Preventing Mother-to-Child Human Immunodeficiency Virus Transmission
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Human immunodeficiency virus (HIV) is a scourge which continues to fatally wound the physical, cultural, social, economic, political, and spiritual health achievements, hopes and aspirations of individuals, families, communities and nations. It is probably an established phenomenon that does not need much debate. 2011 marks the 30th anniversary of the first report of HIV, which came from the United States, where cases of an unusual disease were seen among young gay men. Since the beginning of the epidemic, more than 60 million people have been infected with HIV and nearly 30 million people have died of HIV-related causes. One in four acquired immunodeficiency syndrome (AIDS) deaths is caused by tuberculosis -- a preventable and curable disease. Thirty years later, the location and pace of the epidemic has changes dramatically. Globally, an estimated 33.3 million people are infected or living with HIV at present, of which 22.5 million are in sub-Saharan Africa. In addition, of the 2.5 million children in the world estimated to be living with HIV, 2.3 million are in sub-Saharan Africa. Southern Africa, the most affected region, includes a number of middle- and lower-income nations known as the hyperendemic countries. In South Africa alone, there are about 5.7 million people living with HIV/AIDS. In Swaziland, 42% of women attending antenatal clinics are infected, with similar rates found elsewhere in the region (1). Many children are affected by the disease in a number of ways: they live with sick parents and relatives in house-holds drained of resources due to the epidemic, and those who have lost parents are less likely to go to school or continue with their education. Over the past 20 years, there has been tremendous progress in the reduction of mother-to-child transmission (MTCT) of HIV in the United States and other countries.
The purpose of this article is to review evidence of the prevention of mother-to-child transmission (PMTCT) of HIV through cesarean delivery before labor and before ruptured membranes, the evolution of recommendations regarding the mode of delivery for HIV-infected women, trends in the mode of delivery for HIV-infected women, and the associated risks and cost-effectiveness of cesarean delivery for the prevention of MTCT of HIV. Finally, we summarize unanswered questions regarding the role of cesarean delivery among HIV-infected women. The current and planned research trials on strategies to prevent breastfeeding transmission of HIV from mother to infant worldwide are also discussed.
In June of 1981, a description of the first cases of what are now called AIDS was published in morbidity and mortality weekly report (MMWR)(2). That report established the Center for Disease Control and Prevention's (CDC) reputation for tracking the epidemic, a reputation that has since solidified and expanded. In the first years of epidemic affected gay males, but later, drug users and members of minority groups joined them. Since the early 1980s, there have been those who saw AIDS as a reason to discriminate, and others who saw it as a reason to fight discrimination. Today, people in both developed and developing countries and in every social class are infected. In fact, the spread of HIV in general, and MTCT transmission of HIV, in particular, has bifurcated into two unique epidemics; one in countries with access to highly active therapies, and a much larger one in parts of the world where access to treatment is sporadic at best. The message reflected in the surveillance data from the United States is clear. Remarkable advances have already occurred and, from the perspective of MTCT of HIV, further progress may focus on simplifying protocols as much as amplifying benefits. It is also time to expand and expedite peripartum rapid testing for women with no prenatal care (3). These women are at particularly high risk, and as more and more women with regular care are identified, they are disproportionately bear children in the United States who acquire HIV at birth. The story in developing countries is more complex and more desperate. The infusion of $ 15 billion over 5 years through the President's Emergency Plan for AIDS Relief program (even with some potentially counterproductive earmarks) presents many opportunities to bring treatments to locales that heretofore had minimal access.
The UNAIDS 2010 report on the Global AIDS Epidemic emphasizes that efforts to promote universal access to HIV prevention, treatment, care and support services require a sharper focus on women and girls. The new UNAIDS strategy (2011-2015) emphasizes that meeting the HIV needs of women and girls and calling for zero tolerance for gender based violence are essential to advancing global progress toward universal access to HIV prevention, treatment, care and support and to halting and reversing the spread of HIV, thus contributing to the achievement of the Millennium Development Goals (MDGs) by 2015. The HIV epidemic has taken a devastating toll on the lives of young women, who account for 66% of infections among young people worldwide (1). It is the leading cause of death and disease among women of reproductive age (15-49 years) worldwide. One half of people living with HIV globally are women and 76% of all HIV-positive women live in sub-Saharan Africa (1). Women living with HIV are more likely to experience violence due to their HIV status. Globally, up to 90% of the care due to illness is provided in the home by women and girls (Global Coalition on Women and AIDS, 2004). Women account for two thirds of all caregivers for people living with HIV in Africa; women also comprise 70% of the world's poor and two-thirds of the world's illiterate (UNAIDS 2008: Report on the Global AIDS Epidemic, Executive Summary).
U.S. Experience in Reducing Risk of Mother-to-Child HIV Transmission
In the global HIV pandemic, prevention of MTCT in the United States and Europe has been one of the major success stories, such that transmission rates of less than 2% have been achieved (4). Prior to effective perinatal HIV interventions, about 1 in 4 babies born to HIV-infected women became infected; whereas today an HIV-infected pregnant woman in the United States or Europe receiving highly active antiretroviral therapy (HAART) and with an undetectable viral load has only about 1-2% of transmitting HIV to her infant (4). To reduce the incidence of HIV infection, CDC announced a new initiative, Advancing HIV Prevention (AHP), in 2003 (5). This initiative comprises 4 strategies: making HIV testing a routine part of medical care, implementing new models for diagnosing HIV infections outside medical settings, preventing new infections by working with HIV-infected persons and their partners, and further decreasing perinatal HIV transmission. In 2006, CDC published "Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Settings" (6). To further reduce the number of children who are infected with HIV perinatally, these recommendations called for routine opt-out HIV screening for all pregnant women, with repeat HIV screening in the third trimester for women who meet 1 or more of 4 criteria (for example, women at high risk and women who receive health care in jurisdictions with elevated rates of HIV infection among women). Women whose HIV status is unknown at the time of labor should be offered opt-out screening with a rapid HIV test.
Opt-out HIV testing: women are told that an HIV test will be included in the standard group of prenatal tests but that they may decline HIV testing.
Opt-in HIV testing: women are provided pretest counseling and must specifically consent to an HIV test.
For pregnant women current recommendations are (6):
In the United States, a major break-through in PMTCT occurred in 1994 with the announcement of the Pediatric AIDS Clinical Trial Group Protocol 076 (PACTG 076) results (7). This double-blinded, randomized, placebo-controlled trial, which included and intensive regimen of oral zidovudine (ZDV) given prenatally, intrapartum, and postpartum. It decreased perinatal transmission risk by two-thirds when compared with placebo. Based on these findings, the US Public Health Task Force quickly recommended that all pregnant women should be offered HIV testing and that those women who were identified as HIV infected should be given ZDV according to the PACTG 076 regimen. Widespread implementation of these recommendations (5) led to sharp decreases in perinatal HIV transmission. Furthermore, since the late 1990s, most HIV-infected women in the United States have been prescribed combination regimens, which further reduced the risk (8). The Mother-Infant Rapid Intervention at Delivery (MIRIAD) study attempted to reach the women with unknown HIV status by demonstrating that rapid HIV testing in labor and delivery units was feasible, acceptable and accurate. Based on the rapid test results, peripartum antiretroviral interventions to reduce the risk of transmission were successfully provided (9). The use of opt-out strategy has now been expanded by the CDC in 2006 to include routine HIV testing in health care facilities among all adults and adolescents as well as pregnant women in all antenatal settings and those women at labor/delivery whose HIV status is still unknown (6). The dramatic success in reducing perinatal HIV transmission to less than 2% across the United States was due in large part to the rapid translation of research trial findings into practice.
HIV Counseling and Testing
Between 1 million and 1.2 million individuals in the United States are estimated to be living with HIV or AIDS (10). Women represent the fastest-growing group of individuals with new HIV infections. Many women who are infected with HIV are not aware of their serostatus. The tension between competing goals for HIV testing -- testing broadly in order to treat the maximum number of women infected with HIV and, if pregnant, to protect their newborns, and counseling thoroughly in order to maximally protect a woman's autonomy and right to participate in decision making -- has sparked considerable debate. The major ethical principles that must be considered when formulating policies for HIV counseling and testing include respect for autonomy, confidentiality, justice, protection of vulnerable individuals, and beneficence to both the woman tested and, if she is pregnant, to her newborn as well. Individuals offering testing need to be mindful not only of the benefits of testing but also its potential risks because, if a woman's test result is positive, she faces the possibility of being ostracized by her family, friends, and community or being subjected to intimate partner violence. In addition, although the overt stigma of HIV infection has been reduced over the past 20 years, the potential for job discrimination, loss of health insurance, and loss of housing still exists.
Over time, three potential strategies for HIV testing have been considered by public health and public policy officials: 1) universal testing with patient notification and right to refusal, also called "opt-out" testing; 2) voluntary testing with pretest counseling regarding risks and benefits, also called "opt-in" testing; and 3) mandatory testing with no right to refusal. In order to understand their ethical merits, each is considered briefly in the sections that follow (11). Increasingly, national organizations and federal agencies have recommended opt-out testing in preference to other strategies.
Right to Refusal -- Opt-out Testing: It removes the requirement for pretest counseling and detailed, testing-related informed consent. Under the opt-out strategy, physicians must inform patients that routine blood work will include HIV testing and that they have the right to refuse this test. The goal of this strategy is to make HIV testing less cumbersome and more likely to be performed by incorporating it into the routine battery of tests (e.g., the first trimester prenatal panel or blood counts and cholesterol screening for annual examinations). This testing strategy aims to balance competing ethical considerations. Refusal of testing should not have an adverse effect on the care the patient receives or lead to denial of health care. This guarantee of a right to refuse testing ensures that respect for a woman's autonomy is not completely abridged in the quest to achieve a difficult-to-reach public health goal (11).
Voluntary Testing -- Opt-in Testing: Voluntary testing with counseling is the strategy most consistent with respect for patient autonomy. Under this option, physicians provide both pretest and posttest counseling. Some physicians may perform such counseling themselves, whereas others may prefer to refer the patient for counseling and testing. Patients should be told what information will be communicated and to whom and the possible implications of reporting the information. This approach to testing maintains HIV's status as being in a class by itself (suigeneris), even as many ethicists have acknowledged the end to the exceptionalism that marked this disease in the early years of the epidemic (12).
Mandatory Testing with No Right of Refusal: Mandatory testing strategies are problematic because they abridge a woman's autonomy. In addition, during pregnancy, the public health objective of this strategy, identification of women who are infected with HIV who will benefit from treatment, has been accomplished in certain populations by other ethically sound testing strategies noted previously (13). Some see mandatory testing as a more efficient way of achieving universal testing. Mandatory prenatal testing is difficult to defend ethically and has few precedents in modern medicine, although HIV testing of newborns is now required in New York, Connecticut, and Illinois (there are provisions, however, that permit refusal in a few defined circumstances) (14). Importantly, mandatory testing may compromise the ability to form an effective physician-patient relationship at the very time when this relationship is critical to the success of treatment.
Prenatal HIV Testing: All pregnant women should be screened for HIV infection as early as possible during each pregnancy after they are notified that HIV screening is recommended for all pregnant patients and that they will receive an HIV test as part of the routine panel of prenatal tests unless they decline (opt-out screening). The American College of Obstetricians and Gynecologists (ACOG), American Academy of Pediatrics (AAP), and the Centers for Disease Control and Prevention (CDC) recommend opt-out HIV screening for pregnant women (6). Since the release of CDC recommendations in September 2006 (6), some states have changed their state laws and regulations to opt-out screening. Legal requirements for perinatal HIV testing may be verified by contacting state or local public health departments. The CDC recommends that jurisdictions with barriers to routine prenatal screening using opt-out screening consider addressing them (5).
Perinatal HIV Testing
The conventional HIV testing algorithm, which may take up to 2 weeks to complete if a result is positive, begins with a screening test, the enzyme-linked immunosorbent assay (ELISA) that detects antibodies to HIV; if the results are positive, it is followed by a confirmatory test, either a Western blot or an immunofluorescence assay (IFA). A positive ELISA test result is not diagnostic of HIV infection unless confirmed by the Western blot or IFA. The sensitivity and specificity of ELISA with a confirmatory Western blot test are greater than 99% (15). The false-positive rate for ELISA with a confirmatory Western blot test is 1 in 59,000 tests (15). If the ELISA test result is positive and the Western blot or IFA test result is negative, the patient is not infected and repeat testing is not indicated. If ELISA test result is repeatedly positive and the Western blot result contains some but not all of the viral bands required to make a definite diagnosis, the test result is labeled indeterminate. Most patients with indeterminate test results are not infected with HIV. However, consultation with a healthcare provider well versed in HIV infection is recommended. The specialist may suggest viral load testing or repeat testing later in pregnancy to rule out the possibility of recent infection. If the screening (e.g. ELISA) and confirmatory test (e.g. Western blot or IFA) results are both positive, the patient should be given her results in person. The implications of HIV infection and vertical transmission should be discussed with the patient. Additional laboratory evaluation, including CD4 count, HIV viral load, resistance testing, hepatitis C virus antibody, hepatitis B surface antigen, complete blood count with platelet count, and baseline chemistries with liver function tests, will be useful before prescribing antiretroviral prophylaxis.
A rapid HIV test is an HIV screening test with results available within hours. Obstetricians and gynecologists may use rapid testing as their standard outpatient test. A negative rapid test result is definitive. A positive rapid test result is not definitive and must be confirmed with a supplemental test, such as a Western blot or IFA test. Rapid test results usually will be available during the same clinical visit that the specimen (e.g. blood or oral swab) is collected. Healthcare providers who use these tests must be prepared to provide counseling to pregnant women who receive positive rapid test results the same day that the specimen is collected. Pregnant women with positive rapid test results should be counseled regarding the meaning of these preliminary positive test results and the need for confirmatory testing. As with conventional HIV testing, consultation with a healthcare provider well versed in HIV infection is recommended. Any woman who arrives at a labor and delivery facility with undocumented HIV status should be screened with a rapid HIV test unless she declines (opt-out screening) in order to provide an opportunity to begin prophylaxis of previously undiagnosed infection after delivery (15). Data from several studies indicate that 40%-85% of infants infected with HIV are born to women whose HIV infection is unknown to their obstetric provider before delivery (16). If a rapid test in labor and delivery is used and antibodies for HIV are detected, immediate initiation of antiretroviral prophylaxis should be recommended without waiting for the results of the confirmatory tests to further reduce possible transmission to the infant. All antiretroviral prophylaxis should be discontinued if the confirmatory test result is negative (16).
The rapid HIV antibody screening tests, which are approved by the U.S. Food and Drug Administration (FDA), all have sensitivity and specificity equal to or greater than 99% (17). As with all screening tests, the likelihood of a false-positive result is higher in populations with low HIV prevalence when compared with populations with high HIV prevalence. Additionally, at present it is not known how the false-positive rate for rapid testing will compare with the false-positive rates for conventional testing. If the rapid HIV test result at labor and delivery is positive, the obstetric provider should take the following step (15):
Repeat HIV Testing in Third Trimester
Repeat testing in the third trimester should be considered in jurisdictions with elevated HIV or AIDS incidence and in healthcare facilities in which prenatal screening identifies at least one HIV-infected pregnant woman per 1,000 women screened (6)(15). Additionally, although physicians need to be aware of and follow their state's perinatal HIV screening requirements, repeat testing in the third trimester, preferably before 36 weeks of gestation, is recommended for pregnant women at high risk for acquiring HIV.
Criteria for repeat testing can include:
Women who are candidates for third-trimester testing, including those who declined testing earlier in pregnancy, should be given a conventional or rapid HIV test rather than waiting to receive a rapid test at labor and delivery (as allowed by state laws and regulations).
Community-Based Interventions for Women of Color: Among women of color in USA, adolescent girls are at high risk of HIV infection. In a recent CDC report, among African-American adolescents across 33 states aged 13-24 years in whom HIV/AIDS is diagnosed, approximately 41% are female (18). In a randomized controlled trial that evaluated efficacy of an HIV prevention intervention among sexually experienced African-American adolescent girls, it was found that a gender-tailored and culturally appropriate intervention can enhance HIV-preventive behavior and skills, such as knowledge, attitudes, and partner communications (19). In another randomized controlled trial it was found that skill-based HIV and sexually transmitted diseases (STDs) interventions can reduce sexual risk-taking behavior and rates of STDs among African-American and Latino adolescent girls in clinic settings (20). Despite these findings, more intensive interventions and research designed specifically for African-American and Latino adolescents that demonstrate efficacy in reducing behavior associated with HIV risk in USA are necessary. Behavioral interventions targeting adult women of color are crucial to decrease rates of morbidity and mortality from HIV and AIDS.
Several approaches can reduce the rate of HIV infection in women of color:
A combination of testing, education and brief behavioral interventions can help reduce the rate of HIV infection and its complications among women of color.
Mode of Delivery for HIV-Infected Women
Over the past 20 years, there has been tremendous progress in the reduction of MTCT of HIV-1 in the United States and other countries. This decrease in MTCT of HIV-1 is temporally related to an increase use of antiretrovirals (for prophylaxis or for treatment) during pregnancy and in delivery by cesarean before labor and before ruptured membranes (elective cesarean delivery). The European mode of delivery trial randomized HIV-1-infected women to delivery at 38 weeks to avoid the onset of labor and successfully halved the risk of MTCT (21). Based on the results of this trial and of an individual patient data meta-analysis of prospective cohort studies in North America and Europe (22), both the American College of Obstetricians and Gynecologists (ACOG) and the U.S. Public Health Service have issued guidelines indicating that elective cesarean delivery is recommended for HIV-1-infected pregnant women with peripheral blood viral loads greater than 1,000 copies/mL irrespective of antiretroviral regimen (23). From 1994 to 2000, cesarean delivery rates increased among HIV-1-infected women in the United States from 20% to 50%. Data from the European Collaborative Study suggest there may be some benefit of elective cesarean delivery even in pregnancies in which the viral load is undetectable (200 copies/mL or lower, depending on clinical assay) (24). In a recent report from Sweden, the cesarean delivery rate for HIV-infected women increased from 8% in 1985-1993 to 44% in 1994-1998 and to 80% in 1999-2003 (25). These higher rates may reflect a more aggressive policy of offering cesarean delivery to all women, regardless of viral load. Elective cesarean delivery is likely to remain an important tool in the prevention of MTCT of HIV-1 in the United States and elsewhere.
Associated risks and cost effectiveness of cesarean section delivery for the preventions of the MTCT of HIV: In weighing the risks and benefits of elective cesarean delivery, the benefit of the prevention of MTCT must be carefully weighed against any increase of morbidity or mortality for either the woman or her infant, as well as increased costs and recovery time. A number of studies have addressed the question of whether HIV-infected women have higher post-cesarean complication rates compared with HIV-uninfected control subjects. Most studies demonstrate an increased risk of postoperative morbidity, mostly infectious, in HIV-infected women compared with uninfected control subjects, and the risk of complications is correlated with the degree of immunosuppression (26). However, from a clinical perspective, the pertinent question is whether elective cesarean delivery increases an HIV-infected woman's risk of complications compared with a vaginal delivery or with a non-elective cesarean delivery. Six studies that address this issue were recently summarized in a Cochrane review (27). This review concluded that, among HIV-infected women, non-elective cesarean delivery was associated with the highest rate of postpartum morbidity that elective cesarean delivery was intermediate in risk, and that vaginal delivery had the lowest risk of morbidity. Much of the postpartum morbidity was relatively minor, including postoperative fever, anemia, endometritis, and wound infection. Maternal deaths are rare, and these studies did not have adequate sample size to assess potential differences in maternal mortality rates. Although short-term postoperative morbidity may be increased among HIV-infected women, it does not appear that mode of delivery is associated with more long-term effects, such as subsequent HIV disease progression (28). In resource-limited settings, there are limited data to suggest that the risks of postpartum morbidity and mortality rates among HIV-infected women who undergo cesarean delivery may be magnified. In addition, there may be inadequate resources available to provide cesarean deliveries for all HIV-infected women in settings of high HIV sero-prevalence pregnant women.
Another related unanswered question is whether there is any benefit of elective cesarean delivery in the prevention of MTCT of HIV among women who receive combination antiretroviral regimens, including highly active antiretroviral therapy (HAART). Both the randomized clinical trial and the individual patient data meta-analysis included mostly women who were receiving either no antiretrovirals or zidovudine only (29). Because the risk of transmission already is reduced substantially for women who take HAART prenatally (i.e. 1%-2% transmission rate) (30), a study with a very large sample size would be needed to detect a further reduction in transmission because of elective cesarean delivery. However, there are some studies that shed some light on the issue of whether elective cesarean delivery confers additional benefit among women with low viral loads while receiving HAART. Another unanswered clinical question is how soon after the onset of labor or the rupture of membranes that the benefit of cesarean delivery is lost. Although early studies dichotomized the length of membrane rupture and found that rupture of membranes for >4 hours was associated with a nearly 2-fold increase in transmission rate (27), a subsequent individual patient data meta-analysis demonstrated a continuously increasing risk of MTCT, with the transmission risk increasing approximately 2% for every additional hour of ruptured membranes (31). Therefore, how does one counsel a woman who planned for an elective cesarean delivery but who arrives in early labor or shortly after rupture of membranes? In such situation, if a long period of labor is anticipated, some clinicians may choose to proceed with cesarean delivery; others may choose to proceed with an expedited vaginal delivery. What about the case of HIV-infected woman with a high viral load who arrives with preterm labor or with premature rupture of membranes? In these cases, the preferred mode and timing of delivery should be individualized on the basis of the specific clinical situation.
Current Recommendations for Mode of Delivery
The U.S. Public Health Service guidelines for HIV-1-infected pregnant women recommend that cesarean delivery be done at 38 weeks of gestation by best estimated gestational age without amniocentesis. The guidelines point out that although there is a substantial increase in the risk of infant respiratory distress syndrome with earlier deliveries, this increased risk must be balanced with the risk of onset of labor or rupture of membranes before 39 weeks of gestation (32). The risk of respiratory morbidity with elective cesarean delivery is directly correlated with gestational age, with neonates delivered at 39 weeks or greater having rates that more closely approximate the rate with vaginal delivery. The ACOG recommends that elective cesarean delivery be performed at 39 completed weeks of gestation or later to avoid iatrogenic prematurity but recommends that cesarean delivery for prevention of MTCT of HIV-1 be performed at 38 completed weeks to avoid the onset of labor and rupture of membranes (11). The International Maternal Pediatric, and Adolescent AIDS Clinical Trials Network (IMPAACT) Protocol 1025 (formerly PACTG 1025) is an ongoing, multicenter observational cohort study of HIV-1-infected pregnant women in the United States and Puerto Rico. A recent study estimated risk of infant respiratory morbidity associated with cesarean delivery before labor and ruptured membranes among HIV-1-infected women (33). The conclusion was respiratory distress syndrome (RDS) rates associated with elective cesarean delivery among HIV-1-infected women are low, comparable with published rates among uninfected women. There is minimal neonatal respiratory morbidity risk in near-term infants born by elective cesarean delivery to HIV-1-infected women (33).
Although HIV-infected pregnant women, cesarean delivery before labor and before the rupture of membranes has been shown to be safe and effective in reduction of MTCT of HIV. However, benefits of cesarean delivery in preventing MTCT of HIV must be weighed against potential increases in maternal and infant morbidity and the costs of cesarean delivery. In the United States, the benefits of cesarean delivery for women with viral loads of >1000 copies/mL generally outweigh the increased risk of minor postoperative morbidity. However, a number of important unanswered questions remain, such as how soon after labor onset or rupture of membranes the benefit of cesarean delivery has a role in women with low HIV viral loads while receiving HAART. Furthermore, the appropriate role, if any, of elective cesarean delivery among HIV-infected women in various resource-limited settings with variable degrees of medical infrastructure and HIV prevalence rates will need to be better defined, particularly given the expanding availability of HAART in these settings.
Prevention of HIV-1 Transmission to Infant through Breastfeeding
Currently about 800,000 children become infected with HIV-1 every year through MTCT; 90% of these children live in resource-limited countries (1). Breastfeeding transmission accounts for about one third to one half of all HIV transmission from mother to their infants in resource-limited settings in which breastfeeding into the second year of life is the norm (34). A number of studies have documented the risk of transmission per month of breastfeeding and cumulative risk after the first 1-2 months of age. Data from Malawi found the risk of 0.6-0.7% per months 1 to 12 and 0.3% per month in the second year of lactation (34). Some studies suggested that the highest risk of breast milk transmission of HIV is in the immediate neonatal period. A more recent meta-analysis suggested a more constant risk of about 0.9% per month after the first month of life (35). There is limited information on risk of transmission during the early weeks of life, due in part to the difficulty in differentiating early breast milk transmission from intrapartum transmission. Risk factors for postnatal transmission include: higher deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) viral load in milk and plasma; decreased maternal CD4 cell count; increased maternal illness severity, mastitis and breast milk stasis; thrush and other infant co-infections; type of infant feeding (exclusive breastfeeding versus mixed feeding); longer duration of breastfeeding; and maternal seroconversion or HIV-1 superinfection during lactation (36).
Biology of Breastfeeding Transmission of HIV to the Infant
Virology: HIV is detected in both the liquid phase of breast milk and in breast milk cells. Free virus can be derived from blood, or it can be produced by local replication in macrophages and in ductal and alveolar mammary epithelial cells. Evidence of HIV compartmentalization between blood and breast milk has been conflicting. HIV is detected in the breast milk of HIV-infected mother at varying frequencies across studies (39%-89%) (36). Recently, a 3-fold increase in transmission was demonstrated for every 10-fold increase in cell-free or cell-associated viral load in breast milk; however, no lower threshold for transmission could be determined. Cell-associated virus was found to be a stronger predictor for HIV transmission to the infant than cell-free virus (37). Recent evidence also indicates that HAART, started during pregnancy or postpartum, suppresses HIV RNA, but not DNA (37). In fact, part of the efficacy of the peripartum single-dose nevirapine (sdNVP) regimen may be attributable to its effects in lowering breast milk viral loads early during lactation. Emerging data on pharmacokinetics of antiretroviral agents in breastfeeding mothers indicate that nevirapine (NVP), zidovudine (ZDV), and lamivudine (3TC) achieve HIV inhibitory concentrations in the breast milk (similar or higher than those of serum) and that NVP in addition achieves inhibitory concentrations in the serum of breastfed infants (38). The data suggest that a maternal regimen may be sufficient to provide prophylaxis from breastfeeding transmission to the infant but also that adverse effects of antiretroviral therapy (toxicities, development of resistance) could theoretically be seen among breastfed infants exposed to them.
Immunology: Breast milk contains a multitude of antimicrobial and immunomodulatory factors, including lactoferrin, lysozyme, fibronectin, mucin, lipids, epidermal growth factor, interleukin, transforming growth factor, secretory leukocyte protease inhibitor, defensins, adhesion molecules, selectins, and chemokines. These soluble factors have diverse effects on HIV; some have in vitro anti-HIV activity and others have pro-inflammatory activity that might promote local HIV replication. HIV-specific antibodies have been detected in the breast milk of HIV-infected mothers, predominantly of the immunoglobin (Ig) G isotype (39). Often the specificity of IgG and IgA HIV antibodies in the breast milk differs from that of antibodies in the serum of the same person (39). Recent findings indicate that HIV virions captured by dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) may be transmitted more efficiently through the gastrointestinal tract, suggesting a role in transmission to the infant (40).
Role of mucosal factors: Two nonrandomized studies from southern Africa have suggested that type of infant feeding has a substantial effect on risk of postnatal HIV transmission from mother to their infants (41). Both studies presented observational data suggesting that exclusive breastfeeding is associated with a lower risk of transmission than mixed feeding (breastfeeding and other liquids or solids) among HIV-infected mothers. This study found that in South Africa, at 6 month of age, there was a substantially lower risk of transmission among infants who had been exclusively breastfed during the first 3 months, compared with infants who had received mixed feeding. Recent data from the Zvitambo trial in Zimbabwe found that exclusive breastfeeding in the first 3 months of life was associated with only a 1.3% risk of transmission from 6 weeks to 6 months, which is significantly lower than the transmission risk of 4.4% associated with mixed feeding (41). Possible explanation for this finding include damage to the intestinal mucosa from early introduction of other foods, leading to the delayed closure of the enterocyte junctions in the intestinal mucosal barrier or intestinal immune activation from early introduction of foreign antigens or pathogens, both mechanisms that can enhance transmission of HIV to the infant. Infrequent breast emptying, such as might occur with nonexclusive breastfeeding, may increase the risk of ductal inflammation and mammary permeability and may also lead to sub-clinical mastitis and a higher risk of HIV transmission to the infant.
Current Recommendations of Breastfeeding in Resource-Limited Settings
Prevention of HIV transmission through breastfeeding should be considered against a backdrop of promoting appropriate feeding for all infants and young children. According to current World Health Organization (WHO) recommendations, infants should be exclusively breastfed for the first 6 months of life to achieve optimal growth, development, and health. Thereafter infants should receive nutritionally adequate and safe complementary foods while breastfeeding continues up to 24 months or beyond. However, given the need to reduce the risk of HIV transmission to infants and minimizing the risk of other causes of morbidity and mortality, the guidelines also state that "when replacement feeding is acceptable, feasible, affordable, sustainable, and safe, avoidance of all breastfeeding by HIV-infected mothers is recommended. Otherwise, exclusive breastfeeding is recommended during the first months of life" and should then be discontinued as soon as it is feasible. This would normally imply the same conditions as for replacement feeding from birth, that is, acceptable, feasible, affordable, sustainable, and safe.
For most HIV-infected mothers in resource-limited settings, breastfeeding remains the only feasible and sustainable option, given a societal context of unsafe water and unsanitary or nutritionally deficient home-modified animal milk substitutes, cultural norms for mothers to breastfeed with the risk of stigmatization if not breastfeeding, and prohibitive costs of breast milk substitutes. For an individual HIV-infected mother, balancing risks and benefits is complex. Mothers should receive counseling that includes information about both the risks and benefits of various infant feeding options based on local assessment and guidance in selecting the most suitable option for their situation. The above recommendations on infant feeding and HIV are the same, whether or not the women receive antiretroviral regimens for their own health. Women receiving antiretroviral drugs for their own health who are breastfeeding should continue their antiretroviral regimen. Currently WHO recommended antiretroviral prophylactic regimens for women who do not need HAART for their own health are based on a short antepartum, intrapartum, postpartum, and postnatal component. The short postpartum and postnatal components are mainly designed to reduce the risk of developing maternal resistance to sdNVP and as a post-exposure prophylaxis regimen for the child.
Approaches to Decrease Mother-to-Child HIV Transmission during Breastfeeding
Exclusive replacement (formula) feeding is the most widely used and effective method to prevent MTCT of HIV-1 through breastfeeding in resource-rich settings and is recommended in situations in which this is acceptable, feasible, affordable, sustainable, and safe. In the United States, obstetricians/gynecologists counsel their HIV-infected patients not to breastfeed and to use formula feeding instead. However, in many resource-constrained settings, the above conditions are rarely all met. Based on findings from the studies mentioned above, exclusive breastfeeding for a few (3-6 months) with rapid weaning has been advocated as a strategy that balances optimal nutritional source for the infant's first few months of life with lessening the risk of MTCT of HIV. This approach is currently being evaluated in a number of clinical trials. Recently concerns have arisen that early weaning of HIV-exposed infants may increase infant morbidity and mortality. Two studies from Malawi and Kenya have noted spikes in gastroenteritis in the 2-3 months following weaning at around 6 months of age, and the Kenya study has also noted increased rates of failure to thrive and growth faltering of infants following weaning (42). Results from the MASHI study (42) demonstrated a near doubling of infant mortality at 7 months in infants who were formula fed from birth when compared with those who were breastfed and received ZDV prophylaxis for 6 months; at 12 months, overall HIV-free survival was comparable between the 2 infant-feeding strategies. If these findings concerning the deleterious effects of early weaning are further substantiated, alternative strategies that would allow breastfeeding safely throughout the first year of life will be emphasized.
Sub-clinical mastitis is associated with higher breast milk HIV viral copy number and MTCT of HIV (36). This condition has been shown to be common among HIV-infected, breastfeeding women in Malawi, Zambia, and Zimbabwe (43). It has been hypothesized that mastitis might contribute to transmission in such populations and that empiric treatment for the condition might play a role in the prevention of MTCT. Healthcare providers should counsel breastfeeding, HIV-infected women about the proper breastfeeding technique, treat clinical mastitis with antibiotics, and expressing and discarding breast milk from the affected breast while also continuing feeding from the unaffected breast, and treating infant oral thrush or nipple candidiasis with nystatin. The efficacy of these methods in reducing MTCT, however, has not been formally assessed. Poor maternal nutritional status has been shown in observational studies to be associated with increased risk of HIV disease progression and MTCT of HIV. Low maternal serum vitamin A levels have been associated with increased breast milk viral load and MTCT of HIV (43). However, clinical trials of prenatal vitamin A supplementation have shown no effect on MTCT of HIV, with at least 1 study showing an increase in transmission. There is some evidence pasteurization of breast milk can inactivate HIV in breast milk. The effects of pasteurization on MTCT and on other biological components of breast milk and the feasibility of the method's widespread uptake in real-world settings is unknown but faces obvious obstacles, given cultural norms and logistical barriers.
Our recommendations are:
There are still significant gaps in our understanding of how HIV is transmitted to the infant through breastfeeding, such as whether cell-free or cell-associated virus is the primary mode of transmission and characterizing the immunologic and other properties in breast milk, which help protect most breastfed infants from such transmission despite daily exposure. It is recommended the HIV-infected women should be advised not to breastfeed in parts of the world in which safe substitutes for breast milk exist, but the ideal strategy for the developing world is less clear. Exclusive breastfeeding for 6 months, followed by rapid weaning, has been advocated as a measure to reduce breastfeeding transmission of HIV and is currently being evaluated in clinical trials. However, the balance of risk and benefit for the health, development and survival of the infant and the implementation of this strategy in many resource-limited settings needs to be carefully assessed, given social and cultural practices as well as the economic and logistic challenges. Furthermore, if the current or planned trials demonstrate efficacy of maternal combination antiretroviral treatment or infant antiretroviral prophylaxis during breastfeeding, operational challenges of implementing these programs widely in resource-limited settings will need to be addressed. If antiretroviral drugs for both maternal therapy and prevention of MTCT become more widely available and are demonstrated to be safe, efficacious, and cost effective, extended breastfeeding with antiretroviral prophylaxis could indeed be considered for as long as the mother wishes to breastfeed. The algorithms presented in this paper (44) have better sensitivity and specificity than clinical parameters, with or without rapid HIV testing, for the presumptive diagnosis of severe disease in HIV-positive children less than 18 months of age. If implemented, they can increase the number of HIV-positive children successfully initiated on antiretroviral therapy.
HIV/AIDS is a prism through which the social conscience of individuals is refracted. Our obligation to HIV-infected people does not derive merely from our common humanity, though that alone should suffice. We must also recognize, and appreciate, that what we are now learning about MTCT and how, for example, we should treat American women identified as HIV-infected while in labor, is derived from research being performed in Africa. Our project to eliminate HIV reinforces the reality that we are interconnected in this epidemic. Thus, clinicians should reflect on their obligation to look beyond proper prescribing practices if they want to attain the highest ethical standard of their profession. No illness is more illustrative of the intertwining of the health of a society with the health of its citizens than HIV, and none has greater need of advocacy at home and abroad. Because HIV infection often is detected through prenatal and sexually transmitted disease testing, an obstetrician-gynecologist may be the first health professional to provide care for a woman infected with HIV. Universal testing with patient notification and right of refusal ("opt-out" testing) is recommended by most national organizations and federal agencies. Although "opt-out" and "opt-in" testing (but not mandatory testing) are both ethically acceptable, the former approach may identify more women who are eligible for therapy and may have public health advantages. It is unethical for an obstetrician-gynecologist to refuse to accept a patient or to refuse to continue providing health care for a patient solely because she is, or is thought to be, seropositive for HIV. Given the enormous advances in the prevention of perinatal transmission of HIV, it is clear that early identification and treatment of all pregnant women with HIV is the best way to prevent neonatal disease and also may improve the women's health.