dabis F, Msellati P, Meda N, Welffens-Ekra C, You B, Manigart O, et al. Six months efficacy, tolerance and acceptability of a short regimen of oral zidovudine in reducing vertical transmission of HIV in breast-fed children. A double blind placebo controlled multicentre trial, ANRS049a, Côte d’lvoire and Burkina Faso. Lancet. 1999;353:786–792. [PubMed]
5. Leroy V, Karon JM, Alioum A, Ekpini ER, Meda N, Greenberg AE, et al. Twenty-four month efficacy of a maternal short-course zidovudine regimen to prevent mother-to-child transmission of HIV-1 in West Africa. AIDS. 2002;16:631–641. [PubMed]
6. Meda N, Leroy V, Viho I, Msellati P, Yaro S, Mandelbrot L, et al. Field acceptability and effectiveness of the routine utilization of zidovudine to reduce mother-to-child transmission of HIV-1 in West Africa. AIDS. 2002;16:2323–2328. [PubMed]
7. Jackson B, 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;362:859–867. [PubMed]
8. Moodley D, Moodley J, Coovadia H, Gray G, Mclntyre J, Hofinyer 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. JInfect Dis. 2003;187:725–735. [PubMed]
9. Dorenbaum A, Cunningham CK, Gelber RD, Culnane M, Mofenson L, Britto P, et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission. A randomized trial. JAMA. 2002;288:189–198. [PubMed]
10. The Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda: a randomised, double-blind placebo-controlled trial. Lancet. 2002;359:1178–1186. [PubMed]
11. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, Berrebi A, Benifla JL, Burgard M, et al. Lamivudine-zidovudine combination for prevention of maternal-infant transmission of HIV-1. JAMA. 2001;285:2083–2093. [PubMed]
12. Rouet F, Ekouevi DK, Inwoley A, Chaix ML, Burgard M, Bequet L, et al. Field evaluation of a rapid human immunodeficiency virus (HIV) serial serologic testing algorithm for diagnosis and differentiation of HIV type 1 (HIV-1), HIV-2, and dual HIV-l-HIV-2 infections in west African pregnant women. J Clin Microbiol. 2004;42 :4147–4153. [PMC free article] [PubMed]
13. Nduati R, John G, Mbori-Ngacha D, Richardson B, Overbaugh J, Mwatha M, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1. A randomized clinical trial. JAMA. 2000;283:1167–1174. [PubMed]
14. Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia H. for the South African Vitamin A Study Group. Influence of infant feeding patterns on early mother-to-child transmissionof HIV-1 in Durban, South Africa: a prospective cohort study. Lancet. 1999;354:471–476. [PubMed]
15. Becquet R, Bequet L, Ekouevi DK, Viho I, Toure H, Dabis F, et al. Mortality in breast-fed and formula-fed children born to HIV-infected women in a PMTCT project in Abidjan, (Côte d’lvoire): DITRAME PLUS ANRS 1202. 2nd International IAS Conference on HIV Pathogenesis and Treatment, July 13–16, 2003. Paris, France. Abstract 63. Antiviral Therapy. 2003;8 (Suppl 1):S200.
16. Rouet F, Coulibaly N, Ekouevi D, Chaix ML, Burgard M, Bequet L, et al. Real-time PCR technology for the detection of HIV-1 RNA and HIV-2 DNA permits an inexpensive and early diagnosis of HIV infection in African neonates from Côte d’lvoire. 2nd International IAS Conference on HIV Pathogenesis and Treatment, July 13–16, 2003. Paris, France. Abstract 277. Antiviral Therapy. 2003;8 (Suppl 1):S252.
17. The Ghent Group. Estimating the efficacy of interventions to prevent mother-to-child transmission of HIV in breast-feeding populations: development of a consensus methodology. Stat Med. 2001;20:3539–3556. [PubMed]
18. Rouet F, Montcho C, Rouzioux C, Leroy V, Msellati P, Kotta JB, et al. Early diagnosis of pasdiatric HIV-1 infection among African breast-fed children using a quantitative plasma HIV RNA assay. AIDS. 2001;15:1849–1856. [PubMed]
19. World Health Organization. Scaling up antiretroviral therapy in resource-limited settings : guidelines for a public health approach. 2003 Revision. WHO; Geneva: December . 2003. Available at (accessed November 6, 2004): http://www.who.int/3by5/publications/documents/arv_guidelines/en/
20. World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Guidelines on care, treatment and support for womenliving with HIV/AIDS and their children in resource-constrained settings; Geneva. July 2004; Available at (accessed November 6, 2004): http://www.who.int/hiv/pub/mtct/guidelines/en/
21. European Collaborative Study. HIV-infected pregnant women and vertical transmission in Europe since 1986. AIDS. 2001;15:761–770. [PubMed]
22. Lallemant M, Jourdain G, Le Coeur M, Mary J-Y, Ngo-Giang-Huong N, Koetsawang S, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. NEnglJMed. 2004;351:217–228. [PubMed]
23. Taha TE, Kumwenda NI, Gibbons A, Broadhead RL, Fiscus S, Lema V, et al. Short postexposure in newborn babies to reduce mother-to-child transmission of HIV-1 : NVAZ randomised clinical trial. Lancet. 2003;362:1171–1177. [PubMed]
24. Taha TE, Kumwenda NI, Hoover DR, Fiscus SA, Kafulafula G, Nour S, et al. Nevirapine and zidovudine at birth to reduce perinatal transmission of HIV in an African setting. A randomized controlled trial. JAMA. 2004;292 :202–209. [PubMed]
25. Buekens P, Keusch G, Belizan J, Bhutta ZA. Evidence-based global health. JAMA. 2004;291:2639–2641. [PubMed]
26. Ekouevi DK, Leroy V, Viho I, Bequet L, Horo A, Rouet F, Sakarovitch C. Acceptability and uptake of a package to prevent mother-to-child transmission using rapid HIV testing in Abidjan, Côte d’lvoire. AIDS2W4. 18:697–700. [PubMed]
27. Ekpini RA, Nkengasong JN, Sibailly T, Maurice C, Adjé C, Monga BB, et al. Changes in plasma HIV-RNA viral load and CD4 cell counts, and lack of zidovudine resistance among pregnant women receiving short-course zidovudine. AIDS. 2002;16:625–630. [PubMed]
28. Jackson JB, Becker-Pergola G, Guay LA, Musoke P, Fowler MG, Mofenson LM, et al. Identification of the K103N resistance mutation in Ugandan women receiving nevirapine to prevent HIV-1 vertical transmission. AIDS. 2000;14:Fl 11–5. [PubMed]
29. Eshleman SH, Mracna M, Guay LA, Deseyve M, Cunningham S, Mirochnick M, et al. Selection and fading or resistance mutations in women and infants receiving nevirapine to prevent HIV-1 vertical transmission (HIVNET 012) AIDS. 2001;15:1951–1957. [PubMed]
30. Cunningham CK, Chaix ML, Rekacewicz C, Britto P, Rouzioux C, Gelber RD, et al. Development of resistance mutations in women receiving standard antiretro viral therapy who received intrapartum nevirapine to prevent perinatal human immunodeficiency virus type 1 transmission: a susbstudy of pediatric AIDS Clinical Trials Group Protocol 316/ Infect Dis. 2002;186:181 –188. [PubMed]
31. Chaix ML, Ekouevi DK, Peytavin G, Rouet F, Bequet L, Montcho C, et al. Persistance of nevirapine resistance virus and pharmacokinetic analysis in women who received intrapartum NVP associated to a short course of zidovudine (ZDV) to prevent perinatal HIV-1 transmission: the Ditrame Plus ANRS 1201/02 study, Abidjan, Côte d’lvoire. XIII international HIV drug resistance workshop. June 8–12, 2004, Tenerife, Spain. Antiviral Therapy. 2004 ;9 :SI76.
32. Giuliano M, Palmisano L, Galluzzo CM, Amici R, Germinario E, Okong P, et al. Selection of resistance mutations in pregnant women receiving zidovudine and lamivudine to prevent HIV perinatal transmission. AIDS. 2003;17:1570–1572. [PubMed]
33. Beckerman KP. Long-term findings of HIVNET 012: the next steps. Lancet. 2003;362:842–843. [PubMed]
34. Jourdain G, Ngo-Giang-Huong N, Le Coeur S, Bowonwatanuwong C, Kantipong P, Leechanachai P, et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretro viral therapy. NEngl JMed. 2004;351:229–240. [PubMed]
35. Msellati P, Hingst G, Kaba F, Viho I, Welffens-Ekra C, Dabis F. Operational issues in prevention of mother-to-child transmission of HIV-1 in Abidjan, Côte d’lvoire, 1998-1999. Bull WHO. 2001;79:641–647. [PubMed]
36. Temmerman M, Quaghebeur A, Mwanyumba F, Mandaliya K. Mother-to-child HIV transmission in resource poor settings: how to improve coverage? AIDS. 2003;17:1239–1242. [PubMed]
37. Stringer EM, Sinkala M, Sringer JSA, Mzyece E, Makuka I, Goldenberg RL, et al. Prevention of mother-to-child transmission of HIV in Africa: successes and challenges in scaling-up a nevirapine-based program in Lusaka, Zambia. AIDS. 2003;17:1377–1382. [PMC free article] [PubMed]
38. Gaillard P, Fowler MG, Dabis F, Coovadia H, Van der Horst C, Van Rompay K, et al. Use of antiretroviral drugs to prevent HIV-1 transmission through breast-feeding : from animal studies to randomized clinical trials. JAcquir Immune Defic Syndr. 2004;35:178–187. [PubMed]