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INTRODUCTION — Studies of the use of antiretroviral agents to interrupt HIV transmission were initiated in the early 1990s in the United States and other resource-rich countries. Coupled with the avoidance of breastfeeding and good access to comprehensive HIV and pregnancy care services, these regimens have significantly reduced perinatal transmission in resource-rich countries to one to two percent [1-3]; in the United States, it is estimated that only 69 HIV-infected infants were born in 2013 . Despite substantial barriers, efforts in resource-limited settings to introduce antiretroviral agents for perinatal prevention have also resulted in a marked decrease in perinatal HIV transmission (mother-to-child transmission [MTCT]) from over 570,000 in 2003 to an estimated 110,000 in 2015 within the 21 Global Plan priority countries in sub-Saharan Africa [5,6].
This topic will address the epidemiology of perinatal transmission and present the current antiretroviral recommendations for pregnant women and their infants for prevention of mother-to-child transmission (PMTCT) in resource-limited settings. This topic will also review the remaining barriers to total elimination of MTCT.
Information regarding the prevention of HIV transmission during breastfeeding in resource-limited settings is found elsewhere. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings".)
The management of pregnant HIV-infected women in resource-rich settings is discussed in detail elsewhere. (See "Prenatal evaluation of the HIV-infected woman in resource-rich settings" and "Antiretroviral and intrapartum management of pregnant HIV-infected women and their infants in resource-rich settings".)
The safety and pharmacology of specific antiretroviral agents during pregnancy are discussed in detail elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy".)
EPIDEMIOLOGY — Since the first cases of mother-to-child transmission (MTCT) of HIV were identified in the United States in the early 1980s, extensive research has led to a better understanding of the epidemiology of the global pediatric HIV epidemic, including risk factors for MTCT, potential mechanisms of transmission, and the timing of transmission.
The epidemiology of HIV transmission during breastfeeding is discussed in detail elsewhere. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Epidemiology of HIV transmission through breastfeeding'.)
Burden of disease — Surveillance data from the Joint United Nations Program on HIV/AIDS (UNAIDS) over the past two decades have documented the heavy burden and impact of HIV on mothers and infants living in resource-limited settings [5,7]. Sub-Saharan Africa carries the greatest burden of the epidemic: UNAIDS reported 150,000 pediatric infections worldwide in 2015; 110,000 new cases occurred in 21 countries in Sub-Saharan Africa [6,8].
Risk of MTCT of HIV — Without antiretroviral preventive interventions, the risk of perinatal HIV transmission has varied between 15 and 45 percent, depending on maternal risk factors and whether breastfeeding is practiced . The most important risk factors for transmission have consistently been maternal plasma and breast milk viral load followed by maternal immunologic status and clinical stage, as suggested by observational studies and clinical trials in non-breastfed and breastfed populations. Analyses of viral load levels in the original trial of zidovudine to prevent MTCT (PACTG 076) , as well as studies from Thailand , West Africa , Uganda , and Kenya , all demonstrate a direct positive correlation between maternal plasma viral load and risk of transmission to the infant.
This correlation is observed even among women taking antiretroviral agents. As an example, in a study from the United Kingdom and Ireland of over 10,000 HIV-infected pregnant women, MTCT rates were lower among women who had a viral load <50 copies/mL near delivery compared with women who had higher viral loads (0.09 percent transmission versus 1.0 and 2.6 percent with viral load ranges 50-399 copies/mL and 400-999 copies/mL, respectively) .
Other maternal and infant factors have also been associated with increased risk of transmission. Some associated maternal risk factors include low CD4 cell counts, anemia, more advanced WHO clinical disease stage, maternal mastitis, and acute maternal seroconversion during pregnancy or breastfeeding [14,16]. As an example, in a meta-analysis of 19 studies, which included over 20,000 person-years of follow-up, the pooled incidence of HIV acquisition during pregnancy or postpartum was 2.9 events per 100 person years, and the pooled risk of MTCT among such women was 23 percent .
Timing of HIV transmission from mothers to their infants — Greater than 90 percent of all new pediatric HIV cases result from perinatal transmission of HIV, which can occur during pregnancy (in utero), at labor/delivery (intrapartum), or post-delivery (postnatal) through breastfeeding.
In non-breastfeeding settings prior to the availability of antiretroviral interventions, in utero infections (indicated by a positive HIV nucleic acid amplification test [NAT] in the infant within 72 hours after birth) accounted for about one-third of the infant HIV infections, while about two-thirds of transmissions occurred around the time of labor and delivery (indicated by HIV NAT results in the infant that were negative within the first 72 hours after birth, but then positive by four to six weeks of age) .
In breastfeeding settings prior to the availability of antiretroviral interventions, about 25 to 40 percent of infant infections were estimated to occur in utero, about 50 percent around the time of labor/delivery or through very early breastfeeding, and the remainder during the breastfeeding period .
Mechanisms of transmission
In utero — A majority of in utero transmission is thought to occur during the third trimester. This conclusion is based on low rates of viral detection using HIV NAT on fetal tissue from abortions in the first and second trimester  as well as statistical modeling analyses . In a study of long versus short antenatal zidovudine prophylaxis for prevention of mother-to-child transmission, the rate of in utero transmission was 5.1 percent when starting zidovudine at 36 weeks gestation compared with 1.6 percent when starting zidovudine at 28 weeks gestation, suggesting that a significant proportion of transmission may occur between 28 to 36 weeks gestation, and a smaller residual amount of in utero infection may occur earlier in pregnancy . Mechanisms of transmission are thought to be related to breakdown of the integrity of the placenta, leading to microtransfusions of viremic maternal blood across the placenta to the fetus . A number of studies have shown that genital tract infections and placental inflammation, especially chorioamnionitis, can increase in utero HIV transmission .
Intrapartum — Transmission during the time of labor and delivery is postulated to occur through contact of infant mucosal membranes with HIV virus in blood and secretions during the birth process. In the absence of antiretroviral treatment, duration of membrane rupture greater than four hours has been associated with increased risk of transmission . In addition, microtransfusions across the placenta during labor contractions also likely contribute to the heightened risk of transmission during the labor and delivery period .
During breastfeeding — The mechanism of transmission of HIV during breastfeeding is discussed elsewhere. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Mechanism of breast milk HIV transmission'.)
OVERVIEW OF CARE TO PREVENT TRANSMISSION — Antiretroviral intervention is the cornerstone of strategies to prevent mother-to-child transmission (PMTCT) of HIV. However, the complete cascade of PMTCT services includes additional measures beyond simply administering antiretroviral agents:
●Routine rapid HIV testing during the initial antenatal visit to identify HIV-infected women early during pregnancy
●Initiation of effective lifelong antiretroviral therapy (ART) at the time of diagnosis of HIV infection (see 'Maternal antiretroviral use' below)
●CD4 cell count screening and clinical assessment of World Health Organization (WHO) disease staging (table 1) for women who are HIV-infected
●Antenatal clinic/PMTCT visits during pregnancy for drug refills, toxicity monitoring, and routine pregnancy care
●Delivery by a skilled birth attendant, preferably at a health facility (see 'Mode of delivery' below)
●Infant antiretroviral prophylaxis (see 'Infant antiretroviral use' below)
●Follow-up services at six weeks postpartum for the mother and infant:
•Continued management of lifelong ART (see 'Duration of antiretroviral use' below)
•Counseling on infant feeding, promotion of six months exclusive breastfeeding with continued breastfeeding thereafter with introduction of safely-prepared nutritious, locally available foods at six months (see "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Options for infant feeding')
•Early infant HIV diagnosis using nucleic acid amplification testing (NAT) (see "Diagnostic testing for HIV infection in infants and children younger than 18 months", section on 'HIV-infected mother')
●Ensuring referral and long-term linkage to HIV care and treatment for the mother
●Ensuring counseling for and long-term monitoring of adherence to ART taken by the mother for PMTCT and maternal health
●Ensuring the infant receives routine growth monitoring, routine immunizations, and ongoing evaluation of HIV infection status, including final determination through HIV antibody screening after weaning (see "Diagnostic testing for HIV infection in infants and children younger than 18 months", section on 'HIV-infected mother')
●For children determined to be HIV-infected, rapid referral to HIV care and treatment services for initiation of ART
RECOMMENDED ANTIRETROVIRAL MANAGEMENT — The use of antiretroviral agents by pregnant women and their children is a critical component of prevention of mother-to-child transmission during the antepartum and peripartum periods as well as throughout the duration of breastfeeding. In 2015, the World Health Organization (WHO) revised its guidelines to recommend initiation of lifelong antiretroviral therapy (ART) for all HIV-infected individuals regardless of CD4 cell count, including pregnant and breastfeeding women . Thus, ART should be initiated as early as possible in all HIV-infected pregnant women and continued lifelong. In addition, all infants born to HIV-infected mothers should receive post-exposure antiretroviral prophylaxis. The recommended first-line ART regimen in pregnant and breastfeeding women is the same as recommended in non-pregnant adults: tenofovir plus lamivudine (or emtricitabine) plus efavirenz administered as a fixed dose, once-daily combination regimen.
This section discusses the WHO guidelines for antiretroviral management of pregnant women and their infants in resource-limited settings in further detail.
Maternal antiretroviral use — ART is recommended for all HIV-infected pregnant and breastfeeding women in resource-limited settings, regardless of their CD4 cell count or disease stage, to reduce the risk of transmission to their infants and for their own clinical benefit . The goal of ART is to reduce the viral load to undetectable levels; with regards to prevention, the risk of transmission of HIV decreases with the viral load. (See 'Risk of MTCT of HIV' above.)
Women already taking ART should continue it. For other women, a lifelong ART regimen should be initiated as soon as HIV is diagnosed. Details of the regimen and its duration are discussed below. (See 'Regimen selection' below and 'Duration of antiretroviral use' below.)
The recommendation for initiation of a regimen as early in pregnancy as possible is supported by results from observational studies that suggest that earlier initiation of ART is associated with lower rates of transmission [27,28]. As an example, in a study of 1142 HIV-infected pregnant women in South Africa, lower rates of transmission were observed among women who had initiated ART prior to pregnancy compared with during pregnancy (0.7 versus 5.7 percent) . Early initiation of ART with sustained viral suppression provides maximal protection against transmission; in the French Perinatal Cohort, there were no perinatal transmissions among 2651 HIV-infected pregnant women who initiated ART before conception, continued it throughout pregnancy, and had viral load <50 copies/mL at delivery .
Regimen selection — WHO guidelines recommend initiation of a once-daily, fixed-dose combination of tenofovir, lamivudine (or emtricitabine), and efavirenz in all HIV-infected pregnant or breastfeeding women [26,30].
Tenofovir, lamivudine (or emtricitabine), and efavirenz is also the same preferred first-line regimen for non-pregnant adults and thus allows for streamlining ART administration to all adults in resource-limited settings. Additional advantages of the regimen include antiviral potency, relatively low frequency of severe adverse effects, a greater likelihood of adherence with a once-daily dosing, affordability, and efficacy against hepatitis B virus. In a trial of pregnant women in Uganda, initiation of an efavirenz-containing ART regimen at 12 to 28 weeks gestation resulted in virologic suppression in 98 percent by delivery and 91 percent at 48 weeks postpartum; no perinatal HIV transmissions were observed . (See 'Risk of MTCT of HIV' above and 'Efficacy of maternal ART in preventing transmission' below.)
There are increasing safety data available for tenofovir and efavirenz among pregnant women and their infants. These are discussed in detail elsewhere. (See 'Adverse effects/safety' below and "Safety and dosing of antiretroviral medications in pregnancy", section on 'Efavirenz' and "Safety and dosing of antiretroviral medications in pregnancy", section on 'Tenofovir disoproxil fumarate'.)
For women who cannot tolerate or receive components of the preferred first line regimen, recommended alternative agents are zidovudine to replace tenofovir and nevirapine to replace efavirenz in the three-drug regimen. There are extensive safety and efficacy data on the use of zidovudine and nevirapine in pregnant and breastfeeding women. Dolutegravir and lower-dose efavirenz are also listed as possible alternative first-line options for the general population by the WHO, but they are not recommended for pregnant women because of paucity of data on use of these in pregnancy . (See 'Adverse effects/safety' below and "Safety and dosing of antiretroviral medications in pregnancy", section on 'Zidovudine' and "Safety and dosing of antiretroviral medications in pregnancy", section on 'Nevirapine'.)
For the subset of HIV-infected women in resource limited settings on first-line therapy who develop virologic or clinical failure, develop significant toxicities, or cannot tolerate the preferred or alternative first-line regimen, a switch should be made to a second-line regimen containing a protease inhibitor, such as lopinavir/ritonavir or atazanavir/ritonavir, in addition to a switch in at least one of the nucleoside analogue reverse transcriptase agents.
Duration of antiretroviral use — WHO recommends lifelong ART in all HIV-infected individuals, including women who initiated ART during pregnancy or breastfeeding .
The rationale for the recommendation of lifelong ART includes:
●Evidence of a clinical benefit of ART even at high CD4 cell counts. (See "The impact of antiretroviral therapy on morbidity and mortality of HIV infection in resource-limited settings", section on 'Optimal timing of antiretroviral therapy'.)
●Extended protection against mother-to-child transmission during future pregnancies without frequent treatment interruptions.
●Prevention of HIV transmission to uninfected sexual partners with successful ART. (See "HIV infection: Risk factors and prevention strategies", section on 'Treatment as prevention'.)
●Overall decreasing costs of ART regimens and increased operational feasibility in many countries.
Infant antiretroviral use — In addition to maternal ART, the WHO recommends that all infants receive post-exposure prophylaxis to prevent transmission from exposure to HIV during delivery (and the early breastfeeding period, if applicable). The recommended regimen depends on the infant’s risk of infection, as determined by the timing of maternal infection, maternal ART use, and the type of infant feeding (algorithm 1) . Prophylaxis should start as soon as possible after birth, preferably within 6 to 12 hours.
High-risk infants — High-risk infants are those born to HIV-infected mothers who have a viral load >1000 copies/mL within the four weeks prior to expected delivery, who received no ART or less than four weeks of ART by the time of delivery, or who acquired HIV infection during pregnancy or breastfeeding.
For such infants, the recommended prophylaxis regimen is daily nevirapine plus twice-daily zidovudine for the first six weeks of life (algorithm 1) . Breastfeeding infants should continue an additional six weeks of prophylaxis with the same combination or with nevirapine alone; if the mother cannot tolerate or declines ART, then the infant should continue nevirapine prophylaxis throughout the duration of breastfeeding, until one week following breastfeeding cessation (if nevirapine is not tolerated, daily lamivudine can be used). (See "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Breastfeeding infants'.)
Nevirapine and zidovudine dosing are based on the weight of the infant (table 2). The recommendation for a combination regimen for prophylaxis of high-risk infants is based on evidence demonstrating greater efficacy of two-drug compared with single-drug regimens in preventing perinatal HIV transmission in cases when the mother is not on suppressive ART. (See 'Efficacy in the absence of maternal antiretroviral use' below.)
Management of HIV-exposed infants who are identified in the postpartum period is discussed elsewhere. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Infant antiretroviral use'.)
Infants of mothers on suppressive ART — The risk of HIV infection in infants born to women who had achieved viral suppression on ART or who had been regularly taking ART for more than four weeks by the time of delivery is low. The recommended prophylaxis regimen for such infants is six weeks of daily nevirapine for those who are breastfeeding and four to six weeks of daily nevirapine or twice-daily zidovudine for those who are receiving replacement feeding (algorithm 1) . (See "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Breastfeeding infants'.)
The duration of infant antiretroviral use in situations where the mother is receiving ART is an empiric recommendation based on the estimated time necessary to reduce viral load in women initiating ART and data on safety from infant prophylaxis trials when the mother was not receiving antiretroviral drugs. As an example, the duration of infant nevirapine prophylaxis in the six week extended nevirapine (SWEN) trial was six weeks . In the HPTN 046 clinical trial of infant prophylaxis, in which some mothers were receiving ART for their own health, there was no evidence of additional toxicity when maternal ART were administered with infant nevirapine prophylaxis . (See 'Efficacy of infant antiretroviral use in preventing infection' below.)
EFFICACY OF MATERNAL ART IN PREVENTING TRANSMISSION — Perinatal trials in resource-limited settings have demonstrated the strong impact of maternal antiretroviral drug use (in particular, combination antiretroviral therapy [ART]) on reducing the risk of mother-to-child transmission (MTCT) of HIV. In these studies, the use of antiretroviral interventions has been shown to be the most important factor for reducing the risk of MTCT, overriding clinical, virologic, and immunologic risk factors.
As an example, a multi-site randomized controlled trial in Africa and India that included nearly 4000 HIV-infected pregnant women with a CD4 cell count >350 cells/microL compared two protease inhibitor-containing ART regimens (zidovudine, lamivudine, and lopinavir-ritonavir or tenofovir, emtricitabine, and lopinavir-ritonavir, each initiated antepartum and continued through delivery) with a regimen of antepartum zidovudine combined with single-dose nevirapine at delivery followed by a dual NRTI "tail" . HIV transmission to the infant within 14 days of birth was significantly lower with the ART regimens compared with the zidovudine/single-dose nevirapine regimen (0.5 percent compared with 1.8 percent), although rates of certain adverse maternal effects and pregnancy outcomes were higher (see 'Adverse effects/safety' below). Nevertheless, these data, combined with the results of trials demonstrating a clinical benefit of immediate versus delayed ART initiation even among HIV-infected adults with CD4 cell counts >500 cells/microL [34,35], support the 2015 WHO guidelines for initiation of lifelong ART in all HIV-infected individuals, including pregnant and breastfeeding women. (See 'Maternal antiretroviral use' above and "The impact of antiretroviral therapy on morbidity and mortality of HIV infection in resource-limited settings", section on 'Optimal timing of antiretroviral therapy'.)
The efficacy of combination ART in reducing perinatal transmission has also been demonstrated in several observational studies in resource-limited settings. In these studies, ART was associated with MTCT rates at birth and in the early postpartum period of less than 5 percent, comparable to the low transmission rates achieved in resource-rich settings [36-41].
Prior to the more widespread availability and use of ART regimens, studies in resource-limited settings focused on and demonstrated the efficacy of one- or two-drug regimens (zidovudine, zidovudine/lamivudine, nevirapine) given in the last trimester and around labor/delivery, which were less expensive and more deliverable in resource-limited settings. However, single- or dual-drug antiretroviral prophylaxis regimens, while proven effective, are no longer recommended by the WHO because of complexities of these regimens and the potential additional benefits of maternal ART beyond prevention of MTCT. (See 'Recommended antiretroviral management' above.)
The efficacy of maternal ART use to prevent transmission of HIV during breastfeeding is discussed elsewhere. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Efficacy of maternal antiretroviral drug use'.)
EFFICACY OF INFANT ANTIRETROVIRAL USE IN PREVENTING INFECTION — The role of infant antiretroviral drugs in prevention of mother-to-child transmission (MTCT) as post-exposure prophylaxis following delivery and during breastfeeding has been demonstrated in multiple studies, both in the presence and absence of maternal antiretroviral use. Comparing efficacy among these regimens is complicated by the variable maternal regimens, as well as whether or not the infants were breastfed.
The efficacy of infant antiretroviral regimens in preventing transmission during breastfeeding is discussed elsewhere. (See "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Efficacy of infant antiretroviral prophylaxis'.)
Efficacy in the context of maternal antiretroviral use — Infant antiretroviral prophylaxis is effective when used in combination with maternal ART.
The ACTG 076 trial, performed in resource-rich countries, was the first to demonstrate the efficacy of six weeks of neonatal dosing of zidovudine following birth in combination with maternal zidovudine during pregnancy and intrapartum, with a MTCT rate of 8.3 percent among those mother-infant pairs who received zidovudine compared with 25.5 percent in the placebo group . In resource-limited settings, shorter courses of antiretroviral prophylaxis were evaluated to determine the efficacy of regimens that would have been easier to obtain and administer. In a trial in formula-fed infants in Thailand, there was no difference in transmission rates with three days versus six weeks of infant zidovudine prophylaxis if maternal prophylaxis was started at 28 weeks gestation . In contrast, when maternal prophylaxis was started at 36 weeks gestation, longer (six week) infant prophylaxis resulted in significantly lower transmission than shorter (three days) infant prophylaxis. In the HIVNET 012 trial, in breastfeeding infants whose mothers received intrapartum but no antepartum antiretroviral drugs, a single dose of nevirapine was found to be more effective than short-course zidovudine (one week) [13,42]. The addition of single-dose nevirapine to one week zidovudine for infant prophylaxis appeared beneficial predominantly among breastfeeding and not formula fed infants [43,44].
Efficacy in the absence of maternal antiretroviral use — Despite effective regimens of HIV prophylaxis for prevention of MTCT, some women are not identified as HIV-infected until late in pregnancy, labor, or possibly even after delivery. In the absence of maternal therapy, infant antiretroviral post-exposure prophylaxis is critical for reducing intrapartum (and postpartum if breastfeeding) mother-to-child transmission. Observational studies of infants whose mothers received no intrapartum or antepartum antiretroviral prophylaxis have demonstrated an associated reduction in HIV transmission with infant prophylaxis . Use of a two-drug regimen for prophylaxis is more effective than a single-drug regimen and as effective as a three-drug regimen .
In the NICHD/HPTN 040/P1043 trial, which was conducted both in the United States and internationally, formula-fed infants of women who received no antepartum antiretroviral therapy were randomly assigned to one of three arms: zidovudine for six weeks, zidovudine for six weeks plus three doses of nevirapine within the first eight days of life, and six weeks of zidovudine and lamivudine plus the protease inhibitor nelfinavir for two weeks. At six weeks, transmission rates were lower with the 2- and 3-drug combination therapy arms compared with the zidovudine alone group (2.2 and 2.4 versus 4.8 percent with nevirapine plus zidovudine, the nelfinavir-based regimen, and zidovudine alone, respectively) . However, while there was not a significant difference in transmission between the 2- and 3-drug arms, there was significantly more hematologic toxicity in infants receiving the 3-drug regimen.
Similarly, in another trial of breastfeeding infants whose mothers did not receive antiretroviral prophylaxis, the addition of one week of zidovudine to nevirapine further decreased the transmission risk compared with single-dose nevirapine alone .
ADVERSE EFFECTS/SAFETY — The use of antiretroviral drugs during pregnancy has generally been found safe in trials to date, and the benefits for preventing transmission of a fatal illness have been judged to outweigh the potential adverse reactions that may occur. The currently recommended first-line regimen of tenofovir, lamivudine (or emtricitabine), and efavirenz has been used extensively during pregnancy and appears to be generally well-tolerated and safe [48,49]. However, continued monitoring for end-organ toxicities and birth defects in HIV-infected pregnant women and their infants is necessary to assure both short-term and long-term safety.
Drug resistance — Multi-class resistance in both the mother and infant is possible if there is poor maternal adherence to ART; thus continued counseling and adherence evaluation is a critical aspect of complete prevention of mother-to-child transmission care.
In the United States and Europe, there have been case reports of multi-class resistant HIV strains being transmitted from HIV-infected mothers to their infants [50,51]. Likewise, in two studies from resource-limited settings of infants born to women who were given ART for prophylaxis in a trial setting, multi-class resistance was detected in substantial proportions of infants who acquired HIV infection, particularly among those thought to be infected during the breastfeeding period [52,53]. These reports heighten concerns that there may be rapid emergence of multiclass antiretroviral resistance on a population basis if HIV-infected pregnant and postpartum women do not adhere well to their ART or have treatment interruptions related to loss to follow-up.
Maternal effects — The use of antiretroviral agents is generally safe for the pregnant woman and not associated with adverse effects substantially different from those seen in the general population. (See "Safety and dosing of antiretroviral medications in pregnancy".)
Much data on maternal effects are with regimens other than the first-line regimen of tenofovir, lamivudine (or emtricitabine), and efavirenz. As an example, one randomized trial compared two combination protease inhibitor-based regimens (lopinavir/ritonavir with either tenofovir-emtricitabine [tenofovir-ART] or zidovudine-lamivudine [zidovudine-ART]) with a zidovudine plus single-dose nevirapine regimen in women with high CD4 cell count (>350 cells/microL). Zidovudine-ART was associated with more frequent maternal grade 2 or higher adverse events than the zidovudine/single-dose nevirapine regimen (21 versus 17 percent), and both ART regimens had more frequent grade 2 or higher maternal abnormal chemistry laboratory values, primarily liver function test abnormalities (4.7, 2.9, and 0.8 percent with zidovudine-ART, tenofovir-ART, and zidovudine/single-dose nevirapine) . However, rates of drug discontinuation were low overall and not different between the different regimens.
Another alternative agent is nevirapine, which has been used and studied commonly in resource-limited settings. There is a risk of hepatotoxicity with the use of nevirapine, particularly in individuals with CD4 cell count >350 cell/microL, but there does not appear to be an excess risk during pregnancy. In a meta-analysis of two randomized trials and 18 observational studies that included 3582 women who initiated nevirapine while pregnant, the overall proportion of patients who experienced severe hepatotoxicity was 3.2 percent, similar to that reported in another study of nevirapine hepatotoxicity in a general HIV-infected population . (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Nevirapine'.)
Pregnancy outcomes — Several studies have indicated a higher risk of adverse pregnancy outcomes, such as prematurity, low birth weight, or small for gestational age infants, with the use of ART regimens in resource-limited settings, highlighting the importance of continued monitoring and evaluation of this strategy for prevention of perinatal HIV transmission [33,55-59]. There are more data regarding the use of ART and adverse pregnancy outcomes from resource rich settings such as the United States and Europe, although studies have demonstrated conflicting results [60-72]. This is discussed in detail elsewhere (see "Safety and dosing of antiretroviral medications in pregnancy", section on 'Pregnancy outcomes with combination ART exposure'). Of note, untreated maternal HIV infection itself has been associated with adverse pregnancy outcomes [55,73].
Teratogenicity — Teratogenic effects associated with the use of antiretrovirals during pregnancy have been monitored since 1989 in the voluntary Antiretroviral Pregnancy Registry. Data are updated in semiannual reports that are available online. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Teratogenicity'.)
Although there were initial concerns about a risk of central nervous system birth defects and other midline defects with in utero exposure to efavirenz based on primate data, evaluation of prospectively collected data on human exposures to date are reassuring. This is discussed in detail elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Efavirenz'.)
Tenofovir exposure in utero has not been associated with an increased risk of birth defects.
Other adverse effects — Because many antiretrovirals can cross the placenta, infants may be exposed in utero as well as through antiretrovirals prescribed to the infant. In general, use of antiretrovirals is considered safe in infants. Fetal safety with maternal use of antiretroviral agents are discussed in detail elsewhere. (See "Safety and dosing of antiretroviral medications in pregnancy".)
Expected adverse events related to infant zidovudine use include transient anemia and neutropenia; the incidence varies based on the underlying incidence in the population studied.
Nevirapine is generally safe in infants. Severe rash and potentially life-threatening hepatic injury have not been associated with the use of nevirapine in infants. Currently, long-term follow-up cohorts of HIV and antiretroviral exposed infants are ongoing in resource-rich regions of the world. These studies are unlikely to be replicated in resource-limited regions, but nonetheless, will inform clinicians and policy makers who work in these areas.
MODE OF DELIVERY — Scheduled Cesarean section is associated with reduced rates of mother-to-child transmission (MTCT) among women who have received either no antiretroviral drugs or zidovudine alone [74,75] and is thus recommended for women who have not achieved viral suppression (HIV viral load >1000 copies/mL) in resource-rich regions . However, this recommendation is not practical in resource-limited regions and may increase maternal morbidity; thus, the presence and status of HIV infection in the mother does not affect decisions on delivery mode in resource-limited settings.
CHALLENGES TO IMPLEMENTATION OF PMTCT PROGRAMS — Large scale implementation of antiretroviral interventions demonstrated to be effective in clinical trials of prevention of mother-to-child transmission (PMTCT) of HIV has proved particularly challenging in resource-limited international settings. In 2011, the World Health Organization (WHO) estimated that only 48 percent (716,500 of 1,490,000) of HIV-infected pregnant women in resource limited settings received the most effective antiretroviral regimens for the prevention of MTCT as recommended by the WHO at the time . Progress, however, is being made. The Joint United Nations Program on HIV/AIDS (UNAIDS) reported that coverage of antiretroviral programs for prevention of MTCT increased from 36 percent in 2009 to 80 percent in 2015 among their 21 priority countries .
Obstacles along the prevention cascade — For PMTCT services to be effective, interventions must achieve high uptake in all aspects of PMTCT care, from antenatal services to postpartum linkage to HIV care. Real world challenges to the uptake of PMTCT services can occur at multiple points along the care cascade of antenatal, labor/delivery, and postpartum services. (See 'Overview of care to prevent transmission' above.)
Obstacles at the district health centers in many resource-limited settings include:
●Low uptake of antenatal care: pregnant women not accessing antenatal services at all, or only coming for one antenatal visit
●Limited availability and scale-up of PMTCT services
●Deliveries occurring unassisted at home, or with private midwives or traditional birth assistants and not at health care facilities
●High rates of loss to follow-up attributed to individual, structural, and community factors
●Routine lack of commodities, including HIV test kits, antiretroviral agents, laboratory reagents
●Inadequate health care worker staffing in maternal and child health (MCH) clinics and delivery settings
●Limited numbers of health workers qualified to prescribe antiretroviral agents
Several evaluations have been undertaken to analyze the real world effectiveness of PMTCT programs in resource-limited settings. These have revealed substantial challenges to providing optimal PMTCT services. In a review of PMTCT programs in 21 resource limited countries sub-Saharan Africa and India that receive President’s Emergency Plan for AIDS Relief (PEPFAR) funding, there was reduced uptake of effective interventions at all points of the PMTCT cascade in a number of resource-limited settings, including Cameroon, Chad, Ethiopia, and Uganda . This resulted in suboptimal antiretroviral delivery: less than half of HIV-infected mothers and less than one-third of HIV-exposed infants received appropriate antiretroviral interventions. Similarly, the PEARL study evaluated the uptake of PMTCT services in selected community facilities in South Africa, Cameroon, Zambia, and Cote d’Ivoire . It also included measurement of nevirapine in cord blood. Overall, there were major gaps in all points in the cascade in the delivery of PMTCT services, including failure to test some women and failure to provide antiretroviral interventions, including single dose nevirapine, to mothers or infants. Only 50 percent of mother-infant pairs received both infant and maternal prophylaxis. In addition, a substantial portion of women were lost to follow-up antenatally or failed to come to health centers for delivery.
In contrast, South Africa has established a program to evaluate the effectiveness of their national PMTCT strategies. In a facility-based survey of 580 health care facilities in nine provinces conducted from August 2011 to March 2012 and again from October 2012 to May 2013, 10,106 and 9120 caregiver-infant pairs, respectively, were enrolled at the four- to eight-week infant immunization visit . Among the infants, 32.3 percent were exposed to HIV in 2011 to 2012 and 33.1 percent in 2012 to 2013. The national MTCT rate at four to eight weeks was 2.7 percent in 2011 to 2012 and 2.6 percent in 2012 to 2013. HIV-infected women who received antiretroviral drugs had significantly lower early MTCT than those who did not receive antiretroviral drugs (2.0 versus 10.2 percent, respectively).
Maternal testing issues — Identification of infected pregnant women is critical to control of perinatal transmission. The use of routine or "opt-out" HIV rapid testing strategy has proven highly effective when implemented. This approach informs all pregnant women that they will be tested for HIV unless they specifically decline. The opt-out approach has consistently resulted in >95 percent uptake of rapid same day HIV antibody testing across a variety of international settings .
Maternal adherence and loss to follow-up — Inadequate antiretroviral adherence and follow-up during pregnancy and particularly in the postpartum setting are major obstacles for PMTCT programs. Several reports have documented this issue, citing relatively high rates of loss to follow-up or loss of virologic control [82-85].
As an example, in a study of over 30,000 HIV-infected, pregnant Nigerian women, there was significant loss to follow-up rates at all points along the PMTCT cascade, and 16 percent of women were lost to follow-up after delivery .
Adherence to antiretroviral agents may be better prior to delivery [86,87]. A systematic review and meta-analyses of studies evaluating adherence among HIV-infected pregnant and postpartum women in high and low resource settings suggested that antiretroviral adherence was somewhat better during the antepartum period (70.5 percent, 95% CI 58.3-81.2) compared to the postpartum period (70 versus 52 percent, respectively) . During both time periods, however, adherence was suboptimal for sustaining suppression of HIV viral load (ie, <90 percent adherence).
Optimizing the health care model — Operational research studies have evaluated different health care delivery models for providing PMTCT services. In a study from western Kenya outcomes were compared between 179 HIV-exposed infants seen at clinics that integrated PMTCT follow-up services into Maternal and Child Health (MCH) services and 184 infants in an HIV comprehensive care clinic from age 6 weeks through 12 months . Follow-up was better through PMTCT services that were integrated into the MCH clinics compared to delivery of services in the HIV comprehensive care clinics.
PROGRESS TOWARD ELIMINATION — In 2011, the Joint United Nations Program on HIV/AIDS (UNAIDS) rolled out an ambitious roadmap, "Countdown to zero — Global plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive" . Based on four prongs of service delivery (prevention of new HIV infections in women, reproductive health services, access to antiretroviral drugs for prevention of mother to child transmission and HIV care, and treatment and support for women and children living with HIV and their families), the campaign aimed to reduce the number of new HIV infections among children by 90 percent and the number of AIDS-related maternal deaths by 50 percent by 2015. While this goal was not achieved by 2015, there has been significant progress, with a 60 percent reduction in new pediatric infections (from 270,000 in 2009 to 110,000 in 2015) . Additionally, of the 21 Global Plan countries in sub-Saharan Africa, seven have reduced new infections among children by more than 70 percent since 2009. Continued success will require the collaboration and investment of the community, nation, region, and globe.
Despite the many challenges and obstacles, there have been striking successes of prevention of mother-to-child transmission (PMTCT) services in a number of Sub-Saharan African countries, including South Africa, Botswana, Malawi, Zambia, Zimbabwe, Mozambique, and Namibia, which have reported greater than 80 percent uptake of antenatal testing . In South Africa, Botswana, Swaziland, Lesotho, and Namibia, greater than 90 percent of pregnant women identified as HIV-infected have received effective combination PMTCT regimens through Maternal and Child Health (MCH) clinical services.
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: HIV and pregnancy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●New pediatric HIV infections from mother-to-child transmission remain a substantial health burden in resource-limited settings, particularly in sub-Saharan Africa. With improved access to antiretroviral agents and improved care delivery systems, international organizations have endorsed a goal of virtual elimination of perinatal transmission by 2015. (See 'Introduction' above and 'Burden of disease' above and 'Progress toward elimination' above.)
●Without preventive interventions, the risk of perinatal HIV transmission varies between 15 and 45 percent . (See 'Risk of MTCT of HIV' above and 'Timing of HIV transmission from mothers to their infants' above and 'Mechanisms of transmission' above.)
●The use of antiretroviral agents by pregnant women and their children is the most important intervention for prevention of mother-to-child transmission during antepartum, peripartum, and early postpartum periods. Nevertheless, successful prevention programs must also include other measures for optimal identification and long-term management of HIV-infected pregnant women. These include rapid HIV testing, monitoring and support for antiretroviral adherence and toxicity, counseling on infant feeding, effective family planning and reproductive health services, and linkage to long-term HIV care. (See 'Overview of care to prevent transmission' above.)
●Most clinicians in resource-limited settings will follow the World Health Organization (WHO) guidelines and the individual country’s national HIV program, which take into account not only efficacy but also programmatic feasibility and public health objectives. Various combinations of maternal and infant antiretroviral regimens have demonstrated efficacy in reducing the risk of perinatal HIV transmission. (See 'Efficacy of maternal ART in preventing transmission' above and 'Efficacy of infant antiretroviral use in preventing infection' above.)
●The WHO recommends initiation of ART for all HIV-infected pregnant or breastfeeding women, regardless of their CD4 cell count, as soon as pregnancy is recognized in an HIV-infected woman or HIV is diagnosed in a pregnant or breastfeeding woman. The fixed-dose combination of tenofovir, emtricitabine, and efavirenz is the preferred first-line regimen. ART should be continued lifelong. (See 'Maternal antiretroviral use' above.)
●The WHO recommends that all infants receive post-exposure prophylaxis to prevent transmission from exposure to HIV during delivery (and the early breastfeeding period, if applicable). The recommended regimen depends on the infant’s risk of infection, as determined by the timing of maternal infection and ART use, and the type of infant feeding (table 2 and algorithm 1). (See 'Infant antiretroviral use' above and "Prevention of HIV transmission during breastfeeding in resource-limited settings", section on 'Infant antiretroviral use'.)
●The use of antiretrovirals during pregnancy has generally been found safe in trials and experience to date, and the benefits for preventing transmission of a fatal illness outweigh the potential adverse reactions that may occur. However, continued monitoring for end-organ toxicities and birth defects HIV-infected pregnant women and their infants is necessary to assure both short-term and long-term safety of current ART regimens. (See 'Adverse effects/safety' above and "Safety and dosing of antiretroviral medications in pregnancy".)
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