Advances in the prevention of vertical transmission of human immunodeficiency virus
Section snippets
Overview
Initial trials for prevention of MTCT were targeted at prevention of in utero and intrapartum transmission, as they were conducted in resource-rich countries, where HIV-infected women were advised to formula feed their infants, and, hence, postnatal transmission of HIV through breast-feeding was not a problem. At the time that the first perinatal trial, PACTG 076, was designed (1989 to 1990), HIV was known to be transmitted during both the intrauterine and intrapartum periods, but knowledge was
PACTG 076 and the mechanisms of action of ZDV prophylaxis
PACTG 076 evaluated a 3-part regimen of ZDV monotherapy (Table1). 1 Antenatal ZDV, started at 14 to 34 weeks gestation, targeted transmission occurring in utero but after the first trimester (to avoid the period of maximal organogenesis), with the rationale of lowering maternal viral load and/or preventing or restricting the development of HIV infection in the placenta and fetus. Intravenous ZDV was given to the mother during labor. Because of the rapid passage of ZDV across the placenta to
>Short-course ZDV prophylaxis regimens
Based on the results of PACTG 076, along with accumulating data suggesting that most transmission occurs during delivery and that in utero transmission predominantly occurs during the last 2 months of pregnancy,18 short-course ZDV prophylaxis regimens were designed and evaluated in clinical trials in resource-limited countries. Two studies were conducted in nonbreastfeeding populations in Thailand (Table 1). The first study was conducted in Bangkok, Thailand, and showed that a ZDV regimen
ZDV/lamivudine combination prophylaxis regimens
The question of whether improved efficacy might be observed by combining a second antiretroviral drug with ZDV was a question relevant to both the United States and resource-limited settings, once short-course ZDV was shown to be effective. In nonbreastfeeding populations, 2 open-label, uncontrolled studies were performed. In France, lamivudine (3TC) (Epivir; GlaxoSmithKline, Research Triangle Park, NC) was added to the standard PACTG 076 ZDV regimen and given to 445 HIV-infected women starting
Alternative drug prophylaxis regimens-single-dose nevirapine prophylaxis
Nevirapine (Viramune; Boehringer-Ingelheim Pharmaceuticals, Inc, Ridgefield, CT) is a highly potent antiretroviral drug with a long half-life, and excellent transplacental passage and tissue penetration.22, 23 The HIVNET 012 trial in Uganda compared an intrapartum/newborn regimen of single-dose nevirapine given once orally to women at the onset of labor and once to the infant at 48 to 72 hours of age, with an ultrashort course of ZDV given orally intrapartum and for 1 week to the infant (Table
Combining single-dose nevirapine and ZDV prophylaxis regimens
To improve the efficacy of short-course ZDV regimens but retain a regimen that remains appropriate to the cost constraints existing in resource-limited countries, researchers then evaluated whether the single-dose nevirapine regimen might offer additional benefit when added to short-course ZDV. An ongoing study in Thailand in a nonbreastfeeding population is comparing short-course ZDV alone (starting at 28 weeks gestation, given orally intrapartum and for 1 week to the infant) to short-course
Neonatal antiretroviral prophylaxis
The use of neonatal prophylaxis alone in the absence of maternal treatment is being studied. In the United States, 14 to 20 percent of HIV-infected women lack prenatal care, with lack of prenatal care highest among drug-users.2 On a global basis, many women do not present to the health care system until they are in the late stages of labor. In such situations, only antiretroviral prophylaxis of the neonate may be possible. Observational data indicate that 6 weeks of ZDV prophylaxis
Effect of maternal antenatal highly active antiretroviral therapy
Increased maternal plasma viral load, particularly that occurring near the time of delivery, has been a critical factor in the risk of transmission in women receiving ZDV prophylaxis, although transmission can occur rarely, even at low or undetectable plasma RNA levels.14, 31, 32, 33 Therefore, researchers hypothesized that the antenatal receipt of highly active antiretroviral therapy (HAART), capable of reducing viral replication to undetectable levels, might have enhanced efficacy in reducing
Mode of delivery
Results from a large international individual patient meta-analysis and a European randomized clinical trial have shown that elective cesarean delivery, performed before labor and rupture of membranes, reduces the rates of MTCT by 50 to 87 percent in women receiving either no antiretroviral therapy or ZDV prophylaxis.34, 35 Neither study had data on maternal viral load, and both were conducted before the widespread use of combination antiretroviral therapy during pregnancy, so the effect of
Nonantiretroviral interventions
The efficacy of nonantiretroviral interventions performed to reduce transmission generally has been disappointing, with the exception of elective cesarean delivery (discussed previously). Intrapartum lavage of the cervicovaginal canal with chlorhexidine and the use of 1% benzalkonium chloride vaginal suppositories during the last 4 weeks of pregnancy did not reduce the incidence of MTCT in studies in Malawi, Kenya, Cote d’Ivoire, and Burkina Faso.41, 42, 43 In one chlorhexidine trial, early
Perinatal HIV transmission in the united states and other resource-rich countries
In 1994, the results of PACTG protocol 076 changed the landscape of the perinatal HIV epidemic in resource-rich countries. Before 1994 in the United States, approximately 1,600 infants born to the 6,000 HIV-infected women who give birth yearly became infected with HIV annually through MTCT. Within one year of the announcement of the results of PACTG 076, widespread implementation of ZDV prophylaxis, coupled with implementation of recommendations for universal prenatal HIV counseling and
Current guidelines for prevention of MTCT in the united states
Current guidelines for providing antiretroviral therapy and elective cesarean delivery in the United States are shown in Table 2. 56 Based on studies indicating that perinatal transmission rates are extremely low in women with plasma HIV RNA levels that are very low or undetectable, particularly when they have received antiretroviral therapy,14, 33 HAART is recommended for HIV-infected pregnant women with HIV RNA 1,000 or more copies/mL. Additionally, elective cesarean delivery should be
Barriers to elimination of perinatal HIV infection
Although new perinatal HIV infections are becoming rare occurrences in resource-rich countries, infections continue to occur. The birth of an infected infant is a sentinel event, representing missed opportunities and barriers to prevention.2 An important barrier is the continued increase in rates of HIV infection among women of childbearing age, particularly among adolescents of minority race or ethnicity. These same women at risk for acquisition of HIV infection also are at high risk for
Short-term and long-term safety of antiretroviral exposure
All antiretroviral drugs are known to be associated with some toxicity in HIV-infected individuals receiving chronic therapy. Preclinical data indicate that some antiretroviral drugs, particularly the nucleoside analogues, are carcinogenic in vitro and associated with mitochondrial dysfunction.56 Short- and medium-term data from multiple clinical trials indicate that antiretroviral exposure is associated with transient, mild hematologic abnormalities, such as anemia, that resolve following
Research needs
Important research priorities in resource-rich countries include (1) identifying populations that do not receive prenatal HIV testing or prophylaxis and developing outreach programs and effective interventions for such women; (2) establishing the causes of prophylaxis failures, including the effect of evolving patterns of drug resistance on the efficacy of prophylaxis; (3) developing interventions to reduce further transmission; and (4) evaluating potential short-term and long-term adverse
Perinatal transmission in resource-limited settings
The dramatic public health success that was achieved in resource-rich countries after the results of PACTG 076 were obtained contrasts with the continued perinatal epidemic in resource-limited countries, where the PACTG 076 ZDV prophylaxis regimen is too expensive and complex to implement, operative delivery may not be safe and could threaten the health of the mother, and HIV-infected women continue to breastfeed because they lack safe, sustainable, affordable, and acceptable alternatives. As
Prevention of postnatal breast milk HIV transmission
In countries like the United States, where formula feeding is accessible, affordable, safe, and sustainable, the complete avoidance of breastfeeding by HIV-1-infected women has been recommended and remains the only mechanism by which prevention of HIV transmission by breast milk can be ensured. In a randomized clinical trial conducted in an urban setting, in Nairobi, Kenya, where there was availability of clean water in the household, formula feeding by cup reduced the rates of postnatal
Research needs
Critical research issues for resource-limited countries include (1) the performance of operational studies on how to best implement proven effective regimens relevant for resource-limited settings, such as single-dose nevirapine; (2) the further study of risk factors related to HIV transmission via breast milk and the effect of formula feeding on infant morbidity and mortality in resource-limited settings and the development of effective interventions to reduce MTCT through breast milk; (3)
Conclusion
Although dramatic progress has been achieved in reducing HIV MTCT since 1994, 2 perinatal epidemics now exist. One epidemic is in resource-rich countries, where most HIV-infected women receive HAART, transmission has been reduced to less than 2 percent, and elimination of perinatal infection is within reach. The other is in resource-limited countries, where the majority of HIV-infected women live, and, although effective prophylaxis regimens have been identified, antiretroviral treatment
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