Antiretrovirals for reducing the risk of mother-to-child transmission of HIV infection.
BACKGROUND
Antiretroviral drugs (ARV) reduce viral replication and can reduce mother-to-child transmission of HIV either by lowing plasma viral load in pregnant women or through post-exposure prophylaxis in their newborns. In rich countries, highly active antiretroviral therapy (HAART) has reduced the vertical transmission rates to around 1-2%, but HAART is not yet widely 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.


OBJECTIVE
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.


METHODS
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 We also contacted research organizations and experts in the field for unpublished and ongoing studies.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 updated in 2006.


METHODS
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.


METHODS
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 the identical drug regimens.


RESULTS
Eighteen trials including 14,398 participants conducted in 16 countries were eligible for inclusion in the review. 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. 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 0.64 to 63.36), 3 to 4 months (Efficacy 34.00%; 95% CI 6.56 to 61.44), 6 months (Efficacy 35.00%; 95% CI 9.52 to 60.48), 12 months (Efficacy 34.00%; 95% CI 8.52 to 59.48) and 18 months (Efficacy 30.00%; 95% CI 2.56 to 57.44).ZDV given to mothers from 36 weeks gestation and during labour significantly reduced HIV infection at 4 to 8 weeks (Efficacy 44.00%; 95% CI 8.72 to 79.28) and 3 to 4 months (Efficacy 37.00%; 95% CI 3.68 to 70.32) 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 of life (PETRA 'regimen A') significantly reduced HIV infection (Efficacy 63.00%; 95% CI 41.44 to 84.56) and a combined endpoint of HIV infection or death (Efficacy 61.00%; 95% CI 41.40 to 80.60) 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 of life (PETRA 'regimen B') significantly reduced HIV infection (Efficacy 42.00%; 95% CI 12.60 to 71.40) and HIV infection or death at 4 to 8 weeks (Efficacy 36.00%; 95% CI 8.56 to 63.44) 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 of life significantly reduced HIV infection in babies at 18 months (Efficacy 66.00%; 95% CI 34.64 to 97.36).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 50.00%; 95% CI 12.76 to 87.24) but not at birthZDV 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 of life 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 45.00%; 95% CI 1.88 to 88.12) 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 11.60 to 70.40), 3-4 months (Efficacy 39.00%; 95% CI 11.56 to 66.44), 12 months (Efficacy 36.00%; 95% CI 8.56 to 63.44) and 18 months (Efficacy 39.00%; 95% CI 13.52 to 64.48). In addition, the NVP regimen significantly reduced the risk of HIV infection or death at 4-8 weeks (Efficacy 42.00%; 95% CI 14.56 to 69.44), 3 to 4 months (Efficacy 40.00%; 95% CI 14.52 to 65.48), 12 months (Efficacy 32.00%; 95% CI 8.48 to 55.52) and 18 months (Efficacy 33.00%; 95% CI 9.48 to 56.52). 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 37.00%; 95% CI 3.68 to 70.32). Five trials in non-breastfeeding populations found that:In a population in which mothers were receiving 'standard' ARV 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 of life 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. (ABSTRACT TRUNCATED)
Volmink
J
J
Stellenbosch University, Faculty of Health Sciences, PO Box 19063, Tygerberg, South Africa, 7505. jvolmink@sun.ac.za
Siegfried
N L
NL
van der Merwe
L
L
Brocklehurst
P
P
D019380:Anti-HIV Agents / Q000627:therapeutic use*; D005260:Female; D015658:HIV Infections / Q000517:prevention & control / Q000635:transmission*; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D019829:Nevirapine / Q000627:therapeutic use; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D015215:Zidovudine / Q000627:therapeutic use
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019829:Nevirapine