Women with advanced HIV-1 disease initiating triple ARV therapy during pregnancy had an MTCT rate of 7.5% [95% confidence interval (CI): 3.8 to 14.5], half of the transmissions being late postnatal transmissions. Among women with early-stage disease (asymptomatic and CD4 counts >500 cells/mm3), receipt of the WHO-recommended short-course regimen resulted in a risk of MTCT of HIV-1 below 6%, in a population where 78% of mothers breastfed, with a late postnatal transmission rate less than 1%.
Although much lower than rates observed when similar women received only short-course prophylaxis during pregnancy,18 the transmission rate observed with ART was higher than expected with a fully suppressive ART regimen. However, it was similar to the 6.7% (95% CI: 3.2 to 13.9] transmission rate observed in the Kisumu Breastfeeding Study (KiBS) observational cohort study in Kenya, in a group of mothers with CD4 count <250 at entry who received the same NVP-based ART regimen from 34 weeks gestation until delivery.19 A lower rate of transmission was achieved in the MTCT+ program in Cote d'Ivoire [3.3% (0.0% to 6.9%) at 12 months] using the same NVP-based ART regimen,20 possibly because of an earlier initiation of ART at median 27 weeks of pregnancy, that is, 13 weeks before delivery. It seems difficult to achieve adequate viral suppression by delivery (the time of greatest transmission risk) with a median of 7-8 weeks of ART, as in KiBS and Kesho Bora. Early initiation of ARV is probably particularly important to reduce the risk of transmission among such women.
A relatively low rate of ARV-related toxicity was observed in women and children exposed to ART when compared with those exposed to short-course ARV prophylaxis: no serious hepatic toxicity, more frequent but rapidly reversible hematologic abnormalities, no excess of clinical SAEs, and no increase in the proportion of infants born preterm. Although the rate of low birth weight in cohort A was twice the rate in cohort B, the difference was not statistically significant, possibly due to the small sample size.
Immunocompromised women using ART were less likely to breastfeed their children than healthier women on short-course ARV prophylaxis (61% versus 78%), possibly because they felt too sick to breastfeed or because of greater concerns regarding HIV-1 transmission or ARV toxicity for their breastfed child. This was also observed in a South-African study.21 Despite this higher breastfeeding rate and ART during breastfeeding, half (4 of 8) of the transmissions in cohort A compared with only 1 of 8 transmissions in cohort B clearly occurred during the postnatal period. The risk of late postnatal transmission was only 0.9% in cohort B, similar to the 1.4% risk of transmission between 6 weeks and 24 months among women with CD4 counts >500 cells per cubic millimeter enrolled in a West African study,9 despite no use of ARVs during the postnatal period. This rate of MTCT during breastfeeding is also similar to rates observed when mothers received triple prophylaxis during breastfeeding (women not meeting eligibility criteria for long-term ART)-between 0.5% and 0.9% in Rwanda,22 Mozambique,23 Tanzania,24 and Kenya.19
The overall 18-month rate of transmission in cohort B was 5.8% (95% CI: 2.8 to 11.8), lower-although not significantly-than the 9.1% (95% CI: 4.8 to 13.4) observed in West African women with CD4>500 cells per cubic millimeter receiving ZDV only.9 Earlier initiation or a more intensive prophylactic regimen as now recommended25 may help further reduce the risk of peripartum transmission.
Limitations of this study are similar to those of other observational cohorts. The purpose of this study was not to establish differences between the cohorts, and its design does not allow definitive comparisons between these groups. No factor was found associated with the risk of HIV-1 transmission in either cohort, but this may be due to small size of the 2 cohorts and their relative homogeneity having been established according to CD4 count strata. Because these 2 cohorts of women were part of a larger research project including a randomized controlled trial, the enrolled women benefited from an intensive follow-up and active tracing. The follow-up rates were high in both cohorts (97% and 91% at 18 months in cohorts A and B, respectively). Those women in cohort A had greater motivation to remain in the study because of continued access to ART.
In conclusion, in addition to preserving the health of the mother, ART during pregnancy and breastfeeding for pregnant women with low CD4 counts was associated with a risk of MTCT lower than reported with short-course prophylaxis, but transmissions still occurred. From a programatic perspective, strategies remain to be developed to ensure timely HIV-1 screening and staging (clinical and CD4 counts), rapid and/or priority access to ART when indicated such that treatment can be initiated well before delivery, and comprehensive but rapid counselling to ensure good adherence to treatment. On the other end of the HIV-1 spectrum, asymptomatic women with high CD4 counts-who represented over one third of HIV-1-infected pregnant women in the Kesho Bora study sites (data not shown) and elsewhere26-have a low risk of late postnatal transmission, and the benefits in terms of HIV-1 transmissions avoided may not outweigh the potential problems of continued maternal ARV prophylaxis during breastfeeding such as selection for drug resistance, supply, adherence, and cost issues. A group of experts convened by WHO in October 200925 did not discuss the specific needs of women with CD4 counts> 500 but recommended to provide the same ARV prophylaxis to all women with CD4 >350 cells per cubic millimeter. Based on randomized trials,13,27,28 which also included women with CD4 lower than 350 cells per cubic millimeter, these experts concluded that an ARV prophylaxis during breastfeeding (ARV prophylaxis given either to the lactating mother or to the breastfed child) would be effective to reduce postnatal transmission. In view of the results presented here, the new recommendations may have a greater impact on MTCT rates by promoting early ART initiation for women with CD4 <350 cells per cubic millimeter and early initiation in pregnancy of ZDV-based or even triple ARV prophylaxis for women with CD4 >350 cells per cubic millimeter.
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8. Kourtis AP, Jamieson DJ, de Vincenzi I, et al. Prevention of human immunodeficiency virus-1 transmission to the infant through breastfeeding: new developments. Am J Obstet Gynecol
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12. US National Institutes of Health. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents
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13. Kesho Bora Study Group. Triple-antiretroviral prophylaxis during pregnancy and breastfeeding compared to short-ARV prophylaxis to prevent MTCT: the Kesho Bora randomized controlled clinical trial in five sites in Burkina Faso, Kenya and South Africa. Presented at: Program and Abstracts of the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 19-22, 2009; Cape Town, South Africa. Abstract no. LBPEC01.
16. Gaillard P, Piwoz E, Farley TM. Collection of standardized information on infant feeding in the context of mother-to-child transmission of HIV. Stat Med
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18. Leroy V, Ekouevi DK, Becquet R, et al. 18-Month effectiveness of short-course antiretroviral regimens combined with alternatives to breastfeeding to prevent HIV mother-to-child transmission. PLoS ONE
19. Thomas T, Masaba R, Ndivo R, et al. Prevention of MTCT of HIV-1 among breastfeeding mothers using HAART: the Kisumu breastfeeding study, Kisumu, Kenya, 2003-2007. Presented at: Program and Abstracts of the XV Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008; Boston, MA. Abstract 45aLB.
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21. Coovadia H, Rollins N, Bland R, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet
22. Arendt V, Ndimubanzi P, Vyankandondera J, et al. AMATA study: effectiveness of antiretroviral therapy in breastfeeding mothers to prevent post-natal vertical transmission in Rwanda. Presented at: Program and Abstracts of the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney, Australia. Abstract no. TUAX102.
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APPENDIX I: THE KESHO BORA STUDY GROUP
1. Bobo-Dioulasso, Burkina-Faso (Centre Muraz): Nicolas Meda (principal investigator), Paulin Fao, Odette Ky-Zerbo, Clarisse Gouem (study co-ordinators), Paulin Somda, Hervé Hien, Patrice Elysée Ouedraogo, Dramane Kania, Armande Sanou, Ida Ayassou Kossiwavi, Bintou Sanogo, Moussa Ouedraogo, Issa Siribie (investigators), Diane Valéa (laboratory co-ordinator), Sayouba Ouedraogo and Roseline Somé (data manager), François Rouet (intersites laboratory co-ordination);
2. Mombasa, Kenya (International Centre for Reproductive Health): Stanley Luchters, Marcel Reyners (principal investigators), Eunice Irungu (study co-ordinator), Christine Katingima, Mary Mwaura, and Gina Ouattara (investigators), Kishor Mandaliya, Sammy Wambua (laboratory co-ordination), Mary Thiongo (data manager);
3. Nairobi, Kenya (NARESA): Ruth Nduati (principal investigator), Judith Kose (study co-ordinator), Ephantus Njagi (laboratory co-ordinator), Peter Mwaura (data manager).
1. Agence Nationale de Recherches sur les SIDA et les hépatites virales, France: Brigitte Bazin and Claire Rekacewicz (sponsor representatives);
2. Centers for Disease Control and Prevention, USA: Allan Taylor, Nicole Flowers, Michael Thigpen, Mary Glenn Fowler, Denise Jamieson (sponsor representatives and co-investigators);
3. Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, USA: Jennifer S. Read (sponsor representative and co-investigator);
4. Institut de Recherche pour le Développement, Montpellier, France: Kirsten Bork-Simondon, Cécile Cames and Amandine Cournil (Nutrition Coordination);
5. International Centre for Reproductive Health, Ghent, Belgium: Patricia Claeys, Marleen Temmerman (Sponsor Representatives);
6. Université Montpellier 1, EA 4205 “Transmission, Pathogenèse et Prévention de l'infection par le VIH”; and CHU Montpellier, Laboratoire de Bactériologie-Virologie, Montpellier, France: Philippe Van de Perre, Pierre Becquart (until December 2006), Vincent Foulongne, Michel Segondy (laboratory co-ordination).
World Health Organization, Geneva, Switzerland: Isabelle de Vincenzi (Study Coordinator), Philippe Gaillard (site co-ordinator), Tim Farley (project manager), Ndema Habib (study statistician), Sihem Landoulsi (study analyst).