Clinical Manual for Management of the HIV-Infected Adult
2006 Edition

Section 3: Antiretroviral Therapy

Reducing Maternal-Infant HIV Transmission

Background

In the absence of antiretroviral (ARV) prophylaxis or other interventions, the rate of mother-to-child transmission (MTCT) of HIV in the United States ranges from 16% to 25%. Certain interventions, notably antiretroviral therapy (ART), are highly effective in reducing the risk of perinatal transmission of HIV. ART and may reduce the transmission rate to as low as 1.5% in selected groups. Pregnant women with HIV infection who wish to carry their pregnancies to term should be educated about the risks of perinatal HIV transmission and offered appropriate medical management and ARV medications to maintain or improve their own health and to reduce the risk of HIV transmission to their infants.

This chapter describes strategies to reduce the risk of MTCT of HIV and presents information on HIV testing during pregnancy. It is not intended to be a comprehensive discussion of these topics, and all HIV-infected pregnant women should be treated by an HIV-experienced obstetrician and an HIV specialist. For centers that do not have HIV specialists available, experts at the National Perinatal HIV Consultation and Referral Service Perinatal Hotline (888-448-8765) are available for consultation. For more information on caring for pregnant women, see chapter Care of HIV-Infected Pregnant Women.

Overview of Prevention of Perinatal HIV Transmission

In 1994, an interim analysis of Pediatric AIDS Clinical Trial Group study 076 (PACTG 076) found that ARV treatment during pregnancy could significantly reduce the risk of HIV transmission to the infant. Pregnant women in the intervention group took zidovudine (ZDV) orally during the last weeks of pregnancy, received it intravenously during labor and delivery, and gave it to their newborns for 6 weeks. Only 7.6% of those infants were infected with HIV, compared with 22.6% of infants whose mothers in the control group did not receive ZDV. ART for pregnant women with HIV infection rapidly became the standard of care in the United States and other high-income countries. A task force of the U.S. Public Health Service (USPHS) issued recommendations in August 1994 for the use of ZDV for the reduction of perinatal transmission. Those recommendations were expanded to include guidelines for the medical management of pregnant women with HIV infection, including ARV treatment during pregnancy, as well as recommendations regarding other interventions that can further decrease transmission risk, such as cesarean section. The USPHS task force now meets regularly to review and update these guidelines as new research is published and new ARV drugs are approved. These guidelines, the Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States are available online and in print (see "References" below).

Studies subsequent to PACTG 076 in resource-limited countries as well as resource-abundant areas found that other ARV regimens also reduced the risk of HIV transmission from mother to infant. The Petra study, a placebo-controlled trial in a breast-feeding population in Uganda, South Africa, and Tanzania, found a transmission rate of 9% among women who received oral ZDV plus lamivudine (3TC) intrapartum and for 1 week postpartum and whose infants also received 1 week of ZDV/3TC, compared with a rate of 15% in the placebo group. The HIV NET 012 trial in a breast-feeding population in Uganda compared the efficacy of a single dose of nevirapine (NVP) given to the mother at the onset of labor plus a single dose given to the newborn 48 hours postpartum with oral ZDV given to the mother during labor and to the newborn. The transmission rate was 9% in the NVP arm compared with 21% in the ZDV arm. The results of this study and the low cost of NVP led a number of resource-limited countries to institute NVP prophylaxis as the standard of care for preventing MTCT of HIV. Numerous other trials have demonstrated the efficacy of various ARV strategies, combining different ARVs with different treatment durations, and given to mothers, newborns, or both, in both breast-feeding and non-breast-feeding populations. Some trials have suggested that even late ARV interventions may decrease the infant's risk of HIV infection. A retrospective study of subjects in New York found that the rate of perinatal HIV transmission was 9.3-10% if ZDV was given to both the mothers intrapartum and their newborns or only to the newborn, compared with 26.6% if no ARV medication was given. This study supports the importance of offering ARV interventions to pregnant women with HIV infection whenever they are identified.

In the United States, the PACTG 076 regimen remains the standard of care for preventing perinatal HIV transmission, and usually is incorporated into combination ARV therapy for pregnant women. For international settings, other guidelines have been developed by global agencies such as the World Health Organization (see "References" below) and by individual governments.

Unless otherwise referenced, the information in this chapter is based on the most recent USPHS perinatal guidelines available at the time this chapter was written. The reader should consult the AIDSInfo Web site (http://aidsinfo.nih.gov) for the most current recommendations.

HIV Testing during Pregnancy

The success of interventions to reduce the risk of perinatal HIV transmission has underscored the importance of HIV testing and counseling of all pregnant women. Interventions to interrupt transmission can be effective only if women know their HIV status and can access treatment. The USPHS first recommended universal HIV counseling and testing for pregnant women in 1995. Many nationwide professional and governmental organizations, including the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the U.S. Preventive Services Task Force, have endorsed those recommendations. Current recommendations from the U.S. Centers for Disease Control and Prevention (CDC) urge 3 approaches to HIV testing during pregnancy:

• An "opt-out" approach to HIV testing during pregnancy, whereby a pregnant woman is tested unless she specifically declines testing
• Routine testing with a rapid HIV test for women with unknown or undocumented HIV status who present in labor, in order to offer those testing HIV positive ARV prophylaxis during labor
• Rapid HIV testing for newborns of mothers of unknown HIV status so that they can receive postexposure ARV prophylaxis, if indicated

State laws regarding HIV testing during pregnancy vary widely, and many are under review. Clinicians should be familiar with their state laws regarding HIV testing during pregnancy, opt-out or consent provisions, and regulations about rapid HIV testing during the intrapartum or newborn period.

HIV Education and Counseling of Pregnant Women

Educating pregnant women about the importance of HIV testing is a critical element in preventing perinatal HIV transmission. However, extensive pretest counseling is not essential. A woman must be told that HIV testing is a standard part of prenatal care, that the clinician recommends the tests, and that all pregnant women should be tested for HIV because knowing about HIV infection is important for their health and the health of their babies. Research has shown that a provider's strong endorsement of HIV testing is a major predictor of whether a woman receives an HIV test. Testing should be voluntary and free of coercion, and a woman should know that she can decline testing without the risk of being denied care. A woman's age, cultural background, educational level, and primary language may influence her knowledge about HIV transmission and her willingness to be tested; the clinician should consider these factors carefully when providing education and information.

The following minimum information should be provided through an educational session with a health care provider or through written or electronic media (eg, brochures, videos):

• HIV is the virus that causes AIDS. Approximately 25% of women with HIV who are not treated can transmit the virus to their babies through pregnancy, during labor and delivery, or by breast-feeding.
• A woman could be at risk for HIV infection and not know it.
• Highly effective treatment can protect the infant from being infected with HIV and can improve the mother's health.
• HIV testing is recommended for all pregnant women.
• Women who decline testing will not be denied care.

Women should also be told that test results are confidential to the extent allowed by law and that medical and other services are available for women with HIV infection. Reporting requirements for the specific state should be explained.

Some states require written informed consent before an HIV test is done. Others require patient education and a chart note from the providers. More recently, states are moving to the opt-out approach, whereby a woman is informed that an HIV test will be done unless she declines. Whatever the consent process, a woman should know that an HIV test is being done and should receive at least the information outlined above.

HIV testing should be performed as early in pregnancy as possible to allow for interventions to prevent transmission and for effective management of a woman's HIV infection, if the woman is found to be HIV seropositive. Repeat HIV testing is recommended in the third trimester for women at high risk for acquiring HIV (eg, a history of injection drug use, exchange of sex for money or drugs, multiple sex partners, a partner known to be HIV infected). Any pregnant woman with signs or symptoms of seroconversion should be evaluated for acute HIV infection (see chapter Primary HIV Infection). Some states, such as Florida, now mandate a third-trimester HIV test for all pregnant women. If a client declines testing, the clinician should ask her reasons and follow up at subsequent visits. If a provider is persistent, the woman may choose to have an HIV test at a later visit.

In the United States, the vast majority of pregnant women who are tested for HIV will be HIV seronegative. While giving test results to an HIV-negative woman, the clinician should take the opportunity to discuss risk-reduction strategies to help ensure that a woman remains uninfected by HIV. Women at high risk for HIV infection should be referred for more extensive counseling because recent research indicates that pregnancy may place her at greater risk for acquiring HIV infection.

Counseling a pregnant woman with a positive HIV test result requires knowledge and sensitivity. The clinician should explain that, even though the woman may feel well, she is infected with the virus. The woman should be told about the importance of medical management of HIV for her own health and for the prevention of perinatal transmission, and she should be guided to the medical and social services available in her local community. She also should be referred to an HIV obstetric specialist who can work closely with her primary obstetric and HIV providers to manage her care during the pregnancy. The patient may be surprised or shocked at the HIV diagnosis, or she may have known her status but been reluctant to disclose it. The clinician should emphasize the importance of emotional and social support, assess the patient's social support resources, and offer her referrals as needed.

Rapid HIV Testing during Labor

As discussed earlier, beginning ART during pregnancy offers the greatest chance for preventing MTCT of HIV, but interventions during the intrapartum and neonatal periods still offer opportunities to decrease the risk of HIV transmission. Rapid HIV testing for women who present in labor with unknown or undocumented HIV status can identify HIV-infected women so that interventions can be offered. Newer rapid HIV antibody tests, which are both sensitive and specific, provide results in less than 1 hour. Women who should receive HIV testing during labor include those who have had little or no prenatal care, those who were not offered testing earlier in pregnancy, those who declined previously, and those whose HIV test results are not available at the time of labor. Education and counseling for the woman in labor who needs an HIV test should incorporate the information for prenatal education discussed earlier, and give consideration to the special circumstances of labor. Special educational formats such as flip charts have been developed to help with patient education. Confidentiality should be assured for the information and consent process and for treatment. If an opt-out approach is used in the labor setting, a woman of unknown serostatus should be told that no HIV test is found on her chart, that HIV testing is part of routine care, and that she can decline if she wishes, but that experts recommend HIV testing because interventions are available that decrease her baby's risk of becoming infected with HIV if she is found to be positive.

Factors Influencing Perinatal HIV Transmission

As stated earlier, the rate of MTCT in the United States ranges from 16% to 25% in the absence of ART or other interventions. Perinatal transmission is most likely to occur in the intrapartum period. Several factors influence the risk of transmission from mother to infant. The most influential factor seems to be the mother's HIV RNA level (viral load). Clinical trials and observational studies have shown a strong positive correlation between maternal HIV viral load during pregnancy or at delivery and the risk of perinatal HIV transmission, even among women treated with ARVs. Even for women with viral loads <1,000 copies/mL, in whom the risk of MTCT is lower than in women with higher viral loads, ARV prophylaxis is a critical factor in reducing HIV transmission. One metaanalysis found that women with HIV RNA <1,000 copies/mL who were receiving ART had a transmission rate of only 1%, compared with a 9.8% transmission rate among women taking no ARVs. For that reason, ARV prophylaxis is recommended for all pregnant women with HIV infection. Other factors associated with increased risk of perinatal transmission include chorioamnionitis, low CD4 cell count, sexually transmitted infections, illicit drug use, cigarette smoking, and unprotected sex with multiple partners.

Obstetric factors also affect the risk of transmission. The risk of HIV infection increases linearly with the increased duration of ruptured membranes, although the effect of ruptured membranes in women with low viral loads is not known. Invasive procedures performed at any time during pregnancy, such as amniocentesis or placement of scalp electrodes, also increase the risk by exposing the fetus to maternal blood; these procedures should be avoided. The mode of delivery, whether vaginal or cesarean section, also influences the risk of HIV transmission. Cesarean section decreases the rate of perinatal infection, at least in the absence of other interventions (including ART); see "Mode of Delivery and Intrapartum Management" below for further information.

Breast-feeding increases the risk of HIV transmission by 5-20%. In the United States, where replacement foods and clean water routinely are available, women with HIV should not breast-feed. However, some women with HIV will be under tremendous cultural and family pressure to breast-feed and will need the clinician's ongoing support to use substitute formula.

Because many factors that affect the risk of perinatal HIV transmission may be modified, clinicians should educate pregnant women carefully about the importance of ARV prophylaxis and other strategies to reduce the risk of maternal-fetal transmission of HIV.

Antiretroviral Therapy during Pregnancy

The goals of ART for the pregnant woman are the same as those for any person living with HIV:

• To suppress the level of HIV to as low as possible for as long as possible
• To preserve and restore immune function
• To prolong life and improve quality of life

An additional goal in pregnant women is to reduce the risk of perinatal HIV transmission. The USPHS recommendations discuss in detail the multiple issues that must be considered when balancing the woman's need for therapy for her own health and for decreasing the risk of transmission to the infant. Decisions about ART are complex and should be made by the woman and her health care provider after discussing of the risks and benefits. Clinicians are urged to consult an HIV specialist as well as the most current USPHS recommendations when making therapeutic decisions. The following discussion addresses some of the issues in determining ARV treatment and is taken from the current USPHS Perinatal ARV Guidelines.

A fundamental principle of the guidelines is that therapies of known benefit should not be withheld during pregnancy unless they may cause adverse effects to the woman, fetus, or infant and these adverse effects outweigh the potential benefit to the woman. The woman's clinical, virologic, and immunologic status should be the most important factor in guiding treatment decisions. Combination therapy with 3 ARVs, including agents from at least 2 ARV classes, is the standard therapy for adults and should be discussed with the pregnant woman. Special considerations in choosing drug regimens during pregnancy include changes in dosing requirements because of physiologic changes, the potential effects of ARVs on the woman, and the known and unknown potential effects or ARVs on the fetus or infant.

Safety and Toxicity of Antiretroviral Medications during Pregnancy

Only limited data are available on the safety of ARV drugs in pregnancy, particularly when ARVs are used in combination. The existing safety and toxicity information is derived from animal data, clinical trials, registry data, and anecdotal experience. A few drugs are of special concern when used during pregnancy (Tables 1-2). Efavirenz (Sustiva) is classified by the U.S. Food and Drug Administration (FDA) as a Pregnancy Class D drug because malformations have occurred in monkeys receiving efavirenz during the first trimester. Several cases of neural tube defects have been reported in humans after first-trimester exposure to efavirenz. Efavirenz should be avoided during the first trimester, and women taking efavirenz should be counseled about the risks and the importance of avoiding pregnancy. Use of efavirenz can be considered after the second trimester if other alternatives are unavailable. Amprenavir (Agenerase) oral solution is contraindicated during pregnancy because the high levels of propylene glycol may not be metabolized well during pregnancy. The combination of didanosine (ddI) and stavudine (d4T) should be avoided unless no alternatives are available. Hydroxyurea, a drug previously thought to boost the response to ARVs, is a potent teratogen in various animal species and should not be used in the first trimester. Information on ARV toxicity during pregnancy should be consulted carefully before treatment choices are made.

The USPHS Perinatal ARV Guidelines maintain information on each ARV drug, including preclinical and clinical data, pharmacokinetic and toxicity data, and recommendations regarding use in pregnancy. These guidelines are updated routinely as information is received (Tables 1-2). Of course, numerous other medications are contraindicated during pregnancy, and potential toxicity should be considered carefully before any medication is given to a pregnant woman.

Table 1. Preclinical and Clinical Data Relevant to the Use of Antiretrovirals during Pregnancy

Antiretroviral Drug FDA Pregnancy Category* Placental Passage (Newborn-to-Mother Drug Ratio) Long-Term Carcinogenicity Studies in Animals Teratogen Studies in Animals Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors Abacavir (Ziagen, ABC) C Yes (rats) Positive: malignant and nonmalignant tumors of liver, thyroid in female rats, and preputial and clitoral gland of mice and rats Positive: rodent anasarca and skeletal malformations at 1,000 mg/kg (35x human exposure) during organogenesis; not seen in rabbits Didanosine (Videx, ddI) B Yes (human) [0.5] Negative: no tumors, lifetime rodent study Negative Emtricitabine (Emtriva, FTC) B Unknown Not completed Negative Lamivudine (Epivir, 3TC) C Yes (human) [~1.0] Negative: no tumors, lifetime rodent study Negative Stavudine (Zerit, d4T) C Yes (rhesus monkey) [0.76] Positive: liver and bladder tumors in mice and rats, at very high-dose exposure Negative: but sternal bone calcium decreases in rodents Tenofovir DF (Viread) B Yes (rat and monkey) Positive: hepatic adenomas in female mice at high doses Negative: but osteomalacia when given to juvenile animals at high doses Zalcitabine (Hivid, ddC) C Yes (rhesus monkey) [0.30 - 0.50] Positive: thymic lymphomas in rodents Positive: hydrocephalus at high doses in rodents Zidovudine(Retrovir, AZT, ZDV) C Yes (human) [0.85] Positive: noninvasive vaginal epithelial tumors in rodents Positive at near lethal dose in rodents Nonnucleoside Reverse Transcriptase Inhibitors Delavirdine (Rescriptor) C Unknown Positive: hepatocellular adenomas and carcinomas in male and female mice but not rats; bladder tumors in male mice Positive: ventricular septal defect in rodents Efavirenz (Sustiva) D Yes (cynomolgus monkey, rat, rabbit) [~1.0] Positive: hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas in female but not male mice Positive: anencephaly, anophthalmia, microphthalmia in cynomolgus monkeys Nevirapine (Viramune) C Yes (human) [~1.0] Positive: hepatocellular adenomas and carcinomas in mice and rats Negative Protease Inhibitors Amprenavir (Agenerase) C Unknown Positive: hepatocellular adenomas and carcinomas in male mice and rats Negative, but deficient ossification and thymic elongation in rats and rabbits Atazanavir (Reyataz) B Unknown Positive: hepatocellular adenomas in female mice Negative Fosamprenavir (Lexiva) C Unknown Positive: benign and malignant liver tumors in male rodents Negative for fosamprenavir, but deficient ossification with amprenavir Indinavir (Crixivan) C Minimal (humans) Positive: thyroid adenomas in male rats at highest dose Negative, but extra ribs in rodents Lopinavir/Ritonavir (Kaletra) C Unknown Positive: hepatocellular adenomas and carcinomas in mice and rats Negative, but delayed skeletal ossification and increase in skeletal variations in rats at maternally toxic doses Nelfinavir (Viracept) B Minimal (humans) Positive: thyroid follicular adenomas and carcinomas in rats Negative Ritonavir (Norvir) B Minimal (humans) Positive: liver adenomas and carcinomas in male mice Negative, but cryptorchidism in rodents Saquinavir (Fortovase) B Minimal (humans) Negative Negative Tipranavir (Aptivus) C Unknown In progress Negative, but decreased ossification and weights in rats at maternally toxic doses Fusion Inhibitors Enfuvirtide (Fuzeon) B Unknown Not done Negative

Key to abbreviations: FDA = U.S. Food and Drug Administration. *Food and Drug Administration Pregnancy Categories: A-Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the fetus during the first trimester of pregnancy (and no evidence exists of risk during later trimesters). B-Animal reproduction studies fail to demonstrate a risk to the fetus, and adequate but well-controlled studies of pregnant women have not been conducted. C-Safety in human pregnancy has not been determined; animal studies are either positive for fetal risk or have not been conducted, and the drug should not be used unless the potential benefit outweighs the potential risk to the fetus. D-Positive evidence exists of human fetal risk that is based on adverse-reaction data from investigational or marketing experiences, but the potential benefits from the use of the drug among pregnant women might be acceptable despite its potential risks. X-Studies among animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any possible benefit. Source: Centers for Disease Control and Prevention. Table 2: Preclinical and Clinical Data Relevant to the Use of Antiretrovirals in Pregnancy. In: Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. July 6,2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9.

Table 2. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetics, Toxicity Data, and Recommendations

Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors Antiretroviral Drug Pharmacokinetics during Pregnancy Concerns during Pregnancy Rationale for Recommended Use during Pregnancy Class concerns and comments See text for discussion of potential maternal and infant mitochondrial toxicity. NRTIs are recommended for use as part of combination regimens, usually including 2 NRTIs with either an NNRTI or 1 or more PIs. Use of single or dual NRTIs alone is not recommended for treatment of HIV infection (zidovudine alone may be considered for prophylaxis of perinatal transmission in pregnant women with HIV RNA <1,000 copies/mL). Recommended Agents Zidovudine* (Retrovir, AZT, ZDV) Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated. No evidence of human teratogenicity. Well-tolerated, short-term safety demonstrated for mother and infant. Preferred NRTI for use in combination antiretroviral regimens during pregnancy based on efficacy studies and extensive experience; should be included in regimen unless significant toxicity or stavudine use Lamivudine* (Epivir, 3TC) Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated. No evidence of human teratogenicity. Well-tolerated, short-term safety demonstrated for mother and infant. Because of extensive experience with lamivudine in pregnancy in combination with zidovudine, lamivudine plus zidovudine is the recommended dual NRTI backbone for pregnant women. Alternative Agents Didanosine (Videx, ddI) Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated. Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving didanosine and stavudine together. Alternate NRTI for dual nucleoside backbone of combination regimens. Didanosine should be used with stavudine only if no other alternatives are available. Emtricitabine (Emtriva, FTC) No studies in human pregnancy. No studies in human pregnancy. Alternate NRTI for dual nucleoside backbone of combination regimens. Stavudine (Zerit, d4T) Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated. No evidence of human teratogenicity. Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving didanosine and stavudine together. Alternate NRTI for dual nucleoside backbone of combination regimens. Stavudine should be used with didanosine only if no other alternatives are available. Do not use with zidovudine because of potential for antagonism. Abacavir* (Ziagen, ABC) Phase I/II study in progress. Hypersensitivity reactions occur in ~5-8% of nonpregnant persons; a much smaller percentage are fatal and are usually associated with repeat challenge. Rate of such reactions during pregnancy is unknown. Patient should be educated regarding symptoms of hypersensitivity reaction. Alternate NRTI for dual nucleoside backbone of combination regimens. See footnote regarding use in triple NRTI regimen.# Insufficient Data to Recommend Use Tenofovir DF (Viread) No studies in human pregnancy. Phase I study in late pregnancy in progress. Studies in monkeys show decreased fetal growth and reduction in fetal bone porosity within 2 months of starting maternal therapy. Clinical studies in humans (particularly children) show bone demineralization with chronic use; clinical significance is unknown. Because of lack of data on use in human pregnancy and concern regarding potential fetal bone effects, tenofovir should be used as a component of a maternal combination regimen only after careful consideration of alternatives. Not Recommended Zalcitabine (Hivid, ddC) No studies in human pregnancy Rodent studies indicate potential for teratogenicity and developmental toxicity (see Table 1). Given lack of data and concerns regarding teratogenicity in animals, zalcitabine is not recommended for use in human pregnancy unless alternatives are not available. Nonnucleoside Reverse Transcriptase Inhibitors Antiretroviral Drug Pharmacokinetics in Pregnancy Concerns in Pregnancy Rationale for Recommended Use in Pregnancy Recommended Agents Nevirapine (Viramune) Pharmacokinetics not significantly altered in pregnancy; no change in dose indicated. No evidence of human teratogenicity. Increased risk of symptomatic, often rash-associated, and potentially fatal liver toxicity among women with CD4 counts >250 cells/µL when first initiating therapy; unclear whether pregnancy increases risk. Because of the increased risk of potentially life-threatening hepatotoxicity in women with high CD4 counts, nevirapine should be initiated in pregnant women with CD4 counts >250 cells/µL only if benefit clearly outweighs risk. Women who begin pregnancy on nevirapine regimens and are tolerating them well may continue therapy, regardless of CD4 count. Not Recommended Efavirenz (Sustiva) No studies in human pregnancy. FDA Pregnancy Class D; significant malformations (anencephaly, anophthalmia, cleft palate) were observed in 3 (15%) of 20 infants born to cynomolgus monkeys receiving efavirenz during the first trimester at a dose giving plasma levels comparable to systemic human therapeutic exposure. Three cases were reported of neural tube defects in humans after first-trimester exposure; relative risk is unclear. Use of efavirenz should be avoided in the first trimester, and women of childbearing potential must be counseled regarding risks and avoidance of pregnancy. Because of the known failure rates of contraception, alternate regimens should be strongly considered in women of childbearing potential. Use after the second trimester of pregnancy can be considered if other alternatives are not available and if adequate contraception can be assured postpartum. Delavirdine (Rescriptor) No studies in human pregnancy. Rodent studies indicate potential for carcinogenicity and teratogenicity (see Table 1). Given lack of data and concerns regarding teratogenicity in animals, delavirdine is not recommended for use in human pregnancy unless alternatives are not available. Protease Inhibitors Antiretroviral Drug Pharmacokinetics in Pregnancy Concerns in Pregnancy Rationale for Recommended Use in Pregnancy Class concerns Hyperglycemia, new onset or exacerbation of diabetes mellitus, and diabetic ketoacidosis reported with PI use; unclear if pregnancy increases risk. Conflicting data regarding preterm delivery in women receiving PIs. Recommended Agents Nelfinavir (Viracept) Adequate drug levels are achieved in pregnant women with nelfinavir 1,250 mg, given twice daily. No evidence of human teratogenicity. Well-tolerated, short-term safety was demonstrated for mother and infant. Nelfinavir dosing at 750 mg 3 times daily produced variable and generally low levels in pregnant women. Given pharmacokinetic data and extensive experience with use in pregnancy compared with other PIs, nelfinavir is the preferred PI for combination regimens in pregnant women, particularly if antiretrovirals are being given solely for perinatal prophylaxis. In clinical trials of initial therapy in nonpregnant adults, nelfinavir-based regimens had a lower rate of viral response compared with lopinavir/ritonavir or efavirenz-based regimens, but similar a viral response compared with atazanavir or nevirapine-based regimens. Saquinavir-SGC (Fortovase)/ Ritonavir Adequate drug levels are achieved in pregnant women with saquinavir-SGC 800 mg boosted with ritonavir 100 mg, given twice daily. Recommended adult dosing of saquinavir-SGC 1,000 mg plus ritonavir 100 mg may be used. No PK data exist on saquinavir hard-gel capsule/ritonavir in pregnancy, but better gastrointestinal tolerance in nonpregnant adults. Well-tolerated, short-term safety was demonstrated for mother and infant. Inadequate drug levels were observed in pregnant women with saquinavir-SGC given alone at 1,200 mg 3 times daily. Given pharmacokinetic data and moderate experience with use in pregnancy, ritonavir-boosted saquinavir-SGC can be considered a preferred PI for combination regimens during pregnancy. Alternative Agents Indinavir (Crixivan) Two studies including 18 women receiving indinavir 800 mg 3 times daily showed markedly lower drug levels during pregnancy compared with postpartum, although suppression of HIV RNA was seen. Theoretical concern exists about increased indirect bilirubin levels, which may exacerbate physiologic hyperbilirubinemia in the neonate, but minimal placental passage. Use of unboosted indinavir during pregnancy is not recommended. Alternate PI to consider if unable to use nelfinavir or saquinavir-SGC/ritonavir, but would need to give indinavir as ritonavir-boosted regimen. Optimal dosing for the combination of indinavir/ritonavir during pregnancy is unknown. Lopinavir/Ritonavir (Kaletra) Phase I/II safety and pharmacokinetic study is in progress using twice-daily lopinavir 400 mg and ritonavir 100 mg. Limited experience in human pregnancy. Preliminary studies suggest increased dose may be required during pregnancy, though specific dosing recommendations not established. If used during pregnancy, monitor response to therapy closely. If expected virologic result is not observed, consult with a specialist with expertise in HIV during pregnancy. Ritonavir (Norvir) Phase I/II study during pregnancy showed lower drug levels during pregnancy compared with postpartum. Minimal experience in human pregnancy. Given low levels in pregnant women when used alone, ritonavir is recommended for use in combination with a second PI as low-dose "boost" to increase levels of second PI. Insufficient Data to Recommend Use Amprenavir (Agenerase) No studies in human pregnancy. Oral solution is contraindicated in pregnant women because of high levels of propylene glycol, which may not be adequately metabolized during pregnancy. Safety and pharmacokinetics data in pregnancy are insufficient to recommend use of capsules during pregnancy. Fosamprenavir (Lexiva) No studies in human pregnancy. No experience in human pregnancy. Safety and PK data in pregnancy are insufficient to recommend use during pregnancy. Atazanavir (Reyataz) No studies in human pregnancy. Theoretical concern exists about increased indirect bilirubin levels, which may exacerbate physiologic hyperbilirubinemia in the neonate, although transplacental passage of other PIs has been low. Safety and pharmacokinetics in pregnancy data are insufficient to recommend use during pregnancy. Tipranavir (Aptivus) No studies in human pregnancy. No experience in human pregnancy. Safety and pharmacokinetics in pregnancy data are insufficient to recommend use during pregnancy. Fusion Inhibitor Antiretroviral Drug Pharmacokinetics in Pregnancy Concerns in Pregnancy Rationale for Recommended Use in Pregnancy Insufficient Data to Recommend Use Enfuvirtide (Fuzeon) No studies in human pregnancy. No experience in human pregnancy. Safety and pharmacokinetics data in pregnancy are insufficient to recommend use during pregnancy.

Source: Centers for Disease Control and Prevention. Table 3. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy. In: Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. July 6, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9. Key to abbreviations: HGC = hard-gel capsule; NNRTI = nonnucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NtRTI = nucleotide reverse transcriptase inhibitor; PI = protease inhibitor; SGC = soft-gel capsule. *Zidovudine and lamivudine are included as a fixed-dose combination in Combivir; zidovudine, lamivudine, and abacavir are included as a fixed-dose combination in Trizivir. # Triple NRTI regimens including abacavir have been less potent virologically compared with PI-based ART regimens. Triple NRTI regimens should be used only when an NNRTI- or PI-based ART regimen cannot be used (eg, due to significant drug interactions). A study evaluating use of zidovudine/lamivudine/abacavir among pregnant women with HIV RNA <55,000 copies/mL as a class-sparing regimen is in development.

Adverse Antiretroviral Drug Events during Pregnancy

Concerns have been raised about complications and toxicities related to ART during pregnancy. For example, a European study found a 2-fold increase in preterm birth among mothers who started combination therapy before pregnancy. A metaanalysis of 7 U.S. clinical trials, however, found that ARV use was not associated with preterm labor, low birth-weight, low Apgar scores, or stillbirth. Until more is known, pregnant women who are taking combination regimens should be monitored closely for complications and toxicities and should be educated about the signs of premature labor.

Nucleoside reverse transcriptase inhibitors can cause mitochondrial dysfunction with long-term use. Clinical disorders linked to mitochondrial dysfunction include symptomatic lactic acidosis and hepatic steatosis, which are seen more commonly in women than in men. Three maternal deaths were reported in the United States in women taking ARV regimens that included ddI and d4T in combination with other ARVs. Patients with lactic acidosis with hepatic steatosis often present with 1-6 weeks of symptoms including nausea, vomiting, abdominal pain, dyspnea, and weakness. Because some of the symptoms of lactic acidosis/hepatic steatosis syndrome can mimic those of pregnancy, clinicians must be alert for early signs and symptoms of lactic acidosis and evaluate them promptly. The combination of ddI and d4T should be avoided during pregnancy, and used only when other effective options are not available (Table 2).

Women, including pregnant women, who begin nevirapine therapy when their CD4 count is >250 cells/µL have a 9.8 times higher incidence of hepatotoxicity than women initiated on nevirapine at lower CD4 counts. Symptoms of hepatotoxicity include fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and hepatomegaly. Nevirapine should be initiated as part of an ARV regimen in pregnant women with CD4 cell counts >250 cells/µL only if the benefits clearly outweigh the risks (Table 2).

Hyperglycemia, new-onset diabetes, worsening diabetes, and diabetic ketoacidosis have been reported in patients taking protease inhibitors. In addition, pregnancy itself is a risk factor for hyperglycemia. Clinicians should monitor closely the glucose level of pregnant women taking PIs and should educate them about the symptoms of hyperglycemia. (See chapter Care of HIV-Infected Pregnant Women.)

Recommendations for Antiretroviral Chemoprophylaxis to Reduce Perinatal HIV Transmission

The Perinatal HIV Working Group has offered recommendations on ARV prophylaxis to reduce perinatal HIV transmission based on 4 clinical scenarios:

• HIV-infected women who have not received previous ARV therapy
• HIV-infected women receiving ARV therapy during the current pregnancy
• HIV-infected women in labor who have had no previous therapy
• Infants born to HIV-infected women who received no ARV therapy during pregnancy or intrapartum

Recommendations for ART in these 4 clinical scenarios are listed in Table 3.

Table 3. Clinical Scenarios and Recommendations for the Use of Antiretroviral Drugs to Reduce Perinatal HIV-1 Transmission

SCENARIO #1: HIV-1-infected pregnant women who have not received previous ARV therapy SCENARIO #2: HIV-1-infected women receiving ARV therapy during the current pregnancy Pregnant women with HIV-1 infection must receive standard clinical, immunologic, and virologic evaluations. Recommendations for initiation and choice of ARV therapy should be based on the same parameters used for persons who are not pregnant, although the known and unknown risks and benefits of such therapy during pregnancy must be considered and discussed. The 3-part ZDV chemoprophylaxis regimen, initiated after the first trimester, is recommended for all pregnant women with HIV-1 infection regardless of antenatal HIV RNA copy number to reduce the risk of perinatal transmission. The combination of ZDV chemoprophylaxis with additional ARV drugs for treatment of HIV-1 infection is recommended for infected women whose clinical, immunologic, or virologic status requires treatment or who have HIV-1 RNA >1,000 copies/mL regardless of clinical or immunologic status, and can be considered for women with HIV-1 RNA <1,000 copies/mL. Women who are in the first trimester of pregnancy may consider delaying initiation of therapy until after 10-12 weeks' gestation. HIV-1-infected women receiving ARV therapy in whom pregnancy is identified after the first trimester should continue therapy. ZDV should be a component of the antenatal ARV treatment regimen after the first trimester whenever possible, although this may not always be feasible. For women receiving ARV therapy in whom pregnancy is recognized during the first trimester, women should be counseled regarding the benefits and potential risks of ARV administration during this period, and continuation of therapy should be considered. If therapy is discontinued during the first trimester, all drugs should be stopped and reintroduced simultaneously to avoid the development of drug resistance. Regardless of the antepartum ARV regimen, ZDV administration is recommended during the intrapartum period and for the newborn. SCENARIO #3: HIV-1-infected women in labor who have had no previous therapy SCENARIO #4: Infants born to HIV-1-infected mothers who have received no ARV therapy during pregnancy or intrapartum Several effective regimens are available (see USPHS Perinatal ARV Guidelines,Table 5). These include: Intrapartum intravenous ZDV followed by 6 weeks of ZDV for the newborn; Oral ZDV and 3TC during labor, followed by 1 week of oral ZDV-3TC for the newborn; A single dose of nevirapine at the onset of labor followed by a single dose of nevirapine for the newborn at 48 hours postpartum; The single-dose maternal and infant nevirapine regimen combined with intrapartum intravenous ZDV and 6-week ZDV for the newborn. If single-dose nevirapine is given to the mother, alone or in combination with ZDV, consideration should be given to adding maternal ZDV/3TC starting as soon as possible (intrapartum or immediately postpartum) and continuing for 3- 7 days, which may reduce the development of nevirapine resistance. In the immediate postpartum period, the woman should have appropriate assessments (eg, CD4 count and HIV-1 RNA copy number) to determine whether ARV therapy is recommended for her own health. The 6-week neonatal ZDV component of the ZDV chemoprophylactic regimen should be discussed with the mother and offered for the newborn. ZDV should be initiated as soon as possible after delivery--preferably within 6-12 hours of birth. Some clinicians may choose to use ZDV in combination with other ARV drugs, particularly if the mother is known or suspected to have ZDV-resistant virus. However, the efficacy of this approach for prevention of transmission has not been proven in clinical trials, and appropriate dosing regimens for neonates are incompletely defined for many drugs. In the immediate postpartum period, the woman should undergo appropriate assessments (eg, CD4 count and HIV-1 RNA copy number) to determine whether ARV therapy is required for her own health. The infant should undergo early diagnostic testing so that, if HIV infected, treatment can be initiated as soon as possible.

Key to abbreviations: ARV = antiretroviral; ZDV = zidovudine; USPHS = U.S. Public Health Service; 3TC = lamivudine. Adapted from: Centers for Disease Control and Prevention. Table 4. Clinical Scenarios and Recommendations for the Use of Antiretroviral Drugs to Reduce Perinatal Human Immunodeficiency Virus Type 1 (HIV-1) Transmission. In: Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. July 6, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9.

The USPHS Perinatal ARV Guidelines emphasize that the PACTG 076 regimen is effective not only for women whose clinical status is similar to that of the participants in the original study, but also for women with advanced HIV disease, low CD4 counts, and previous ZDV therapy.

Because the goals of ART in a pregnant woman are not only to maintain her health, but also to prevent transmission to her infant, the considerations in ART differ from those in nonpregnant adults. Because the HIV viral load strongly influences the risk of HIV transmission, a primary goal of therapy should be to suppress the viral load to very low levels (preferably to undetectable levels) during pregnancy and throughout delivery; this goal guides treatment decisions. For nonpregnant adults, the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents recommend that treatment be deferred in certain persons, depending on the CD4 cell count and the HIV viral load. (See chapter Antiretroviral Therapy.) In contrast, the USPHS Perinatal ARV Guidelines recommend that all pregnant women, regardless of CD4 cell count, receive the 3-part ZDV prophylaxis regimen used in PACTG 076, that is, ZDV orally (200 mg 3 times a day or 300 mg twice a day) beginning after the first trimester, intravenous ZDV during labor, and ZDV given orally to the newborn for 6 weeks. The guidelines also recommend that women with an HIV RNA level >1,000 copies/mL (regardless of CD4 cell count) or with immunologic, virologic, or clinical indications for treatment be offered a combination ART regimen that includes ZDV and other ARV drugs. Even women with HIV RNA levels <1,000 copies/mL should be considered for combination therapy.

The specific ART regimen should be selected with a view to the limited information available about the efficacy and potential toxicities of ARV combinations during pregnancy. The USPHS offers recommendations on the use of specific ARV agents during pregnancy (Table 2).

Mode of Delivery and Other Intrapartum Management

All pregnant women with HIV infection should receive the intrapartum and neonatal components of ZDV prophylaxis used in the PACTG 076 protocol, as outlined earlier. ZDV should be given to the woman intravenously during labor in a 1-hour initial loading dose of 2 mg per kilogram body weight followed by a continuous infusion of 1 mg/kg body weight per hour until delivery. The newborn should receive ZDV syrup at a dose of 2 mg/kg body weight per dose every 6 hours beginning 8-12 hours after birth and continuing for the first 6 weeks of life.

Early studies before the availability of viral load testing found that cesarean delivery performed before the onset of labor or rupture of membranes significantly reduced the risk of perinatal transmission. However, now that many HIV-infected pregnant women in the United States and other high-income settings are receiving combination ART, transmission rates of 1.2-1.5%, unadjusted for mode of delivery, have been reported). Because the transmission rate is so low in women taking effective ART, it is difficult to determine whether cesarean section offers any additional benefit. For women with a viral load <1,000 copies/mL, it is unlikely that cesarean section would provide additional benefit.

The American College of Obstetricians and Gynecologists recommends consideration of cesarean section at 38 weeks for HIV-infected women with a viral load >1,000 copies/mL at or near the time of delivery. The woman and her health care providers should decide about mode of delivery before the onset of labor, based on her current viral load, her health status, and discussion about other concerns. Pregnant women who have not achieved optimal virologic control and whose viral load remains >1,000 copies/mL in the weeks before delivery, should be counseled about the risks and benefits of cesarean section. A planned cesarean section should be scheduled for 38 weeks' gestation, because the benefits of cesarean section once the membranes have ruptured are unknown. Intravenous ZDV should be started 3 hours before the scheduled cesarean section. Prophylactic antibiotics are recommended at the time of cesarean section in HIV-infected women, to decrease the risk of maternal infection. The USPHS Perinatal ARV Guidelines outline 4 scenarios in which the clinician must decide whether cesarean section is needed (Table 4). The data on the benefits of cesarean section are complex and must be balanced with the increased risk to the mother after surgery. The clinician may want to consult an obstetric/HIV specialist to discuss specific situations.

Questions remain about the management of labor when a vaginal delivery is planned. Because the duration of ruptured membranes is a risk factor for perinatal transmission, pregnant women with HIV infection should be counseled to go to a hospital for care at the first signs of labor or rupture of membranes. If the membranes rupture spontaneously before labor occurs or early in labor, the clinician should consider interventions to decrease the interval to delivery, such as administration of oxytocin. Procedures that increase the neonate's exposure to maternal blood, such as the use of scalp electrodes or artificial rupture of membranes, should be avoided.

Table 4. Clinical Scenarios and Recommendations regarding Mode of Delivery to Reduce Perinatal HIV-1 Transmission

Mode of Delivery Clinical Scenario Recommendations Scenario A: An HIV-1-infected woman presenting in late pregnancy (after about 36 weeks of gestation), known to be HIV-1-infected but not receiving ART, and who has HIV-1 RNA level and lymphocyte subsets pending but unlikely to be available before delivery Therapy options should be discussed in detail. The woman should be started on ART, including at least the PACTG 076 ZDV regimen. The woman should be counseled that scheduled cesarean section is likely to reduce the risk of transmission to her infant. She should also be informed of the increased risks to her of cesarean section, including increased rates of postoperative infection, anesthesia risks, and other surgical risks. If cesarean section is chosen, the procedure should be scheduled at 38 weeks of gestation, based on the best available clinical information. When scheduled cesarean section is performed, the woman should receive continuous intravenous ZDV infusion beginning 3 hours before surgery and her infant should receive 6 weeks of ZDV therapy after birth. Options for continuing or initiating combination ART after delivery should be discussed with the woman as soon as her viral load and lymphocyte subset results are available. Scenario B: An HIV-1-infected woman who initiated prenatal care early in the third trimester, is receiving highly active combination ART, and has an initial virologic response, but has HIV-1 RNA levels that remain substantially >1,000 copies/mL at 36 weeks of gestation The current combination ARV regimen should be continued because the HIV-1 RNA level is dropping appropriately. The woman should be counseled that, although she is responding to ART, it is unlikely that her HIV-1 RNA level will fall below 1,000 copies/mL before delivery. Therefore, scheduled cesarean section may provide additional benefit in preventing intrapartum transmission of HIV-1. She also should be informed of the increased risks to her of cesarean section, including increased rates of postoperative infection, anesthesia risks, and surgical risks. If she chooses scheduled cesarean section, it should be performed at 38 weeks' gestation according to the best available gestational dating parameters, and intravenous ZDV should be begun at least 3 hours before surgery. Other ARV medications should be continued on schedule as much as possible before and after surgery. The infant should receive oral ZDV for 6 weeks after birth. The importance of adhering to therapy after delivery for the woman's own health should be emphasized. Scenario C: An HIV-1-infected woman taking combination ART with an undetectable HIV-1 RNA level at 36 weeks of gestation The woman should be counseled that her risk of perinatal transmission of HIV-1 with a persistently undetectable HIV-1 RNA level is low, probably 2% or less, even with vaginal delivery. There is no information currently available to evaluate whether performing a scheduled cesarean section will decrease her risk further. Cesarean section increases the risk of complications for the woman as compared with vaginal delivery, and these risks must be balanced against the uncertain benefit of cesarean section in this case. Scenario D: An HIV-1-infected woman who has opted for scheduled cesarean section but presents in early labor or shortly after rupture of membranes Intravenous ZDV should be started immediately because the woman is in labor or has ruptured membranes. If labor is progressing rapidly, the woman should be allowed to deliver vaginally. If cervical dilatation is minimal and a long period of labor is anticipated, some clinicians may choose to administer the loading dose of intravenous ZDV and proceed with cesarean section to minimize the duration of membrane rupture and avoid vaginal delivery. Others might begin oxytocin augmentation to enhance contractions and potentially expedite delivery. If the woman is allowed to labor, scalp electrodes and other invasive monitoring and operative delivery should be avoided if possible. The infant should be treated with 6 weeks of ZDV therapy after birth.

Key to abbreviations: ART = antiretroviral therapy; PACTG 076 = Pediatric AIDS Clinical Trial Group study 076; ZDV = zidovudine; ARV = antiretroviral Adapted from: Centers for Disease Control and Prevention. Table 7. Clinical Scenarios and Recommendations Regarding Mode of Delivery to Reduce Perinatal Human Immunodeficiency Virus Type 1 (HIV-1) Transmission. In: Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States. July 6, 2006. Available online at aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?GuidelineID=9.

Postpartum Follow-Up of the Woman with HIV Infection

Women with HIV infection who have delivered recently need access to a comprehensive array of services for themselves and their infants. The clinician should refer the postpartum woman not only to her primary obstetric and HIV providers for family planning and HIV management, but also to a pediatric HIV specialist for care for her infant. She should also be referred as needed for mental health, substance abuse, and social support services. The clinician should be alert for indications of postpartum depression and should offer treatment promptly. Adherence to ARV regimens may be particularly difficult in the immediate postpartum period because of the physical changes postpartum and the demands of a new baby.

Women should be evaluated for their ongoing need for ART postpartum. If combination ART was given only or primarily to reduce the risk of perinatal transmission, the woman and her clinician may wish to consider discontinuing therapy after pregnancy, with the option to resume ART when she meets the criteria for treatment. Generally, all drugs should be stopped at once, but if the drugs have very different half-lives, their discontinuation should be staggered to decrease the risk of resistance, (eg, in regimens containing nevirapine, which has a long half-life). Drugs with a short half-life should be continued for several days to 1 week after the nevirapine is discontinued.

Follow-Up of the HIV-Exposed Infant

The HIV-exposed infant should be referred to a pediatric HIV specialist for diagnostic testing and monitoring of health status. Newborns should be discharged home with a supply of ZDV oral syrup. The newborn should receive ZDV syrup at a dose of 2 mg/kg body weight per dose every 6 hours beginning 8-12 hours after birth and continuing for 6 weeks.

Traditional HIV antibody testing cannot be used in infants because maternal antibodies may persist for up to 18 months. Diagnosis of HIV infection in infants requires virologic testing with HIV DNA polymerase chain reaction (PCR) or HIV RNA PCR. The DHHS Pediatric ARV Guidelines recommend testing at birth to 14 days, at 1-2 months, and at 3-6 months. HIV DNA PCR is a sensitive test that detects viral DNA in the patient's peripheral monocytes. Although the sensitivity of DNA PCR is <40% if performed at <48 hours of age, by 2-4 weeks of age, the sensitivity is >90%. HIV RNA PCR detects extracellular viral RNA in the plasma and is as sensitive as DNA PCR for early diagnosis in infants. Some clinicians recommend using the HIV RNA assay as a confirmatory test for an infant with a positive DNA PCR result. This approach confirms the diagnosis and can help guide treatment decisions. HIV viral culture is also sensitive, but it is expensive and results may not be available for 2-4 weeks.

HIV can be diagnosed in an infant on the basis of 2 positive virologic tests done on separate blood samples at any time. HIV reasonably can be excluded in an infant with 2 negative virologic tests done at >1 month of age, with 1 being done at >4 months of age. Antibody testing is recommended at age 12-18 months to document seroreversion.

Infants should have a baseline complete blood count and should be monitored for anemia while they are taking ZDV. The DHHS Perinatal ARV Guidelines recommend Pneumocystis jiroveci pneumonia (PCP) prophylaxis for HIV-exposed infants beginning at 6 weeks (when the ZDV is completed) and continuing until age 6 months or until HIV infection can be ruled out.

Parents and family care givers need to be educated that the infant must be monitored closely until an HIV diagnosis is made or is ruled out. They also need to know that the infant's exposure to ARV agents in utero is an important part of the infant's medical history and should be shared with future health care providers. Although no long-term consequences of ARV exposure have been confirmed, the child may be at risk for long-term problems.

Antiretroviral Pregnancy Registry

To improve tracking of pregnancy-related adverse effects and fetal effects, an Antiretroviral Pregnancy Registry has been established as a collaborative project among the pharmaceutical industry, pediatric and obstetric providers, the CDC, and the National Institutes of Health. The registry collects observational data on HIV-infected pregnant women taking ARV medications to determine whether patterns of fetal or neonatal abnormalities occur. Pregnant women taking ARVs can be placed in this confidential follow-up study by calling 800-258-4263, 8:30 am to 5:30 pm eastern time; the fax number is 800-800-1052. Information is confidential and patients' names are not used. Providers are encouraged to add to the available information on fetal risk by using this registry at first contact with a pregnant woman taking ARVs. More information can be obtained at http://www.APRegistry.com.

Patient Education

• The clinician should provide the pregnant woman with the most current information on the risk of mother-to-child HIV transmission and the importance of ARV prophylaxis.
• The clinician and the pregnant woman should have a detailed discussion about whether she needs ART for her health and the ARV regimen that would be most appropriate for her to decrease the risk of perinatal transmission.
• The clinician should review the critical importance of adherence to ARV regimens before prescribing a regimen.
• Once a regimen is begun, the clinician should review possible adverse effects of the drugs and give the woman specific instructions about managing them if they are mild or getting medical advice if they represent a more serious adverse effect, such as ongoing fatigue, persistent nausea and vomiting, or signs of hyperglycemia.
• Early in the third trimester, the clinician and patient should discuss the risks and potential benefits of cesarean section based on her viral load and clinical status.
• Intrapartum management, including intrapartum ZDV, should be discussed with the patient so that she knows that she should tell the delivery team about her HIV status when she presents in labor.
• The signs of early labor should be explained to the pregnant woman and she should know that she should seek care immediately if her membranes rupture or she believes she is in labor.
• The clinician should discuss infant feeding plans with the mother and reinforce that she should not breast-feed. The clinician may need to provide ongoing support for formula feeding.
• The clinician should discuss follow-up plans and make referrals for the pregnant woman and her infant. If at all possible, the woman should meet the pediatric HIV team before delivery or in the postpartum period. The importance of ARV prophylaxis and follow-up for the newborn should be stressed.

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