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--> 4 Natural History, Detection, and Treatment of HIV Infection in Pregnant Women and Newborns In the United States the transmission of HIV from mother to infant (known as perinatal or vertical transmission) accounts for almost all new HIV infections in children (CDC, 1997c). Prior to the widespread use of antiretroviral therapy, transmission rates ranging from 14% to 33% were reported in the United States and Western Europe (Report of a Consensus Workshop, 1992). In the developing world, rates as high as 43% have been reported (Datta et al., 1994). Recent improvements in the understanding of the timing and pathogenesis of perinatal HIV infection have allowed the development of effective strategies to prevent perinatal HIV transmission. The prenatal identification of HIV-seropositive women is crucial for the successful implementation of these strategies. In addition, it allows for optimal medical management of HIV-infected women and their infants. Improved detection and treatment of HIV infection in pregnant women has greatly reduced perinatal HIV transmission in the United States. In addition, advances in the early diagnosis and treatment of HIV-infected infants have markedly improved the clinical outcome following perinatal infection. Timing Of HIV Transmission HIV transmission from mother to infant can occur antepartum (in utero), intrapartum (during labor or delivery), or postpartum (through breast-feeding) (Report of a Consensus Workshop, 1992). Available data suggest that at most 25% to 30% of perinatal HIV transmission occurs in utero (Rogers et al., 1989; Ehrnst et al., 1991; Luzuriaga et al., 1993). Evidence of infection in aborted first trimester fetal tissues has been reported (Sprecher et al., 1986), though potential contamination with maternal blood has not always been excluded. The intrauterine
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--> transmission of HIV is also suggested by the occasional isolation of HIV from amniotic fluid and cells. Finally, the isolation of HIV from, or the detection of the HIV genome in, blood samples obtained at birth from some HIV-infected infants also suggests intrauterine HIV transmission (Rogers et al., 1989; Ehrnst et al., 1991; Luzuriaga et al., 1993). The proportion of infants infected during each trimester of pregnancy is unknown. Indirect evidence suggests that 70% to 75% or more of vertical HIV transmission can occur during delivery (Ehrnst et al., 1991; Luzuriaga et al., 1993; Rogers et al., 1994). Negative diagnostic studies in the first two days of life followed by the detection of infection after one week of age are compatible with intrapartum transmission (Luzuriaga et al., 1993). Increased risk of vertical HIV transmission has been correlated with increased duration of rupture of the membranes prior to delivery, particularly in the presence of acute chorioamnionitis (Landesman et al., 1996; Popek et al., 1997). A higher risk of transmission to the firstborn twin, particularly following prolonged labor (Duliege et al., 1995), also supports the concept of intrapartum transmission. The mechanism(s) of intrapartum transmission are unknown, but might include transplacental microtransfusion or infection through mucocutaneous exposure to maternal blood or cervical secretions. The establishment of infection following the inoculation of the simian homolog of HIV (simian immunodeficiency virus) into the conjunctival sac or oropharynx of newborn macaque monkeys also supports the mucocutaneous route of human neonatal infection (Baba et al., 1994). Vertical HIV transmission can also occur through breast-feeding (Ziegler et al., 1985; Bulterys et al., 1995). HIV RNA and proviral DNA have been detected using the polymerase chain reaction (PCR) in breast milk; viral load appears to be particularly high in colostrum (Ruff et al., 1994). Large, prospective cohort studies suggest an increased risk of transmission associated with breast-feeding. In a meta-analysis, Dunn and colleagues (1992) have estimated that the proportion of transmission attributable to breast-feeding worldwide from an HIV-seropositive woman is 14% (95% confidence interval, 7% to 22%). The risk of breast milk transmission appears to be particularly high when maternal primary infection occurs within the first few months following delivery (Palasanthiran et al., 1993). For these reasons, HIV-seropositive women in industrialized countries are advised not to breast-feed their babies (AAP, 1995a). In July 1998, the World Health Organization recommended that HIV-infected women in developing countries be given information about the benefits and risks of breast-feeding, and an opportunity to make an informed choice about breast-feeding (WHO, 1998). Factors Associated With HIV Maternal-Child Transmission The observed variability in reported transmission rates probably reflects the multiple factors that influence perinatal HIV transmission. Several studies have
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--> linked high maternal viral loads to increased risk of HIV perinatal transmission (Borkowsky et al., 1994; Weiser et al., 1994; Dickover et al., 1996; Cao et al., 1997; Thea et al., 1997). In aggregate, however, there is no identified absolute viral threshold value that can discriminate between transmitters and nontransmitters. Transmission may be observed across the full range of viral levels. Maternal immune depletion also appears to correlate with vertical HIV transmission. Several cohort studies have documented an increased risk of vertical transmission with maternal AIDS or lowered CD4 T-cell counts (Study, 1994; Landesman et al., 1996). Maternal HIV specific immunity may also be important. A reduced risk of transmission has been reported from women with high titers of serum antibodies capable of neutralizing their own viral strains in vitro (Scarlatti et al., 1993). Others, however, have not found any association between maternal neutralizing antibody titers and transmission (Husson et al., 1995). Little is known regarding the potential role of maternal HIV cell-mediated immunity (e.g., HIV specific cytotoxic T-lymphocytes) in protection from transmission. Recently, an abnormality in a cell surface receptor for HIV (CCR-5) was identified in uninfected adult individuals at high risk for infection through sexual or parental exposure (reviewed in D'Souza and Harden, 1996). Lymphocytes from these individuals were relatively resistant to infection with primary HIV isolates in vitro, suggesting that the defect in the co-receptor may have protected these individuals from infection. The frequency of the homozygous deletion is approximately 1% in Caucasians. It appears to be extremely rare in Asian and African populations. Heterozygous individuals do not appear to be protected from infection. Studies are currently in progress to determine to what extent mutations in infant CCR-5 alleles and other cellular HIV co-receptors may influence perinatal HIV transmission. Other sexually transmitted infections may increase the risk of perinatal HIV transmission. An increased risk of vertical HIV transmission with maternal vitamin A deficiency has been reported (Semba et al., 1994). Duration of membrane rupture, hemorrhage during labor, chorioamnionitis, and invasive procedures during delivery have all been associated with an increased risk of perinatal HIV transmission (Minkoff et al., 1995; Landesman et al., 1996; Mandlebrot et al., 1996). Strategies To Prevent Perinatal HIV Transmission Recent advances in our understanding of the timing and pathogenesis of vertical HIV infection have led to the evaluation of a variety of strategies to prevent vertical HIV transmission, including the management of maternal co-infections, maternal nutritional intervention, bypassing the route of exposure, maternal and infant antiretroviral therapy, and vaccination. The primary focus has been on the use of perinatal antiretroviral therapy to prevent vertical HIV transmission. Recently, a profound and significant reduction in vertical HIV transmission was observed in mother-infant pairs treated
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--> with zidovudine (ZDV; also known as AZT). Those receiving ZDV had a transmission rate of 7.6% compared to 22.6% for those who received placebo (Connor et al., 1994). In this study, therapy consisted of oral administration of ZDV five times per day during pregnancy, intravenous administration of ZDV to the mother during delivery, and six weeks of postnatal treatment of the infant with oral ZDV. The only observed short-term toxicity in ZDV treated infants was anemia, which was not clinically significant. While the risk of vertical HIV transmission in this study was directly correlated with maternal blood viral load and indirectly correlated with maternal CD4 count, the treatment effect was independent of maternal viral load and CD4 count (Sperling et al., 1996). Studies conducted in the United States and Europe indicate widespread acceptance of the recommended ZDV regimen, and report resultant reductions in transmission rates to between 3% and 10% (Fiscus et al., 1996; Mayaux et al., 1997). In ACTG 185 (AIDS Clinical Trials Group protocol number 185), the ACTG 076 regimen was administered to women with advanced HIV infection and their infants; the perinatal HIV transmission rate was 4.8% (Mofenson, 1998). The extent to which each component of the ACTG 076 regimen (i.e., the prenatal and intrapartum therapy of the mother and the postpartum therapy of the infant) contributes to this success is unclear. Receipt of only part of the ACTG 076 regimen may be associated with decreased risk of perinatal transmission (Birkhead et al., 1998). Several trials evaluating the efficacy of shorter and less intensive antiretroviral regimens are in progress. In Thailand, the use of short-course oral ZDV administered during the last two weeks of pregnancy and during labor and delivery resulted in a significant decline in HIV perinatal transmission. The estimated HIV transmission risks for placebo and ZDV groups were 18.6% and 9.2%, respectively, representing a 51% decrease in transmission risk (CDC, 1998a). The most recent Public Health Service Task Force recommendations for the use of antiretroviral drugs among HIV-infected pregnant women in the United States have updated the 1994 guidelines, which were based on the findings of ACTG 076 (CDC, 1998d). Advances in the understanding of the pathogenesis of HIV infection have resulted in recent changes in the standard recommended antiretroviral therapy in HIV-infected adults. Combination drug regimens to maximally suppress the virus are now recommended (CDC, 1998e). Although considerations associated with pregnancy may affect decisions regarding the timing and choice of therapy, pregnancy is not a reason to defer standard combination antiretroviral therapy. It is recommended that offering antiretroviral therapy to HIV-infected women during pregnancy—whether primarily to treat HIV infection, to reduce perinatal transmission, or both—be accompanied by a discussion of the known and unknown potential benefits and risks of such therapy to the woman and infant. Optimal antiretroviral regimens should be discussed and offered to an HIV-infected woman and ZDV prophylaxis for perinatal transmission should be incorporated into those regimens whenever possible (CDC, 1998d).
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--> Potential adverse effects of antiretroviral therapy on the mother and fetus should be discussed during counseling. Experience to date with the administration of antiretrovirals other than ZDV during pregnancy is quite limited. Table 4.1 summarizes the potential toxic effects of these drugs.* Several programs have been developed to identify potential risks of antiretroviral therapy administered during pregnancy or early infancy. Animal models are often used to screen for potential toxicities and teratogenic properties of antiretroviral agents before these agents are evaluated clinically in humans. While the relevance of these models to human therapy is unproven, they may be useful in identifying agents of concern. Recently, severe congenital anomalies were identified in 3 of 13 infant monkeys born to mothers who had received Efavirenz, a non-nucleoside reverse transcriptase inhibitor, during pregnancy (DuPont-Merck, 1998). The doses used in this study were those anticipated to achieve plasma concentrations similar to those achieved in humans on standard recommended doses of the drug. Congenital anomalies were not observed in any of the 13 infants of mothers treated with the vehicle control. As a result of these studies, women receiving Efavirenz are advised to avoid pregnancy. The Phase I evaluation of combination antiretroviral regimens, including protease inhibitors, in pregnant women and young infants is now under way through the ACTG. An ACTG Phase II/III trial evaluating the efficacy of nevirapine (a non-nucleoside reverse transcriptase inhibitor) in preventing perinatal HIV transmission is also under way. All ACTG protocol participants exposed to antiretroviral agents in utero or during infancy are encouraged to enroll in ACTG protocol 219, which will evaluate them at least through age 21 for potential long-term sequelae. Several pharmaceutical companies (Glaxo Wellcome, Inc.; Hoffmann-LaRoche, Inc.; Bristol-Myers Squibb Co.; and Merck & Co., Inc.), in cooperation with the Centers for Disease Control and Prevention (CDC), maintain a registry to assess the safety of ZDV, didanosine (ddI), lamivudine (3TC), saquinavir (SAQ), stavudine (d4t), and dideoxycytidine (ddC) during pregnancy. Providers are encouraged to enroll in this registry women who receive any of these drugs during pregnancy. The registry findings did not indicate any increase in the number of birth defects after receipt of ZDV alone. No consistent pattern of birth defects that would suggest a common cause has been observed. The number of cases reported through February 1997, however, was insufficient to reliably estimate the quantitative risk of birth defects after the administration of these agents, alone or in combination, to pregnant women and their infants. * In July, 1998, a high rate of prematurity was reported in a study of infants whose mothers received antiretroviral therapy during pregnancy (Lorenzi et al., 1998). The small numbers of subjects and limited information about background rates of prematurity in this study limit the ability to attribute the prematurity to the antiretroviral therapy, and the PHS treatment recommendations (CDC, 1998d) have not been changed. Ongoing perinatal trials are being monitored intensively to evaluate potential relationships between antiretroviral use and adverse pregnancy outcomes.
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--> TABLE 4.1 Potential Toxic Effects of Antiretrovirals Antiretroviral Drug FDA Pregnancy Category Placental Passage Long-Term Animal Carcinogenicity Studies Side Effects Zidovudine (ZDV) C In humans Positive (rodent, noninvasive vaginal epithelial tumor) Anemia, gastrointestinal (GI) upset, headache, myopathy Zalcitabine (ddC) C In rhesus monkeys Positive (rodent thymic lymphomas) Pancreatitis, stomatitis, peripheral neuropathy Didanosine (ddI) B In humans Negative Pancreatitis, diarrhea, peripheral neuropathy Stavudine (d4T) C In rhesus monkeys Not completed Pancreatitis, peripheral neuropathy Lamivudine (3TC) C In humans Negative Minimal toxicity Nevirapine C In humans Not completed Rash Delavirdine C Unknown Not completed Rash Indinavir C In rats Not completed Nephrolithiasis, hyperbilirubinemia, drug interactions Ritonavir B In rats Not completed GI upset, paresthesias, drug interactions Saquinavir (SAQ) B In rats/rabbits Not completed GI upset Nelfinavir B Unknown Not completed Diarrhea Efavirenz (EF) Congenital anomalies in 13 infant monkeys whose mothers received EF during gestation Central Nervous System (anencephaly, microphthalmia, cleft palate) SOURCES: CDC 1998c, 1998d, 1998e; Dupont-Merck, 1998
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--> Since maternal sexually transmitted diseases or chorioamnionitis may increase the risk of vertical HIV transmission, efforts to prevent, detect, or treat these infections are important. Similarly, since active drug use may increase the risk of perinatal transmission (Landesman et al., 1996; Rodriguez et al., 1996) and may interfere with the ability of expectant women to seek and comply with appropriate medical care, efforts to improve access to drug treatment programs for pregnant women are also important. As previously discussed, a majority of infants acquire HIV infection during delivery through mucosal exposure to maternal blood and/or vaginal secretions. Optimizing obstetrical practices (e.g., limiting the duration of rupture of membranes prior to delivery, avoidance of invasive procedures including scalp electrodes during delivery) might help to limit the risk of transmission. Cesarean section has been proposed as a means of reducing the risk of exposure, particularly if performed prior to the rupture of membranes. A meta-analysis suggested that cesarean section might protect against vertical HIV transmission (Rogers, 1997). In a recently reported study, cesarean section appeared to reduce the risk of vertical HIV-1 transmission; however, the benefit of cesarean section was only apparent when performed prior to the onset of labor and in mother-infant pairs who received ZDV (Mandelbrot et al., 1998). Virocidal cleansing of the birth canal prior to vaginal delivery has also been proposed as a means of reducing intrapartum HIV transmission, though a study in Malawi that evaluated chlorhexidine vaginal cleansing during labor did not find an overall reduction in transmission (Biggar et al., 1996). There was, however, a reduction in transmission if the chlorhexidine was administered to women whose membranes ruptured at least four hours prior to delivery (Biggar et al., 1996). Diagnosis Of HIV Infection In Women And Infants The HIV testing algorithm recommended by the Public Health Service (PHS) for pregnant women is comprised of initial screening with a Food and Drug Administration (FDA) licensed enzyme-linked immunosorbent assay (ELISA). Confirmatory testing of repeatedly reactive ELISAs with an FDA-licensed supplemental test (e.g., Western blot or immunofluorescence assay) must be done. The diagnosis of HIV infection in adults requires that both the ELISA and the confirmatory test be positive. According to the manufacturers, the third generation ELISAs are 100% sensitive (probability that the test will be positive if the individual tested is truly infected) in individuals infected long enough to have developed HIV antibodies and 99.9% specific (probability that the test will be negative if the individual tested is truly not infected). Despite these excellent performance characteristics, there may be a problem with false positive results in low-prevalence areas. For example, in a population of pregnant women where the prevalence of HIV is 0.03%, only 23% of samples with positive ELISA would be found to be truly positive by confirmatory Western blot test. In a high-prevalence
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--> area with 2% HIV infection, the positive predictive value of the ELISA would increase to 95% (see Appendix K). To maximize prevention efforts, women must be identified as HIV-infected as early as possible during pregnancy. Early diagnosis of HIV infection allows the mother to avail herself of effective antiretroviral therapy for her own health, and that can significantly reduce perinatal transmission. Women who know their HIV status can be counseled not to breast-feed their infants. HIV-infected pregnant women can also be referred to appropriate psychological, social, legal, and substance abuse services. Reporting of conventional ELISA and Western blot tests typically takes one to two weeks. At present, one rapid test (Single Use Diagnostic System HIV Test, Murex Corporation, Norcross, Georgia) is commercially available in the United States. As discussed in Chapter 7, an accurate rapid test would have utility among pregnant women in labor who do not know their HIV status. It would help identify HIV-infected pregnant women whose infants might still benefit from the intrapartum and postpartum components of the ACTG 076 regimen. Rapid tests can also be performed on newborns to ascertain their HIV exposure. The sensitivity and specificity of current rapid assays are comparable to those of ELISAs. Because the predictive value varies with the prevalence of HIV infection in the population tested, the positive predictive value of the test will be low in populations with low-prevalence, yielding many false positive results. A reactive rapid test must therefore be confirmed by standard testing. If a second rapid test is licensed, its performance would be independent of the current test, and the sensitivity and specificity of the pair would be sufficient for use in perinatal settings (CDC, 1998g). See Chapter 7 for further discussion. Early diagnosis of HIV-infected infants is crucial for optimal medical management. Serologic methods are of limited utility for the early diagnosis of perinatal HIV infection. With efficient transfer of antibodies from an infected woman to her fetus during the third trimester of pregnancy, all infants born at or near term to an HIV-infected woman will be HIV-seropositive; uninfected infants may retain passively acquired antibodies through 18 months of age. The detection of HIV proviral genome in peripheral blood mononuclear cells using the polymerase chain reaction (DNA PCR) is a highly sensitive, specific, rapid, and cost-effective screening test for vertical infection (Bremer et al., 1996; Luzuriaga et al., 1996). Using DNA PCR, 25% to 30% of infected infants may be identified at birth and the remaining 70% to 75% of infected infants can be identified by one month of age. According to the guidelines, the evaluation of the infants' infection status should begin within 48 hours of birth, with repeated evaluations at one to two weeks and at one, two, and six months (CDC, 1998c). Infants with single positive DNA PCR results should have a follow-up blood specimen drawn immediately for confirmatory studies (DNA PCR and viral isolation). The likelihood of infection is extremely low in those infants with negative DNA PCR studies through 6 months of age; subsequent serologic follow-up
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--> through 18 months of age is advised to document the loss of passively acquired maternal antibodies (CDC, 1998c). Because transmission of HIV occurs primarily in utero and intrapartum, there is only limited utility in infant testing. When maternal serostatus is unknown, however, HIV antibody testing of the newborn is important for the identification of children at risk for perinatal HIV infection and early referral for appropriate medical evaluation and care. Control of viral replication and preservation of the developing immune system have been demonstrated in infants who initiated intensive combination antiretroviral therapy in early infancy (Luzuriaga et al., 1997). In addition, the initiation of prophylaxis against PCP at age four to six weeks has been recommended for all infants born to HIV-infected women; such prophylaxis should be continued until HIV infection has been excluded (CDC, 1995a). Summary Perinatal transmission can occur antepartum, intrapartum, and postpartum. Several factors, including maternal and virologic factors, fetal factors, placental conditions, obstetric factors and breast-feeding, may influence the risk of perinatal transmission. Recent improvements in our understanding of the timing and pathogenesis of perinatal HIV infection have allowed the development of effective strategies to prevent perinatal HIV transmission. To maximize prevention efforts, women must be identified as HIV-infected as early as possible during pregnancy and offered effective antiretroviral therapy. Postnatal evaluation of the HIV at-risk infant, beginning immediately after birth, is important for early diagnosis and optimal medical management.
Representative terms from entire chapter: