Mother-to-child transmission (MTCT) of the human immunodeficiency virus (HIV) occurs in an estimated 1,600 of newborn infants every day and is a major problem worldwide. An estimated 700,000 neonates acquired HIV from their mothers in 2000, mainly during the peripartum period, i.e. during or shortly after delivery (1). Globally, breastfeeding has been associated with 30-50% of perinatal HIV-1 transmission and for this reason, HIV-infected women in the developed world are advised not to breastfeed their infants (2). However, the situation is more complex in developing countries where there are often cultural, economic and hygienic reasons that prevent mothers from seeking alternatives to breastfeeding, such as artificial breast milk (formula feed) (3-6). There is therefore a significant need for the development of simple and effective methods to reduce MTCT transmission of HIV in developing and developed countries (7). This paper reviews the pathogenesis of MTCT and the current approaches to prevent infants from becoming infected, including ARV regimens composed of drugs such as nevirapine and zidovudine.
PATHOGENESIS OF VERTICAL HIV-1 TRANSMISSION
HIV-1 can be transmitted from an HIV-infected mother to her baby at various stages of pregnancy. These are during pregnancy (in utero), during delivery (intrapartum) or via breastfeeding (postpartum) (1,8). The majority of MTCT (greater than 75%) occurs during or after delivery. Mothers with a high plasma viral load (pVL) during pregnancy are more likely to transmit virus to their infants during the in utero or intrapartum periods, particularly if they seroconvert while pregnant (9). The risk is further increased with prolonged breastfeeding. The majority of HIV transmission via breast milk occurs within the first six months of breastfeeding and risk factors such as young maternal age, seroconversion during breastfeeding and presence of mastitis and/or breast damage are associated with an increased risk of transmission (10). A younger maternal age probably correlates with less experience in breastfeeding that can lead to an increase in breast damage. Damaged breast tissue enables the virus to transfer more readily from the mother to the breast milk and hence to the infant. In HIV-infected infants that are breastfed, 35-45% of infections can be attributed to breastfeeding, whereas in infants who are not breastfed, the majority of infections (75%) occur during labor and delivery.
Regardless of the timing of transmission of the HIV from mother to infant, the mechanism of infection is the same. Virus in vaginal secretions, mother's blood and breast milk enter the infant's mucosal tissues either during or after delivery. Within hours, the virus is taken up by the Langerhans cells and key immune cells such as dendritic cells, macrophages and lymphocytes (CD4 T cells). Within a few days of exposure, these cells transport the virus to the lymph nodes where it replicates. In 5-7 days HIV appears in the blood within infected CD4 T cells and as free virions (11). This process is illustrated in Figure 1.
Most infants with HIV infection (90%) are born in developing countries. In the developed world, HIV-infected mothers are advised not to breastfeed their infants but to provide them with formula feed. However, this is not practical in many developing countries due to economic, hygienic, and social reasons. For example, in some developing countries, women who do not breastfeed are ostracized from society and there may be no access to sterile equipment or uncontaminated water for mixing formula feed. In a randomized clinical trial conducted in Nairobi, Kenya, 44% of all infant HIV infections were attributed to breastfeeding (12). Because of the major role of breastfeeding in MTCT of HIV-1, methods to reduce transmission via this route are urgently needed.
PROGRESS TOWARDS THE ERADICATION OF VERTICAL HIV-1 INFECTION
1. Developed World
Recently, rates of MTCT of HIV-1 have fallen significantly in developed countries. In Europe rates are now less than 10% and they are less than 2% in the USA (13). This reduction can be attributed to the use of the AIDS Clinical Trials Group (ACTG) 076 regimen incorporating zidovudine for the prevention of MTCT and by treating HIV-infected women with highly active antiretroviral therapy (HAART) (4,13). The ACTG 076 regimen is a regimen of zidovudine (both intravenous and oral) given to HIV-infected pregnant women before, during, and after delivery (4). Transmission rates were reduced by approximately 67% in women with both high and low plasma viral loads (pVLs) taking zidovudine. In women not receiving zidovudine, the risk of transmission increased with increasing pVLs. In a study by Wade et al. (14), the transmission rate in women who only received zidovudine during the intra- and postpartum periods was 10% compared with 26.6% in women not receiving zidovudine, and 6.1% in those who received the full ACTG 076 regimen. Similarly, 9.3% of infants who received zidovudine within 48 hours of birth were infected with HIV compared with 18.4% who received zidovudine more than 72 hours after delivery.
The mode of delivery affects MTCT HIV infection rates. Elective caesarian section decreases MTCT of HIV-1 by 50%, as compared with vaginal delivery. Elective caesarian sections are therefore routinely offered to HIV-infected women in developed countries (15).
The ACTG 250 study investigated the potential of nevirapine, a potent non-nucleoside reverse transcriptase inhibitor (NNRTI), to prevent MTCT by examining its pharmacokinetics in pregnant women and neonates. Nevirapine was administered as a single maternal oral dose during labor and a single dose to the infant 24-48 hours post birth (1). The NNRTI was rapidly absorbed, producing plasma concentrations in excess of the IC50 in both mother and infants. Additional studies (16) have demonstrated that a single 200 mg dose of nevirapine reduces pVL by 1.3 log10 copies/mL within seven days; nevirapine has a long half-life (23.3 hours at steady state), transfers quickly across the placenta, and is present in breast milk because it is lipophilic.
The PACTG 316 study investigated the addition of a single dose of nevirapine to ARV regimes, administered for the mothers' own health and to prevent MTCT. PACTG 316 was a multi-centre, phase III trial that was conducted in the U.S.A., Europe, the Bahamas, and Brazil (13). NNRTI-naïve women were given open-label ARV therapy for their own HIV infection. They were then randomized to receive either single dose nevirapine or placebo. All infants born to the women who had received nevirapine also received a single dose of nevirapine within 72 hours of birth. The primary endpoint was the incidence of transmission of HIV from mother-to-child. The ARV regimes being taken by the women changed considerably during the course of PACTG 316, mainly due to the widespread introduction of HAART, and the study was terminated prematurely in June 2000. It had become impossible, with the planned sample size, to determine if the addition of single dose nevirapine to the mothers' ARV regimes had reduced the MTCT rate (Table 1). Recent data from the European-US Registry have demonstrated that the MTCT rate in women who had pVLs <1000 copies/ml was 9.8% in women who did not receive ARV drugs and 1.0% in those who did (17). These data indicate that it is preferable for all HIV-infected pregnant women to be offered ARV therapy for their own health, as well as to reduce the risk of transmitting HIV to their infants (18).
2. Developing World
The majority of infants with HIV infection are born in the developing world, mainly in sub-Saharan Africa. The United Nations Programme on HIV/AIDS (UNAIDS) estimates that 1500 children under 15 years are infected with HIV every day, the vast majority of whom have been infected by MTCT. There is, therefore, a clear need for strategies to prevent MTCT in developing countries and several studies have investigated ARV prophylaxis in this setting (2,19-21,23-27). In many developing countries, health care provision during childbirth is limited, hence it is essential that interventions to prevent MTCT are simple and low cost.
The Perinatal HIV Prevention Trial (PHPT) was conducted in Thailand and enrolled HIV-infected mothers and their infants (20). Its aim was to investigate the effect of a combination of long and/or short courses of zidovudine on MTCT rates. The mothers and infants were assigned to one of the following arms: long/long, long/short, short/long or short/short. In the long/long arm, mothers received zidovudine from 28 weeks of gestation and during labor, while their infants received zidovudine every six hours for the first six weeks of life. In the short/short arm, maternal dosing began at 35 weeks of gestation and the infants dosing was shortened to three days. The other two arms were combinations of these long or short regimens. The transmission rate in the short/short arm was significantly higher (10.6%) than in the arms containing long courses of zidovudine (5.7-8.4%), suggesting that ultra short courses of zidovudine were less effective than longer courses. Only 1% of infants born to women who received zidovudine from 28 weeks of gestation were infected at birth, compared with 5.1% of infants born to women who received zidovudine from 35 weeks of gestation, suggesting that in utero transmission occurs predominantly in the last trimester of pregnancy.
Several other similar studies have been conducted in the developing world using short course regimens of zidovudine (21,22). The results of these studies demonstrated that the HIV transmission rate was lower in the zidovudine arms than the control groups. The PETRA study compared three different regimens of zidovudine/lamivudine with placebo (23,24). The HIV transmission rate was significantly reduced when the drugs were given to women in late gestation (arm 1) or at the onset of labor (arm 2) and to the infant for one week after birth. No decrease in transmission was seen when drugs were only given to the mother during labor (arm 3).
The HIV Network for Prevention Trials (HIVNET) 012 study was conducted in Uganda (25,19). Mothers were randomized to receive either zidovudine or a single dose of nevirapine (200 mg) during labor. Infants born to women who received nevirapine also received a single dose of nevirapine (2 mg/kg) within 72 hours of birth. The zidovudine regimen was more complex. Mothers received 600 mg zidovudine at the beginning of labor and then 300 mg every 3 hours. Their infants received 4 mg/kg twice a day for seven days post birth. The rate of HIV-1 infection in the babies at 12 months post birth was 13% and 25% in the nevirapine and zidovudine arms, respectively. This represented a 42% reduction in the transmission rate of HIV-1. The nevirapine regimen is simple, practical and can be administered easily in existing healthcare facilities in many developing countries.
The South African Intrapartum Nevirapine Trial (SAINT) was similar in design to the HIVNET 012 study except that mothers received a second dose of nevirapine during the first few days post delivery (26). The rationale for the second dose was to protect their infants from infection during early breastfeeding, when the risk of transmission is high. In the comparator arm, mothers received zidovudine and lamivudine prepartum, peripartum and postpartum, while their infants received zidovudine/lamivudine for one week after delivery. Excluding infections that occurred during pregnancy (in utero), the rate of HIV infection or death at 56 days post birth was similar for infants in both the nevirapine (12.3%) and zidovudine/lamivudine (9.3%) arms. It was possible to evaluate the impact of the ARV interventions on the intrapartum infection rate, as 55% of the women in the SAINT study formula fed their infants. In the nevirapine arm, there was a twofold-increased odds of HIV infection rate during the first four weeks postpartum. Furthermore, the risk of infection via breastfeeding was cumulative. During the first 4-8 weeks of follow-up, the risk of infection increased in infants that were breastfed to approximately 7× higher than that for formula-fed infants (26).
A number of effective, low-cost interventions with minimal adverse effects that can reduce MTCT of HIV are therefore available. Many of these involve short courses of ARV prophylaxis and incorporate nevirapine (Table 2). However, successful ways to reduce transmission during breastfeeding are still required in resource-limited countries.
Widespread ARV use has also been associated with increased ARV drug resistance. This has raised concerns that drug resistance may reduce the effectiveness of perinatal ARV prophylaxis as well as therapeutic intervention strategies (27). Reduced susceptibility to ARV drugs is due to the presence of viral mutations; for example, the most important mutations associated with resistance to nevirapine are K103N and Y181C. The PACTG 316 study investigated whether such mutations were present in isolates obtained from pregnant women given nevirapine prophylaxis (28). Viral isolates were obtained at baseline and at 6 weeks postpartum from women who had pVLs >400 copies/mL. The proportion of isolates carrying mutations associated with reduced susceptibility to ARV drugs at baseline was considerable. Fifty-five percent of the isolates had mutations that are associated with reduced susceptibility to nucleoside reverse transcriptase inhibitors (NRTIs); 45% of these isolates carried the M184V mutation. Only 1% of isolates had a mutation (Y181C) associated with reduced susceptibility to NNRTIs. Furthermore, mutations associated with reduced susceptibility to protease inhibitors (PIs) were observed in a significant proportion of isolates (16%). Postpartum, the proportion of isolates with mutations exhibiting reduced susceptibility to NNRTIs had increased: isolates from 11% of the mothers assigned to the nevirapine arm carried these mutations compared with 2% from the control arm.
Viral isolates were also obtained from women who had taken part in the HIVNET 012 study (29). Mutations associated with reduced susceptibility to NNRTIs were identified in 18% of samples obtained 6-8 weeks after nevirapine administration. The most common mutation was K103N, but it was not detected 12-24 months after receiving the single dose of nevirapine.
These limited and preliminary data suggest that mutations associated with reduced susceptibility to NNRTIs can emerge following a single intrapartum dose of nevirapine, but may not be detected 24 weeks after administration of that single dose. To date, the clinical consequences of the transient selection of nevirapine resistant viral strains are uncertain. However, there is no evidence that the presence of these mutations is associated with an increased risk of transmission of HIV-1 to the infant. Studies are ongoing to determine if the presence of these mutations has implications for subsequent administration of nevirapine, either to prevent MTCT of HIV-1 or for the mother's own health.
PERINATAL TRANSMISSION: FUTURE OPTIONS TO PREVENT TRANSMISSION THROUGH BREAST MILK
As discussed earlier, breastfeeding is a key route for the transmission of HIV infection from mother-to-child worldwide (2). However, in many settings in the developing world, the increase in infant mortality and morbidity associated with the use of formula food could outweigh any reduction in the risk of HIV-1 transmission. There is an urgent need, therefore, to develop a method for protecting infants from HIV infection during breastfeeding, particularly in the developing world.
One possibility is to administer nevirapine chronically throughout the lactation period (breastfeeding). It is hoped that the antiviral effect of nevirapine would enable infants to benefit from breastfeeding without incurring the risk of MTCT of HIV-1. Studies, such as HIVNET 023, are therefore in progress to evaluate the feasibility of administering an ARV drug or drugs to breastfed infants on a once daily or periodic basis, and to evaluate delivery of an ARV drug via a slow release device. An additional option that is in the early stages of research is to immunize infants actively against HIV using a preventative vaccine.
MTCT of HIV is a major problem worldwide and breastfeeding is a key route of transmission. This was highlighted in the PETRA study, where the initial efficacy of ARV prophylaxis was reduced by factors such as breastfeeding. However, the results from studies involving ARV prophylaxis to prevent MTCT, such as HIVNET 012 and SAINT, are very encouraging, particularly as they included breastfeeding populations within the cohorts (30). Furthermore, despite the differences in study populations and regimens used, the data supporting the use of nevirapine in MTCT are comparable across studies.
However, further research and trials are required to provide evidence of effective prevention of MTCT, particularly if we are to succeed in UNAIDS' aim to reduce the proportion of infants infected with HIV by 50% before 2010. It is also essential to continue, in both the developed and developing world, to monitor the adverse effects of ARV drugs, and the emergence of ARV resistance in the setting of MTCT prevention. Further research is ongoing to determine whether administration of a single dose of nevirapine to mothers for prevention of MTCT affects their ability to respond to NNRTI-based regimens that would be given for treatment of their own HIV infection or to prevent MTCT of HIV-1 in subsequent pregnancies.
Finally, any regimen that prevents MTCT only has a limited effect if the infant survives but the mother dies due to AIDS. Infants born to untreated, HIV-infected women have a lower survival rate than those born to noninfected women, regardless of their own infection status. It is therefore essential not only to advance research into the prevention of MTCT but also to extend triple-combination ARV treatment to all HIV-positive mothers worldwide. The infrastructure, which is currently being developed for the prevention of MTCT, could be utilized for the delivery of ARV therapy to mothers, in order to protect the health of the next generation of children.
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This publication has been made possible by an educational grant from Boehringer Ingelheim.