Reducing Perinatal HIV Transmission

Background

This chapter describes strategies for reducing the risk of perinatal HIV, based on the U.S. Department of Health and Human Services (HHS) Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. 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 are available for consultation through the Perinatal HIV Hotline (888-448-8765). For more information on other aspects of caring for HIV-infected pregnant women, see chapter Care of HIV-Infected Pregnant Women.

Unless otherwise referenced, the information in this chapter is based on the most recent HHS perinatal guidelines available at the time this chapter was published. Consult the AIDSinfo website for the most current recommendations.

Overview of Prevention of Perinatal HIV Transmission

In the absence of antiretroviral (ARV) prophylaxis or other interventions, the rate of perinatal HIV transmission in the United States ranges from 16% to 25%. Antiretroviral therapy (ART) is highly effective in reducing the risk of perinatal transmission of HIV, to as low as <1%. It probably prevents HIV transmission in several ways, including by reducing the mother's viral load in blood and genital secretions and by providing pre- and postexposure prophylaxis for the infant. All pregnant women with HIV infection should be educated about the risks of perinatal HIV transmission and offered ART and other medical management to maintain or improve their own health and to reduce the risk of HIV transmission to their infants.

In 1994, the Pediatric AIDS Clinical Trial Group study 076 (PACTG 076) found that ARV treatment during pregnancy could significantly reduce the risk of HIV transmission to infants. The intervention, consisting of zidovudine (ZDV) given PO to the women during the last weeks of pregnancy and IV during labor and delivery, as well as to the newborns for 6 weeks, reduced the rate of infant infection from 25.5% to 8.3%. The ZDV regimen quickly became the standard of care in the United States and other high-income countries. Subsequent studies showed that combination ARV regimens with suppression of maternal HIV viral load to undetectable levels further reduced the risk of perinatal infection.

Studies in resource-limited countries as well as in resource-abundant areas have examined various ARV strategies for reducing the risk of perinatal HIV transmission. The Petra study, a placebo-controlled trial in a breast-feeding population in Uganda, South Africa, and Tanzania, found a transmission rate of 8.9% among women who received PO 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 15.3% 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 that of PO ZDV given to the mother during labor and to the newborn. The transmission rate was 11.8% in the NVP arm, compared with 20.0% in the ZDV arm. The results of this study and the low cost of NVP prompted a number of resource-limited countries to institute NVP prophylaxis as the standard of care for preventing mother-to-child transmission 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. Research has shown that ARV interventions even late in the peripartum or newborn periods 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 either to both the mothers intrapartum and their newborns or to the newborns only, compared with 26.6% if no ARV medication was given. This study underscores the importance of offering ARV interventions to pregnant women with HIV infection whenever they are identified during pregnancy or during labor and delivery, or as an intervention with the newborn.

In the United States, the PACTG 076 regimen remains an important component in the prevention of perinatal HIV transmission, and usually is incorporated into combination ART 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.

Mother-to-child transmission also can occur through breast-feeding. Recent studies have shown that ART given to the nursing mother and/or her infant decreases but does not eliminate the risk of HIV transmission to the infant. In the United States, because substitute feeding is safe, affordable, feasible, sustainable, and available, mothers in the United States should not breast-feed.

HIV Testing During Pregnancy

The success of interventions to reduce the risk of perinatal HIV transmission has been achieved through the routine HIV testing and counseling of all pregnant women. Interventions to prevent transmission can be effective only if women know their HIV status and have access to treatment. HHS has recommended universal HIV counseling and testing for pregnant women since 1995. Many national 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, endorse those recommendations. Current recommendations from the U.S. Centers for Disease Control and Prevention (CDC) feature the following three approaches to HIV testing during pregnancy:

  • Routine testing as part of first-trimester prenatal screening tests for all pregnant women, using an "opt-out" policy whereby a pregnant woman is tested unless she specifically declines testing
  • Routine "opt-out" testing with a rapid HIV test for women who present in labor with unknown or undocumented HIV status, in order to offer ARV prophylaxis during labor for those who test positive for HIV
  • Expedited HIV testing for newborns of mothers of unknown HIV status so that they can receive postexposure ARV prophylaxis, if indicated

The CDC also recommends repeat HIV testing in the third trimester for women who receive health care in jurisdictions with an elevated incidence of HIV or AIDS among women, as well as for women at high risk of acquiring HIV (e.g., a history of injection drug use, exchange of sex for money or drugs, multiple sex partners, or a partner known to be HIV infected). Jurisdictions in which repeat third-trimester testing is recommended include Alabama, Connecticut, Delaware, District of Columbia, Florida, Georgia, Illinois, Louisiana, Maryland, Massachusetts, Mississippi, Nevada, New Jersey, New York, North Carolina, Pennsylvania, Puerto Rico, Rhode Island, South Carolina, Tennessee, Texas, and Virginia. A number of states mandate a third-trimester HIV test for all pregnant women.

Any pregnant woman with signs or symptoms of acute HIV infection should be evaluated (see chapter Early HIV Infection) and receive an HIV plasma RNA test as well as an antibody test.

State laws regarding HIV testing during pregnancy vary widely, and many are currently under review. A number of states have adopted the opt-out approach, whereas some still require written informed consent before an HIV test is done. Others require patient education and a chart note from the providers. Clinicians should be familiar with relevant state laws regarding HIV testing during pregnancy, opt-out or consent provisions, and regulations about rapid HIV testing during the intrapartum or newborn period. (Information on state laws regarding HIV testing during pregnancy can be found at the National HIV/AIDS Clinicians' Consultation Center's Compendium of State HIV Testing Laws at www.nccc.ucsf.edu.) Whatever the consent process, a woman should know that an HIV test is being done and should receive at least the information outlined below.

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 component of prenatal care, that her 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 (e.g., brochures, videos):

  • HIV is the virus that causes AIDS.
  • Without treatment, approximately 25% of babies born to HIV-infected women will be infected, either during pregnancy, during labor and delivery, or by breast-feeding.
  • A woman could be at risk of HIV infection and not know it.
  • ART is highly effective in protecting 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 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.

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. The CDC recommends repeat HIV testing in the third trimester for women who have risk factors for HIV or who live in areas with a high incidence of HIV in women; some states mandate third-trimester testing for all pregnant women.

If the client declines testing at any point, the clinician should inquire about her reasons and follow up at subsequent visits. If the 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. When giving test results to an HIV-negative woman, the clinician should take the opportunity to discuss risk-reduction strategies to help ensure that she remains uninfected by HIV. Women at risk of HIV infection should be referred for more extensive counseling because some research indicates that pregnancy may place them at greater risk of acquiring HIV infection, and acute HIV infection may confer greater risk of transmission to the fetus.

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 upon receiving 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.

Expedited HIV Testing During Labor

As discussed earlier, beginning ART during pregnancy offers the greatest chance for preventing perinatal transmission of HIV, but interventions during the intrapartum and neonatal periods also offer opportunities to decrease the risk of HIV transmission. Expedited HIV testing for women who present in labor with unknown or undocumented HIV status can identify women who are infected with HIV so that interventions can be offered. Available rapid HIV antibody tests are both sensitive and specific and provide results in as little as 20 minutes. Fourth-generation antigen-antibody HIV tests also are becoming increasingly available through hospital laboratories using random access machines that deliver results in 30 minutes to 2 1/2 hours.

Women who should receive HIV testing during labor include the following:

  • Those who have had little or no prenatal care
  • Those who were not offered testing earlier in pregnancy
  • Those who declined previously
  • 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, with consideration given 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 available interventions can decrease her baby's risk of becoming infected with HIV if she is found to be seropositive.

Women who present in labor with unknown HIV serostatus should undergo expedited HIV antibody testing. If the results are positive, a confirmatory HIV test should be sent as soon as possible but maternal prophylaxis should be started immediately (intravenous ZDV). This should be followed by combination ARV prophylaxis (ZDV + NVP) for the infant beginning as soon as possible after birth. ARV drugs should be initiated pending results of the confirmatory test. If the confirmatory HIV test result is positive, infant ARV drugs should be continued for 6 weeks. If the confirmatory test result is negative, the infant ARV drugs should be stopped.

Factors Influencing Perinatal HIV Transmission

Perinatal transmission is most likely to occur in the intrapartum period. Several factors influence the risk of transmission from mother to infant. One of these is 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 during delivery and the risk of perinatal HIV transmission, even among women receiving treatment with ARVs. However, HIV transmission may occur at any level of maternal HIV RNA, including (rarely) when the viral load is undetectable. HIV RNA levels in the blood and the genital tract generally correlate but discordance may occur. Low-level cervical-vaginal HIV shedding has been found even in women on ART with undetectable plasma HIV RNA, particularly in the presence of genital infections.

ARV prophylaxis is a critical factor in reducing HIV transmission. For women on effective combination ART with undetectable HIV RNA, the rate of perinatal HIV transmission is approximately 1%. Thus, ARV prophylaxis with full suppression of HIV RNA is recommended for all pregnant women with HIV infection, regardless of HIV viral load. Note that ART may exert protective effects not only by lowering maternal HIV RNA but also (for ARVs with good transplacental passage) by providing pre- and postexposure prophylaxis for the infant.

Other maternal factors associated with increased risk of perinatal transmission include low CD4 cell count, sexually transmitted diseases, active genital herpes during labor, illicit drug use, cigarette smoking, and unprotected sex with multiple partners.

Obstetric factors also affect the risk of HIV transmission. Infection risk 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, placement of scalp electrodes, artificial rupture of membranes, episiotomy, or operative (forceps) delivery may increase risk by exposing the fetus to maternal blood; these procedures should be avoided (though the risk of transmission in women on fully suppressive ART is not clear). In addition, the mode of delivery, whether vaginal or cesarean, can influence the risk of HIV transmission. Scheduled cesarean delivery decreases the rate of perinatal infection for women with an HIV RNA level of >1,000 copies/mL, but its efficacy is not clear for women whose labor has begun or for those whose membranes have ruptured; see "Intrapartum Management and Mode of Delivery," below, for further information.

Infant risk factors for HIV infection include premature birth, low birth weight, skin and mucous membrane lesions such as thrush, and breast-feeding. Breast-feeding increases the risk of HIV transmission by 5-20%. In the United States, where safe, affordable replacement feeding and clean water routinely are available, women with HIV should not breast-feed. However, some women with HIV will be under tremendous cultural and familial 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 as low as possible for as long as possible
  • To preserve and restore immune function
  • To prolong life and improve quality of life
  • To reduce risk of HIV transmission to sex partners

An additional, and crucial, goal of ART for pregnant women is to reduce the risk of perinatal HIV transmission through maximal HIV suppression.

The HHS recommendations discuss in detail the multiple issues that must be considered when balancing the woman's need for therapy for her own health and the need to decrease the risk of transmission to the infant. Combination ART is recommended for all HIV-infected pregnant women regardless of CD4 count or HIV viral load. Decisions about ART are complex and should be made by the woman and her health care provider after discussing the risks and benefits. Clinicians are urged to consult an HIV specialist and the most current HHS recommendations when making therapeutic decisions. The Perinatal HIV Hotline (888-448-8765) provides free clinical consultation on all aspects of perinatal HIV care. The following discussion addresses some of the issues in determining ART strategies and is taken from the HHS Perinatal ARV Guidelines.

The HHS Perinatal HIV Guidelines Working Group recommends fully suppressive combination ART for all pregnant women, unless there are compelling reasons based on pregnancy-specific maternal and fetal safety issues to modify this approach. Key recommendations from the HHS Perinatal ARV Guidelines include the following:

  • Assess the woman's HIV disease status and make recommendations about initiating or altering an ARV regimen, as part of the initial evaluation.
  • Recommend ARV prophylaxis to all pregnant women regardless of HIV viral load or CD4 count.
  • Discuss known benefits and potential risks of ART.
  • If HIV RNA level is >500-1,000 copies/mL, perform drug-resistance testing prior to starting or changing ART.
  • If HIV is diagnosed late in pregnancy, ART should be initiated promptly without waiting for results of resistance testing.
  • Emphasize the importance of adherence to the regimen.
  • Ensure that the woman has access to and coordination of services among perinatal, primary care, and HIV providers as well as mental health and drug abuse services and income support as needed.
  • Considerations about continuing ART after pregnancy are the same as for nonpregnant individuals.

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 benefits. Thus, women should be advised of the potential risks and benefits of ART (to the woman, fetus, and infant) and of the limited long-term data on outcomes for infants with in utero exposure to ARVs, but treatment decisions should be guided by the woman's clinical, virologic, and immunologic status and by the goal of preventing perinatal transmission. An additional benefit of ART is the reduction in risk of transmission to sex partners. Women should be educated and counseled on the importance of close adherence to the ART regimen (see chapter Adherence).

Drug-resistance testing should be conducted for all pregnant women before the initiation of therapy, and for women who are already on ART without fully suppressed HIV RNA.

All women receiving ARVs during pregnancy for prophylaxis or for treatment should receive a combination containing at least three agents, with the aim of viral suppression to undetectable levels (i.e., <20-75 copies/mL, depending on the assay). Monotherapy (e.g., with ZDV) and dual therapy are not as effective and generally are not recommended. Current Guidelines recommend that the regimen include two nucleoside reverse transcriptase inhibitors (NRTIs) and either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Regimen selection should be individualized on the basis of factors such as anticipated safety and efficacy, ARV history, results of resistance testing, and comorbidities (e.g., hepatitis B virus [HBV]) (see chapter Antiretroviral Therapy for considerations in selecting ARVs). It should be recognized that only limited information is available for many ARVs and ARV combinations regarding potential toxicities for the fetus or infant (see Table 5 of the Guidelines), and for dosage requirements with pregnant women.

The HHS Perinatal ARV Guidelines offer recommendations on the use of specific ARV agents during pregnancy. The table below shows "Preferred" and "Alternative" ARVs; others are classified as "Use in special circumstances" or "Insufficient data to recommend use." For more complete information, see Table 5 of the Guidelines).

Recommendations for ARV Use During Pregnancy
ARV ClassPreferred AgentsAlternative Agents

* For women with CD4 counts of >250 cells/µL, NVP should be initiated only if benefit clearly outweighs risk, owing to the increased risk of potentially life-threatening hepatotoxicity in women with high CD4 counts. Women who are already taking NVP at the start of pregnancy and are tolerating it well may continue NVP, regardless of CD4 count.

# Risk of hypersensitivity reaction; should be given only to patients who test negative for HLA-B*5701. Test for HLA-B*5701 before starting abacavir.

Adapted from U.S. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Accessed December 1, 2013.

NRTI
  • Lamivudine
  • Zidovudine
  • Abacavir#
  • Emtricitabine
  • Tenofovir
NNRTI
  • Nevirapine*
 
PI
  • Atazanavir/ritonavir
  • Lopinavir/ritonavir (Kaletra)
  • Darunavir/ritonavir
  • Saquinavir/ritonavir

The guidelines' preferred NRTI component is ZDV/3TC, because of data showing safety and efficacy in pregnancy. Alternative NRTIs listed above may be used for women with intolerance to ZDV (e.g., severe anemia) or documented resistance to ZDV (see "Safety and Toxicity of Antiretroviral Medications During Pregnancy," below). Tenofovir + 3TC or FTC is the preferred NRTI pair for women with hepatitis B coinfection (see "Special Circumstances," below).

Of the NNRTIs, NVP may be started for women with CD4 counts of ≤250 cells/L or continued for women who are already on NVP-containing regimens. NVP generally should not be started for treatment-naive women with CD4 counts of >250 cells/L because of an increased risk of symptomatic and potentially fatal hepatic and rash toxicity. Efavirenz is not recommended for use during the first 5-6 weeks of pregnancy because of concern for potential teratogenicity, but it can be continued in pregnant women already taking an effective efavirenz-based regimen who present for antenatal care in the first trimester, and it can be considered for other women (after the first 6 weeks of pregnancy) if other agents are not appropriate (see "Safety and Toxicity of Antiretroviral Medications During Pregnancy," below). There are insufficient pharmacokinetic and safety data to recommend the use of etravirine or rilpivirine during pregnancy.

Atazanavir + ritonavir and lopinavir/ritonavir are recommended PIs based on efficacy studies in adults and experience in pregnant women. For both of these (and for darunavir), serum levels may be low in the second and third trimesters; see the Guidelines for recommendations about dosage adjustments. The alternative PIs are ritonavir-boosted darunavir and ritonavir-boosted saquinavir, although pharmacokinetic data during pregnancy are limited. Nelfinavir has been used widely for pregnant women but current guidelines recommend its use only in "special circumstances" because, in nonpregnant adults, it has shown inferior efficacy compared with first-line agents. Indinavir also may be considered when preferred and alternative agents are not available. Fosamprenavir and tipranavir are not recommended because of lack of data in pregnancy, but they may be considered if other agents are not tolerated or are not appropriate.

The integrase inhibitor raltegravir may be considered if preferred or alternative agents are not appropriate. Pharmacokinetic and safety data in pregnancy are not sufficient to recommend the use of maraviroc or enfuvirtide, and they do not consider the newer agents rilpivirine, etravirine/cobicistat, or dolutegravir; these may be considered for use by women for whom drugs in other classes have failed but they should be prescribed in consultation with HIV and obstetric specialists.

ART Recommendations by Clinical Scenario

Recommendations for ARV Use by Pregnant Women

The HHS Perinatal ARV Guidelines offer recommendations on ART for pregnant women based on four clinical scenarios; these are categorized by the woman's ART status when she presents for care (see Table 6 of the Guidelines). Note that current adult and adolescent guidelines recommend ART for all, regardless of CD4 cell count (see chapter Antiretroviral Therapy).

HIV-infected pregnant women currently receiving ART

Women already receiving ART should, in general, continue to receive it during pregnancy if it is suppressing viral replication. If the woman has detectable virus (e.g., >500-1,000 copies/mL) on therapy, HIV drug-resistance testing should be performed, and the regimen should be optimized to maximize the likelihood of achieving virologic suppression. Women presenting in the first trimester should be counseled about the risks and benefits of ART during this period. Discontinuation of therapy could lead to increased viral load and potential for transmission to the fetus.

Pregnant women receiving NVP-containing regimens should continue them, regardless of CD4 count, if they are virologically suppressed and tolerating the regimen. For women who become pregnant while taking efavirenz, current Guidelines state that, because the risk of neural tube defects is limited to the first 5 to 6 weeks of pregnancy and pregnancy is rarely recognized before 4 to 6 weeks of pregnancy, efavirenz can be continued (assuming the regimen is maximally suppressive).

HIV-infected pregnant women who are ARV naive

All pregnant women should start potent combination ART. The drug regimen should be based on the recommendations of the Perinatal ARV Guidelines (see above and Table 5 of the Guidelines). As in other scenarios, drug-resistance testing should guide ARV selection.

Starting ART early in pregnancy may be more effective in reducing perinatal HIV transmission but the potential benefits of early ART must be weighed against potential fetal effects of first-trimester exposure. Starting ART after the first trimester can be considered in women with high CD4 T-lymphocyte (CD4-cell) counts and low HIV RNA levels.

Inclusion of NRTIs with good placental passage (zidovudine, lamivudine, emtricitabine, tenofovir, or abacavir) is recommended.

ART should be continued intrapartum. ZDV should be administered to HIV-infected women by continuous IV infusion if they have HIV RNA levels of > 400 copies/mL (or unknown HIV RNA levels) near delivery, regardless of ART regimen or mode of delivery.

After delivery, consider the indications for continuing ART and the woman's willingness and ability to do so (note that ART currently is recommended for all adults and adolescents); see "Postpartum Follow-Up of HIV-Infected Women," below, and chapter Antiretroviral Therapy.

HIV-infected pregnant women who previously have received ART or prophylaxis but are not currently receiving any ARV medications

In some instances, a pregnant woman has been on ART for her own treatment or for prophylaxis during a previous pregnancy and subsequently discontinued the medications. ARV drug-resistance testing should be conducted prior to initiating ART. The regimen should be chosen on the basis of previous ART experience and the reasons for stopping and results of past and current resistance testing, with avoidance of drugs and combinations with adverse maternal effects. The selection of an ART regimen for women with advanced HIV disease or a history of extensive prior therapy can be challenging, and consultation with an HIV specialist is recommended. Principles of ARV selection are as described above.

For women who present late in pregnancy, ART should be started promptly, without waiting for results of resistance testing. The use of raltegravir during late pregnancy for women who have high viral loads has been suggested because of its ability to suppress viral load rapidly (an approximately 2-log10 copies/mL decrease by week 2 of therapy). However, the efficacy and safety of this approach have not been evaluated and only anecdotal reports are available. Until more data become available on the safety of raltegravir use during pregnancy, this approach cannot be recommended for treatment-naive women.

Intrapartum ZDV infusion should be given as described above if the HIV viral load is >400 copies/mL near the time of delivery.

HIV-infected women who have received no ARV before labor and their Infants

HIV-infected pregnant women who have not received ARV prior to labor should be given ZDV as a continuous infusion during labor. The mother's need for continuing ARV treatment postpartum should be evaluated. Infants born to women who had no ART during pregnancy should begin ARV prophylaxis as close to birth as possible. In addition to receiving ZDV for 6 weeks, the infant should also be given three doses of NVP in the first week of life (at birth, 48 hours later, and 96 hours after the second dose).

Pharmacokinetic Considerations During Pregnancy

Physiologic changes that occur during pregnancy (e.g., prolonged gastrointestinal transit time; increase in body fat and water; and changes in cardiac, circulatory, hepatic, and renal function) may affect the kinetics of drug absorption, distribution, and elimination. Few pharmacokinetic studies have been conducted on levels of ARVs during pregnancy, but available data suggest that altered dosing for some PIs (e.g., atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir) may be required (see Table 5 of the Guidelines).

Special Circumstances

Hepatitis B Coinfection

Screening for HBV infection with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and hepatitis B surface antibody (anti-HBs) is recommended for all pregnant women who have not been screened during the current pregnancy. The HBV vaccine series should be administered to pregnant women who screen negative for hepatitis B.

For pregnant women coinfected with HIV and HBV, providers should treat both infections at once, by including a two-NRTI combination that is active against both infections. The NRTI combination tenofovir + 3TC or FTC is preferred for pregnant women with HIV/HBV, in combination with an NNRTI or PI. Liver transaminases should be monitored for signs of hepatotoxicity or HBV flare. Treatment may be complicated, and consultation with an expert is recommended. Also see the relevant discussion in the HHS Perinatal ARV Guidelines, and chapter Hepatitis B Infection in this manual.

HBV-infected pregnant women who are not immune to hepatitis A should be vaccinated. Infants born to coinfected women should receive HBV immune globulin and start the HBV vaccine series within 12 hours after birth (with subsequent vaccine doses per usual protocol).

Hepatitis C Coinfection

Treatment for hepatitis C virus (HCV) is not recommended during pregnancy. Recommendations for ART during pregnancy are the same for women who are HIV/HCV coinfected as for those without HCV coinfection. Liver transaminases should be monitored for signs of hepatotoxicity.

Coinfected pregnant women should be tested for immunity to hepatitis A and HBV; if not immune, they should be vaccinated. Infants born to coinfected women should be evaluated for HCV infection.

See the relevant discussion in the HHS Perinatal ARV Guidelines, and chapter Hepatitis C Infection in this manual.

Safety and Toxicity of Antiretroviral Medications During Pregnancy

Limited data are available on the safety of ARVs during pregnancy, particularly when ARVs are used in combination. The existing safety and toxicity information is derived from animal and human studies, clinical trials, registry data, and anecdotal experience.

Several drugs are of special concern when used during pregnancy (see HHS Perinatal ARV Guidelines; Table 5), including the following:

  • Efavirenz: Efavirenz 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 in humans after first-trimester exposure to efavirenz have been reported. As mentioned above, the Guidelines state that alternative ARVs should be strongly considered in women who are planning to become pregnant or are not using effective contraception with male partners. For pregnant women who present for antenatal care in the first trimester, discontinuation of efavirenz is not necessary, because the risk of neural tube defects is limited to the first 5-6 weeks of pregnancy and pregnancy is rarely recognized before 4-6 weeks.
  • Nevirapine: Women, including pregnant women, who begin NVP therapy when their CD4 count is >250 cells/L have nearly a 10 times higher incidence of hepatotoxicity than women initiated on NVP at lower CD4 counts. Symptoms of hepatotoxicity include fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and hepatomegaly. NVP should be initiated as part of an ARV regimen for pregnant women with CD4 counts of >250 cells/L only if the benefits clearly outweigh the risks (see Table 5 of the Guidelines). Women with higher CD4 cell counts who are already taking and tolerating NVP may continue it.
  • Didanosine + stavudine: The combination of didanosine and stavudine may cause fatal lactic acidosis and hepatic steatosis and should be avoided unless no alternative is available. Patients may present with symptoms 1-6 weeks in duration that include nausea, vomiting, abdominal pain, dyspnea, and weakness; clinicians should be alert for early signs and symptoms of lactic acidosis and evaluate them promptly.

In addition, PIs have been associated with an increased risk of new-onset diabetes, worsening diabetes, and diabetic ketoacidosis. Of course, pregnancy itself is a risk factor for hyperglycemia. Clinicians should monitor the glucose levels of pregnant women taking PIs and should educate them about the symptoms of hyperglycemia. The HHS Perinatal ARV Guidelines recommend that pregnant women on ART should be screened with a standard 50 g glucose loading test at 24-28 weeks (see chapter Care of HIV-Infected Pregnant Women).

Information on ARV toxicity during pregnancy should be consulted carefully before treatment choices are made. The HHS Guidelines provide information on each ARV drug, including preclinical and clinical data, pharmacokinetic and toxicity data, and recommendations regarding use during pregnancy. These guidelines are updated routinely as information is received (see Table 5 and Appendix A of the Guidelines). Numerous other medications also are contraindicated for use during pregnancy, and potential toxicity should be considered carefully before any medication is given to a pregnant woman.

Adverse Events Related to ARV Drugs During Pregnancy

A number of studies have identified an increased risk (up to double) of preterm delivery in women who take combination therapy during pregnancy (whether started before or during pregnancy), while other studies have not. Given the conflicting data, the Guidelines advise clinicians to be aware of a possible small increased risk of preterm birth among women who receive ART. However, the benefit of ART for the mother's health and for prevention of perinatal transmission is clear, and combination ART should not be withheld. 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.

Antiretroviral Pregnancy Registry

The Antiretroviral Pregnancy Registry collects observational data on HIV-infected pregnant women taking ARV medications to determine whether patterns of fetal or neonatal abnormalities occur. This is a project initiated by the pharmaceutical industry and overseen by an advisory committee comprising representatives from the CDC, National Institutes of Health, FDA, pediatric and obstetric providers, and others. Providers who care for pregnant women taking ARVs are encouraged to enroll patients in the registry at the time of initial evaluation. Information is confidential and patients' names are not used. More information can be obtained by visiting the registry website (www.apregistry.com/) or by calling 800-258-4263, 8:30 a.m. to 5:30 p.m. eastern time.

Intrapartum Management and Mode of Delivery

In 2012, a significant change was made in the Guidelines recommendation regarding intrapartum management of the woman with HIV infection. For women on ART with HIV RNA levels of <400 copies/mL near delivery, IV ZDV during labor can be considered but is not required (though they should continue their usual ARV medications). IV ZDV is recommended for HIV-infected women with HIV RNA levels of ≥400 copies/mL (or with unknown viral loads) near delivery, regardless of antepartum regimen or mode of delivery. IV ZDV should be given to the woman during labor as a 1-hour loading dose of 2 mg/kg followed by a continuous infusion of 1 mg/kg per hour until delivery. Women on ART should continue their regimen on schedule as much as possible during labor, except that women receiving ZDV or a ZDV-containing fixed-dose combination whose viral load is ≥400 copies/mL should be given IV ZDV, with other components continued orally. For women on a stavudine-containing regimen, the stavudine component should be discontinued while IV ZDV is being administered.

For women on ART who have detectable viral load at the time of delivery, the addition of the single-dose NVP protocol (single dose to the woman during labor, single dose to the neonate) is not recommended in the United States, because clinical trials have not shown benefit and there is a risk of NVP resistance. For the neonate, an expanded infant prophylaxis regimen may be indicated (see "Follow-Up of HIV-Exposed Infants," below).

Studies conducted 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, in the United States and other settings where HIV-infected pregnant women typically receive potent combination ART, rates of HIV transmission rates are very low (<1%, unadjusted for mode of delivery) and it is difficult to determine whether delivery by cesarean section further decreases the risk of peripartum transmission.

For a woman with a viral load of <1,000 copies/mL, cesarean delivery is not routinely recommended; decisions on mode of delivery should be individualized and based on discussions between the woman and her obstetric clinician. 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 the outcome of discussions about other concerns, which should include counseling about the risks and benefits of cesarean delivery. If cesarean delivery is planned for standard obstetrical indications it should be scheduled for 39 weeks' gestation.

For a woman with HIV RNA levels of >1,000 copies/mL at or near the time of delivery, the HHS Perinatal ARV Guidelines and the American College of Obstetricians and Gynecologists recommend delivery by scheduled cesarean section at 38 weeks' gestation.

IV ZDV should be started 3 hours before a scheduled cesarean delivery. Prophylactic antibiotics are recommended at the time of cesarean delivery for HIV-infected women to decrease the risk of maternal infection.

It is not clear whether cesarean delivery provides any benefits in preventing perinatal HIV transmission once labor has begun or membranes are ruptured. Management of a woman for whom a scheduled cesarean was planned but who presents in labor or with ruptured membranes should be individualized on the basis of her HIV viral load, current ART regimen, length of time since membrane rupture, duration of labor, and other clinical factors.

The HHS Perinatal ARV Guidelines outline several scenarios in which the clinician must decide whether cesarean delivery is needed; see Table 8 of the Guidelines for further information. The data on the benefits of cesarean delivery are complex and must be considered alongside the increased risk to the mother after surgery. The clinician should consult an obstetric/HIV specialist to discuss specific situations.

A woman who presents in labor without a documented HIV status should receive an expedited HIV antibody test and, if the result is positive, should be presumed to be infected until the confirmatory HIV test result is received. She should receive IV ZDV immediately to prevent perinatal transmission, and her infant should start infant prophylaxis pending the mother's confirmatory results (see "Follow-Up of HIV-Exposed Infants," below). She will need confirmation and staging of her HIV infection (e.g., CD4 cell count, HIV RNA viral load) as well as referral to care for her own health and ongoing psychological support.

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 potentially increase the neonate's exposure to maternal blood, such as the use of scalp electrodes or artificial rupture of membranes, should be avoided. Operative interventions with forceps or vacuum extractor and episiotomy should be performed only in select circumstances.

For management of postpartum hemorrhage owing to uterine atony, note that Methergine has significant interactions with PIs and with NNRTIs, and may interact with the pharmacokinetic booster cobicistat. Methergine should not be administered to women taking PIs, if possible. If alternative treatments are not available and Methergine must be used, it should be given at the lowest possible dosage and for the shortest possible duration. If Methergine is given to women taking NNRTIs, its dosage may need to be increased or additional uterotonic medications may be needed.

Postpartum Follow-Up of HIV-Infected Women

Women with HIV infection who have recently delivered 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 of her infant. She should 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, if indicated. Adherence to ARV regimens may be particularly difficult for a woman in the immediate postpartum period because of postpartum physical and psychological changes and the demands of caring for a newborn; accordingly, the woman may require new or continued support services.

Women who are diagnosed through preliminary rapid HIV testing in labor will need thorough evaluation and management including confirmatory HIV testing and immediate linkage for medical and social services. They should not breast-feed unless the results of the confirmatory tests are received as negative.

Women should be evaluated regarding their ongoing need and desire for ART postpartum. Long-term ART generally should be recommended for all women, regardless of nadir CD4 count, in accordance with current HHS adult and adolescent guidelines. If ART was given only or primarily to reduce the risk of perinatal transmission, a discussion about continuing ART should include factors such as the woman's health status, her CD4 counts, the HIV status of her partner(s), and adherence issues. If the woman elects to discontinue ART postpartum, her need for treatment and willingness to restart ART should be reevaluated on an ongoing basis.

If ART is being discontinued, all drugs should be stopped at the same time if they have similar half-lives. NNRTIs have longer half-lives than other agents, so an NNRTI should be discontinued for a period of time (the duration of this time has not been defined) before other ARVs, in order to avoid a period of NNRTI monotherapy and the development of NNRTI resistance mutations. Alternatively, a PI may be substituted for the NNRTI several weeks before stopping all the ARV agents. Note that, for women with HBV coinfection, discontinuation of NRTIs with anti-HBV activity (e.g., 3TC, emtricitabine, tenofovir) may result in a flare of HBV; consult with an expert before discontinuing ART.

Contraceptive counseling is an important aspect of postpartum care. Women should be offered dual-method contraception if pregnancy is not desired in the short-term future or if the ART regimen contains potentially teratogenic drugs such as efavirenz. Note that there are significant interactions between some hormonal contraceptives and PIs, NNRTIs, and elvitegravir/cobicistat. (See chapters Care of HIV-Infected Pregnant Women and Health Care of HIV-Infected Women Through the Life Cycle.)

Breast-feeding is not recommended in the United States or other parts of the world where replacement feeding is affordable, feasible, acceptable, sustainable, and safe. Women may experience culture-based and family pressure to breast-feed and may need support to use replacement feeding.

Follow-Up of HIV-Exposed Infants

The HIV-exposed neonate born to a mother with HIV infection should receive ZDV syrup at a dose based on the infant's gestational age. Infants at ≥35 weeks' gestation infant should be given ZDV syrup at a 4 mg/kg/dose PO BID, beginning as soon as possible after birth, preferably within 6-12 hours, and continuing for 6 weeks. Dosing for premature infants is detailed in the Guidelines. In the United States, the use of ARV drugs other than ZDV and NVP cannot be recommended for premature infants because of lack of dosing and safety data.

Newborns should be discharged home with a supply of PO ZDV syrup. The use of ZDV for the neonate is recommended regardless of whether the mother has a history of resistance to ZDV. Two-drug therapy - specifically, ZDV by standard protocol for 6 weeks plus 3 doses of NVP given at birth, 48 hours later, and 96 hours after the second dose - is recommended for infants of mothers who did not receive ART before delivery or received ZDV only intrapartum. Few data are available to guide use of other combination therapies for neonates; consult with a pediatric HIV expert. Every HIV-exposed infant should be referred to a pediatric HIV specialist for diagnostic testing and monitoring of health status.

For an infant born to a mother whose HIV status is unknown, expedited HIV testing of the mother or the infant should be done as soon as possible. If the result for either is positive, ZDV prophylaxis for the infant should be started immediately. A confirmatory HIV test (e.g., Western blot) should be done at the same time and prophylaxis should be discontinued if the result is negative. If positive, the infant should be tested with an HIV DNA polymerase chain reaction (PCR) assay or an HIV RNA assay. If the newborn's HIV viral load test result is positive, prophylaxis should be discontinued and the infant should be referred urgently to a pediatric HIV specialist for management of HIV infection using combination ART.

Traditional HIV antibody testing cannot be used with infants because maternal antibodies may persist for up to 18 months. Diagnosis of HIV infection in infants requires virologic testing (HIV DNA or HIV RNA). Virologic testing should be performed by age 14-21 days, then at 1-2 months, and at 4-6 months. HIV can be diagnosed in an infant on the basis of two positive results from virologic tests done on separate blood samples at any time. HIV can be excluded presumptively in an infant with two or more negative results from virologic tests, with one done at ≥14 days of age and one done at ≥1 month of age, or one negative virologic test result at ≥2 months of age, or one negative HIV antibody test result at ≥6 months of age. HIV can be excluded definitively with two or more negative virologic test results, with one test done at age ≥1 month and one done at ≥4 months. However, these tests may not be accurate in infants who are receiving combination ART. Some experts recommend retesting, using an antibody test, at age 12-18 months as a confirmatory test.

Infants should have a baseline complete blood count and differential and should be monitored for anemia while they are taking ZDV. Monitoring for anemia should be based on the infant's gestational age, ZDV dose, clinical condition, and maternal ARV history. Infants on ZDV/3TC prophylaxis should have a hemoglobin and neutrophil count at 4 weeks after initiation of ARVs.

Pneumocystis jiroveci pneumonia (PCP) prophylaxis for HIV-exposed infants is recommended starting at 6 weeks when the ZDV prophylaxis regimen is completed and continued until they are determined presumptively or definitively to be HIV seronegative. Initiation of PCP prophylaxis should be stopped or avoided altogether when HIV has been presumptively excluded.

Parents and family caregivers must be taught how to monitor the infant for signs of illness until an HIV diagnosis is made or 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 enduring consequences of ARV exposure have been confirmed, the child may be at risk of long-term problems.

Patient Education

  • The clinician should provide the pregnant woman with the most current information on the risk of perinatal HIV transmission and the importance of ARV prophylaxis.
  • The clinician and the patient should have a detailed discussion about ART, both for the patient's own health and for decreasing the risk of perinatal transmission.
  • The clinician should review with the patient the critical importance of her adherence to ART regimens before prescribing a regimen.
  • The clinician should review possible adverse effects of the ARVs and give the patient specific instructions about managing them if they are mild or seeking medical advice if they are more serious, such as ongoing fatigue, persistent nausea and vomiting, or signs of hyperglycemia.
  • The clinician should explain the signs and symptoms of early labor to the patient and emphasize the importance of seeking medical care if she has signs and symptoms of early labor or premature rupture of membranes.
  • Early in the third trimester, the clinician and the patient should discuss the risks and potential benefits of cesarean section based on her viral load and clinical status.
  • Intrapartum management, including the possible need to use intrapartum ZDV, should be discussed with the patient so that she knows to tell the delivery team about her HIV status when she presents 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 advise HIV-infected mothers against premastication of the infant's food and promote safer feeding options.
  • The clinician should discuss follow-up plans and make referrals for the patient and her infant. If 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 emphasized.

References

  • American College of Obstetricians and Gynecologists, Committee on Obstetric Practice. Prenatal and perinatal human immunodeficiency virus testing: expanded recommendations. ACOG Committee Opinion No. 418. Washington, DC: American College of Obstetricians and Gynecologists; 2008.
  • American College of Obstetricians and Gynecologists. Routine human immunodeficiency virus screening . ACOG Committee Opinion No. 411. Washington, DC: American College of Obstetricians and Gynecologists; 2008.
  • American College of Obstetricians and Gynecologists. Scheduled cesarean delivery and the prevention of vertical transmission of HIV infection. ACOG Committee Opinion No. 234. Washington, DC: American College of Obstetricians and Gynecologists; 2000.
  • Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January 2013. Wilmington, NC: Registry Coordinating Center; 2009. Accessed December 1, 2013.
  • Branson BM, Handsfield HH, Lampe MA, et al.; Centers for Disease Control and Prevention. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006 Sep 22;55(RR-14):1-17.
  • Bulterys M, Jamieson D, O'Sullivan MJ, et al. Rapid HIV-1 testing during labor: a multicenter study. JAMA. 2004 Jul 14;292(2):219-23.
  • Centers for Disease Control and Prevention. U.S. Public Health Service recommendations for human immunodeficiency virus counseling and voluntary testing for pregnant women. MMWR Recomm Rep. 1995 Jul 7;44(RR-7):1-15.
  • Centers for Disease Control and Prevention. Rapid HIV-1 Antibody Testing during Labor and Delivery for Women of Unknown HIV Status: A Practical Guide and Model Protocol. January 30, 2004. Accessed December 1, 2013.
  • Centers for Disease Control and Prevention. Recommendations of the U.S. Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR Recomm Rep. 1994 Aug 5; 43(RR-11):1-20.
  • International Perinatal HIV Group. Duration of ruptured membranes and vertical transmission of HIV-1: a meta-analysis from 15 prospective cohort studies. AIDS. 2001 Feb 16;15(3):357-68.
  • Ioannidis JP, Abrams EJ, Ammann A, et al. Perinatal transmission of human immunodeficiency virus type 1 by pregnant women with RNA virus loads <1000 copies/ml. J Infect Dis. 2001 Feb 15; 183(4):539-45.
  • Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Accessed December 1, 2013.
  • Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Accessed December 1, 2013.
  • Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomised, double-blind, placebo-controlled trial. Lancet. 2002 Apr 6;359(9313):1178-86.
  • Sperling RS, Shapiro DE, Coombs RW, et al.; Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med. 1996 Nov 28;335(22):1621-9.
  • U.S. Department of Health and Human Services. A Guide to the Clinical Care of Women with HIV - 2013 Edition. Rockville, MD: U.S. Department of Health and Human Services; 2013. Accessed March 1, 2013.
  • U.S. Department of Health and Human Services. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Accessed December 1, 2013.
  • World Health Organization. Rapid advice: use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. Geneva: World Health Organization; November 30, 2009. Accessed December 1, 2013.

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly