Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection

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Abstract
Antiretroviral drugs reduce viral replication and can reduce mother-to-child transmission of HIV either by lowering plasma viral load in pregnant women or through post-exposure prophylaxis in their newborns. In rich countries, highly active antiretroviral therapy (HAART) which usually comprises three drugs, has reduced the mother-to-child transmission rates to around 1-2%, but HAART is not always available in low- and middle-income countries. In these countries, various simpler and less costly antiretroviral regimens have been offered to pregnant women or to their newborn babies, or to both. To determine whether, and to what extent, antiretroviral regimens aimed at decreasing the risk of mother-to-child transmission of HIV infection achieve a clinically useful decrease in transmission risk, and what effect these interventions have on maternal and infant mortality and morbidity. We sought to identify all relevant studies regardless of language or publication status by searching the Cochrane HIV/AIDS Review Group Trials Register, The Cochrane Library, MEDLINE, EMBASE and AIDSearch and relevant conference abstracts. We also contacted research organizations and experts in the field for unpublished and ongoing studies. The original review search strategy was conducted in 2002 and updated in 2006 and again in 2009. Randomised controlled trials of any antiretroviral regimen aimed at decreasing the risk of mother-to-child transmission of HIV infection compared with placebo or no treatment, or compared with another antiretroviral regimen. Two authors independently selected relevant studies, extracted data and assessed trial quality. For the primary outcomes, we used survival analysis to estimate the probability of infants being infected with HIV (the observed proportion) at various specific time-points and calculated efficacy at a specific time as the relative reduction in the proportion infected. Efficacy, at a specific time, is defined as the preventive fraction in the exposed group compared to the reference group, which is the relative reduction in the proportion infected: 1-(Re/Rf). For those studies where efficacy and hence confidence intervals were not calculated, we calculated the approximate confidence intervals for the efficacy using recommended methods. For analysis of results that are not based on survival analyses we present the relative risk for each trial outcome based on the number randomised. No meta-analysis was conducted as no trial assessed identical drug regimens. Twenty-five trials including 18,901 participants with a median trial sample size of 627 ranging from 50 to 1,844 participants were included in this update. Twenty-two trials randomised mothers (18 pre-natally and four in labour) and followed up their infants, and three trials randomised infants. The first trial began in April 1991 and assessed zidovudine (ZDV) versus placebo and since then, the type, dosage and duration of drugs to be compared has been modified in each subsequent trial. We present the results stratified by regimen and type of feeding. Antiretrovirals versus placebo In breastfeeding populations, three trials found that: ZDV given to mothers from 36 to 38 weeks gestation, during labour and for 7 days after delivery significantly reduced HIV infection at 4-8 weeks (Efficacy 32.00%; 95% CI 1.50 to 62.50), 3 to 4 months (Efficacy 33.07%; 95% CI 5.57 to 60.57), 6 months (Efficacy 34.55%; 95% CI 9.05 to 60.05), 12 months (Efficacy 34.31%; 95% CI 9.30 to 59.32) and 18 months (Efficacy 29.74%; 95% CI 2.73 to 56.75). ZDV given to mothers from 36 weeks gestation and during labour significantly reduced HIV infection at 4 to 8 weeks (Efficacy 43.78%; 95% CI 8.78 to 78.78) and 3 to 4 months (Efficacy 36.95%; 95% CI 2.94 to 70.96) but not at birth. ZDV plus lamivudine (3TC) given to mothers from 36 weeks gestation, during labour and for 7 days after delivery and to babies for the first 7 days after birth (PETRA 'regimen A') significantly reduced HIV infection (Efficacy 62.75%; 95% CI 40.76 to 84.74) and a combined endpoint of HIV infection or death (Efficacy 62.75 [, ]61.00%; 95% CI 40.76 to 84.74) at 4 to 8 weeks but these effects were not sustained at 18 months. ZDV plus 3TC given to mothers from the start of labour until 7 days after delivery and to babies for the first 7 days after birth (PETRA 'regimen B') significantly reduced HIV infection (Efficacy 41.83%; 95% CI 12.82 to 70.84) and HIV infection or death at 4 to 8 weeks (Efficacy 35.91%; 95% CI 8.41 to 63.41) but the effects were not sustained at 18 months. ZDV plus 3TC given to mothers during labour only (PETRA 'regimen C') with no treatment to babies did not reduce the risk of HIV infection at either 4 to 8 weeks or 18 months. In non-breastfeeding populations, three trials found that: ZDV given to mothers from 14 to 34 weeks gestation and during labour and to babies for the first 6 weeks after birth significantly reduced HIV infection in babies at 18 months (Efficacy 66.22%; 95% CI 33.94 to 98.50). ZDV given to mothers from 36 weeks gestation and during labour with no treatment to babies ('Thai-CDC regimen') significantly reduced HIV infection at 4 to 8 weeks (Efficacy 50.26%; 95% CI 13.80 to 86.72) but not at birth ZDV given to mothers from 38 weeks gestation and during labour with no treatment to babies did not influence HIV transmission at 6 months. Longer versus shorter regimens using the same antiretrovirals One trial in a breastfeeding population found that: ZDV given to mothers during labour and to their babies for the first 3 days after birth compared with ZDV given to mothers from 36 weeks and during labour (similar to 'Thai-CDC') resulted in HIV infection rates that were not significantly different at birth, 4-8 weeks, 3 to 4 months, 6 months and 12 months. Three trials in non-breastfeeding populations found that: ZDV given to mothers from 28 weeks gestation during labour and to infants for the first 3 days after birth compared with ZDV given to mothers from 35 weeks gestation through labour and to infants from birth to 6 weeks significantly reduced HIV infection rate at 6 months (Efficacy 45.35 %; 95% CI 1.39 to 89.31) but compared with the same regimen ZDV given to mothers from 28 weeks gestation through labour and to infants from birth to 6 weeks did not result in a statistically significant difference in HIV infection at 6 months. ZDV given to mothers from 35 weeks gestation during labour and to infants for the first 3 days after birth was considered ineffective for reducing transmission rates and this regimen was discontinued. An antenatal/intrapartum course of ZDV used for a median of 76 days compared with an antenatal/intrapartum ZDV regimen used for a median 28 days with no treatment to babies in either group did not result in HIV infection rates that were significantly different at birth and at 3 to 4 months. In a programme where mothers were routinely receiving ZDV in the third trimester of pregnancy and babies were receiving one week of ZDV therapy, a single dose of nevirapine (NVP) given to mothers in labour and to their babies soon after birth compared with a single dose of NVP given to mothers only resulted in HIV infection rates that were not significantly different at birth and 6 months. However the reduction in risk of HIV infection or death at 6 months was marginally significant (Efficacy 45.00%; 95% CI -4.00 to 94.00). Antiretroviral regimens using different drugs and durations of treatment In breastfeeding populations, three trials found that: A single dose of NVP given to mothers at the onset of labour plus a single dose of NVP given to their babies immediately after birth ('HIVNET 012 regimen') compared with ZDV given to mothers during labour and to their babies for a week after birth resulted in lower HIV infection rates at 4-8 weeks (Efficacy 41.00%; 95% CI 11.84 to 70.16), 3-4 months (Efficacy 38.91%; 95% CI 11.24 to 66.58), 12 months (Efficacy 35.98 [9.25, 62.71]36.00%; 95% CI 8.56 to 63.44) and 18 months (Efficacy 39.15%; 95% CI 13.81 to 64.49). In addition, the NVP regimen significantly reduced the risk of HIV infection or death at 4-8 weeks (Efficacy 41.74%; 95% CI 14.30 to 69.18), 3 to 4 months (Efficacy 40.00%; 95% CI 14.34 to 65.66), 12 months (Efficacy 32.17%; 95% CI 8.51 to 55.83) and 18 months (Efficacy 32.57 [9.93, 55.21]33.00%; 95% CI 9.93 to 55.21). The 'HIVNET 012 regimen' plus ZDV given to babies for 1 week after birth compared with the 'HIVNET 012 regimen' alone did not result in a statistically significant difference in HIV infection at 4 to 8 weeks. A single dose of NVP given to babies immediately after birth plus ZDV given to babies for 1 week after birth compared with a single dose of NVP given to babies only significantly reduced the HIV infection rate at 4 to 8 weeks (Efficacy 36.79%; 95% CI 3.57 to 70.01). Five trials in non-breastfeeding populations found that: In a population in which mothers were receiving 'standard' antiretroviral for HIV infection a single dose of NVP given to mothers in labour plus a single dose of NVP given to babies immediately after birth ('HIVNET 012 regimen') compared with placebo did not result in a statistically significant difference in HIV infection rates at birth and at 4 to 8 weeks. The 'Thai CDC regimen' compared with the 'HIVNET 012 regimen' did not result in a significant difference in HIV infection at 4 to 8 weeks. A single dose of NVP given to babies immediately after birth compared to ZDV given to babies for the first 6 weeks after birth did not result in a significant difference in HIV infection rates at 4-8 weeks and 3 to 4 months. ZDV plus 3TC given to mothers in labour and for a week after delivery and to their infants for a week after birth (similar to 'PETRA regimen B') compared with NVP given to mothers in labour and immediately after delivery plus a single dose of NVP to their babies immediately after birth (similar to 'HIVNET 012 regimen') did not result in a significant difference in the HIV infection rate at 4 to 8 weeks. An evaluation of various antiretroviral drugs given to mothers from 34 to 36 weeks and during labour with the same drugs given to their babies for 6 weeks after birth: stavudine (d4T) versus ZDV, didanosine (ddI) versus ZDV and d4T plus ddI versus ZDV did not result in statistically important differences in HIV infection rates at birth, 4 to 8 weeks, 3 to 4 months and 6 months. TRIPLE regimens versus other Two trials compared a regimen of three antiretrovirals given to the mother, which we refer to as TRIPLE, with other regimens. In a breastfeeding population, a trial of TRIPLE regimen commenced at 34 weeks compared with only ZDV for the same period until labour when sdNVP was added found no babies infected with HIV at birth in either group and at 6 months post delivery there was no statistically significant difference in HIV infection between groups (Efficacy -84.62%, 95%CI: -490.35 to 321.11). The infants in the TRIPLE group did not receive any drugs while those in the ZDV group received sdNVP at birth. In a non-breastfeeding population, a trial compared a protease inhibitor-based TRIPLE regimen combination of lopinavir/ritonavir, ZDV and lamivudine from 26 to 34 weeks gestation through 6 months post-partum with a shorter regimen of ZDV from 28 to 36 weeks, then ZDV and 3TC and sdNVP at onset of labour, followed by ZDV and 3TC for one week after delivery. Infants in both groups received sdNVP within 72 hours of delivery and ZDV for one week. There was no statistically significant difference between groups in HIV infection at birth (Efficacy 18.18%, 95%CI -83.48 to 119.84) or at four to eight weeks (Efficacy 31.25%, 95%CI -29.29 to 91.79). At six months, HIV infection was higher but not statistically significantly so in the non-TRIPLE group (Efficacy 42.35%, 95%CI -0.57 to 85.27). At 12 months HIV infection was statistically significantly higher in the non-TRIPLE group (Efficacy = 42.11%, 95%CI 0.66 to 83.56). At 6 months, the HIV infection or death incidence remained higher in the non-TRIPLE group (RR 34.13, 95%CI [-0.29 to 68.55) and at 12 months this difference was statistically significant (RR 36.20, 95%CI 5.92 to 66.48). TRIPLE regimen versus TRIPLE regimen In a breastfeeding population, one trial compared two triple combination antiretroviral regimens with each other, viz abacavir, lamivudine and ZDV with lopinavir/ritonavir and ZDV and lamivudine in the mother from 26 to 34 weeks and continued for six months post-partum. Infants in both groups received sdNVP and one month of ZDV. This trial found no significant difference in HIV infection rates at birth (Efficacy -189.47%; 95%CI -715.29 to 336.35) with incidence at six months remaining non-significant with transmission rates being very low (< 1%). Adverse effects The incidence of serious or life-threatening events was not significantly different in any of the trials included in this review. A regimen combining triple antiretrovirals is most effective for preventing transmission of HIV from mothers to babies. The risk of adverse events to both mother and baby appears low in the short-term but the optimal antiretroviral combination and the optimal time to initiate this to maximise prevention efficacy without compromising the health of either mother or baby remains unclear. Short courses of antiretroviral drugs are also effective for reducing mother-to-child transmission of HIV and are not associated with any safety concerns in the short-term. ZDV given to mothers during the antenatal period, followed by ZDV+3TC intrapartum and postpartum for one week, and sd-NVP given to infants within 72 hours of delivery and ZDV for one week, may be most effective when considering short antiretroviral courses. Where HIV-infected women present late for delivery, post-exposure prophylaxis with a single dose of NVP immediately after birth plus ZDV for the first 6 weeks after birth is beneficial. The long term implications of the emergence of resistant mutations following the use of these regimens, especially those containing Nevirapine, require further study. Antirétroviraux visant à réduire le risque de transmission mère-enfant du VIH Les médicaments antirétroviraux réduisent la réplication virale et peuvent réduire la transmission mère-enfant du VIH soit en diminuant la charge virale plasmatique chez les femmes enceintes, soit à travers une prophylaxie post-exposition chez leurs nouveau-nés. Dans les pays riches, le traitement antirétroviral hautement actif (TAHA), comprenant généralement trois médicaments, a réduit les taux de transmission mère-enfant d'approximativement 1-2 %, mais le TAHA n'est pas toujours disponible dans les pays à faible et moyen revenus. Dans ces pays, des traitements variés plus simples et à coût moindre ont été offerts aux femmes enceintes ou à leurs nouveau-nés, voire aux deux. Déterminer si, et dans quelle mesure, les traitements antirétroviraux visant à diminuer le risque de transmission mère-enfant du VIH atteignent une réduction clinique utile du risque de transmission, et quels sont les effets de ces interventions sur la mortalité et la morbidité maternelles et infantiles. Nous avons tenu à identifier toutes les études pertinentes quels que soient le langage ou l'état de publication en recherchant le registre d’essais cliniques Cochrane spécialisé dans le VIH/SIDA, Bibliothèque Cochrane, MEDLINE, EMBASE et AIDSearch, ainsi que tous les résumés de conférence pertinents. Nous avons également contacté des organisations de chercheurs et des experts travaillant dans le domaine pour obtenir des essais non publiés et des études en cours. La stratégie de recherche documentaire a été initialement conduite en 2002 puis mise à jour en 2006 et en 2009. Essais contrôlés randomisés des traitements antirétroviraux visant à réduire le risque de transmission mère-enfant du VIH par rapport à un placebo ou sans traitement, ou par rapport à un autre traitement antirétroviral. Deux auteurs ont sélectionné indépendamment les études pertinentes, extrait les données et évalué la qualité des essais. Pour les critères de jugement principaux, nous avons utilisé une analyse de survie afin d'estimer la probabilité pour les nourrissons d'être infectés par le VIH (la proportion observée) à divers points temporels, et avons calculé l'efficacité à un moment précis comme réduction relative de la proportion infectée. L'efficacité à un moment précis est définie comme la fraction préventive au sein du groupe exposé par rapport au groupe de référence, c'est à dire la réduction relative de la proportion infectée : 1-(Re/Rf). Pour les études dans lesquelles l'efficacité et donc les intervalles de confiance n'ont pas été calculés, nous avons calculé les intervalles de confiance approximatifs pour mesurer l'efficacité à l'aide des méthodes recommandées. Pour les analyses de résultats qui ne sont pas basées sur les analyses de survie, nous présentons le risque relatif pour chaque critère d'essai, basé sur le nombre randomisé. Aucune méta-analyse n'a été conduite puisqu'aucun essai n'a évalué des traitements de médicaments identiques. Vingt-cinq essais comprenant 18 901 participants avec une taille d'échantillon médiane de 627, allant de 50 à 1 844 participants, ont été inclus dans cette mise à jour. Vingt-deux essais ont randomisé les mères (18 en phase prénatale et quatre en phase de travail) et suivi leurs nourrissons, et trois essais ont randomisé les nourrissons. Le premier essai a commencé en avril 1991 et a évalué la zidovudine (ZDV) par rapport à un placebo et, depuis, le type, le dosage et la durée des médicaments à comparer a été modifiée dans chaque essai postérieur. Nous présentons les résultats classés par traitement et type d'alimentation. Antirétroviraux par rapport à un placebo Chez les populations ayant recours à l'allaitement, trois essais ont observé que : La ZDV administrée aux mères en gestation de 36 à 38 semaines, pendant le travail et 7 jours après l'accouchement, a réduit de manière significative l'infection par le VIH à 4-8 semaines (Efficacité de 32,00 % ; IC à 95 % de 1,50 à 62,50), 3 à 4 mois (Efficacité de 33,07 % ; IC à 95 % de 5,57 à 60,57), 6 mois (Efficacité de 34,55 % ; IC à 95 %, de 9,05 à 60,05), 12 mois (Efficacité de 34,31 % IC à 95 % de 9,30 à 59,32) et 18 mois (Efficacité de 29,74 % ; IC à 95% entre 2,73 et 56,75). La ZDV administrée aux mères en gestation de 36 semaines et pendant le travail a réduit de manière significative l'infection par le VIH à 4 à 8 semaines (Efficacité de 43,78 % ; IC à 95 % de 8,78 à 78,78) et 3 à 4 mois (Efficacité de 36,95 % ; IC à 95 % de 2,94 à 70,96), mais pas à la naissance. Le traitement de ZDV plus lamivudine (3TC) administré aux mères en gestation de 36 semaines, pendant le travail ou bien 7 jours après l'accouchement, ainsi qu'aux bébés lors des 7 premiers jours suivant la naissance (traitement A PETRA), a réduit de manière significative l'infection par le VIH (Efficacité de 62,75 % ; IC à 95 % de 40,76...