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

At the end of 2009, 2.5 million children under the age of 15 years were estimated to be living with HIV/AIDS (WHO 2011). The majority of these children acquired their infections as a result of mother-to-child transmission during pregnancy, labor, or breastfeeding. Antiretroviral drugs administered to the HIV-infected mother and/or to her child during pregnancy, labor, or breastfeeding can reduce mother-to-child transmission of HIV. The objective of this review is to determine whether a regimen of antiretroviral drugs leads to a significant reduction in HIV transmission during pregnancy and labor without serious side-effects.

The 25 trials found eligible for this review included 18,901 participants.The included trials compared the use of antiretrovirals versus placebo, longer regimens versus shorter regimens using the same antiretrovirals, and antiretroviral regimens using different drugs and drug combinations. This review of trials found that short courses of certain antiretroviral drugs are effective in reducing mother-to-child transmission of HIV, but are not associated with any safety concerns in the short term.

Authors' conclusions: 

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.

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Background: 

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.

Objectives: 

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.

Search strategy: 

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.

Selection criteria: 

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.

Data collection and analysis: 

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.

Main results: 

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.

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