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MD Consult: Books: Goldman: Cecil Medicine: Chapter 260 – HUMAN IMMUNODEFICIENCY VIRUS IN PREGNANCY

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 260 – HUMAN IMMUNODEFICIENCY VIRUS IN PREGNANCY

Stephen A. Spector

Epidemiology

The World Health Organization and the Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated that by the end of 2004 approximately 40 million people were living with human immunodeficiency virus (HIV) infection, including 1 in every 100 adults in the sexually active ages of 15 to 49 years. Overall, approximately 14,000 new HIV infections occur daily, more than 95% of them in developing countries. In sub-Saharan Africa, 57% of infected persons are women. In the United States, the Centers for Disease Control and Prevention (CDC) reports that approximately 22% of persons living with the acquired immunodeficiency syndrome (AIDS) are women. Women also comprise 27% of those with new infections, and AIDS is the fifth most common cause of death in women between 24 and 44 years of age ( Chapter 410 ).

Pregnant women are at risk of transmitting HIV to their newborns; approximately 25% of exposed infants will become infected unless intervention occurs. The exact timing of HIV transmission from mother to infant is unknown. The best estimate is that in developed countries, approximately one third of infections occur in utero, usually late in pregnancy, and two thirds occur intrapartum. Risk factors for increased mother-to-child transmission include women with low CD4+ lymphocyte counts, high HIV RNA loads, the presence of active sexually transmitted diseases, rupture of amniotic membranes beyond 4 hours, and prematurity of birth. Of all risk factors, plasma HIV RNA load is most important in determining the risk for mother-to-child transmission.

Women can also transmit HIV through their breast milk, and such transmission accounts for one third of all infections in infants in developing countries, where most HIV-infected women breast-feed their infants. In developing countries, the benefits of exclusive breast-feeding are believed by some experts to outweigh the risk of transmission of HIV through milk. Although exclusive breast-feeding may decrease the risk of transmission from an infected mother to her infant, few women are able to maintain a regimen of exclusive breast-feeding. Therefore, most experts believe that substitute feeding should be used whenever possible to prevent mother-to-child transmission of HIV. HIV-infected women in developed countries should be strongly discouraged from breast-feeding their newborns.

Treatment

Use of Antiretroviral Agents during Pregnancy

Treatment recommendations for HIV-infected pregnant women are based on the premise that therapies known to be of benefit should not be withheld during pregnancy unless they are known to be harmful to the mother or fetus ( Chapter 412 ). Thus, unless specific reasons exist for withholding antiretroviral therapy, pregnant women should be given optimal combination therapy, usually including two reverse transcriptase inhibitors and a protease inhibitor. When possible, one of the reverse transcriptase inhibitors should include zidovudine because it has clearly been demonstrated to decrease vertical transmission and to be safe for mother and infant. In a controlled trial conducted by the Pediatric AIDS Clinical Trials Group (PACTG 076), HIV infection occurred in 25% of infants when the mother and infant received placebo compared with 8% of infants when mother and infant received zidovudine.[1] The treatment regimen used for the PACTG 076 study and the currently used preferable zidovudine regimens are summarized in Figure 260-1 . The intervention involves three parts: (1) treatment of the mother with oral zidovudine during pregnancy, (2) administration of intravenous zidovudine during labor, and (3) 6 weeks of oral zidovudine administered to the infant after birth. Each of these three parts is thought to contribute to decreasing transmission, and all three parts of the intervention should be administered whenever possible.

In another study (PACTG 185), blocking mother-to-infant transmission with zidovudine intervention was shown to be even more effective, and the regimen decreased transmission to approximately 5%.[2] The use of HIV-specific immunoglobulin provides no additional benefit over the use of zidovudine alone. A study in Thailand found that mother-to-child transmission can be reduced when women receive zidovudine only in their last month of preg-nancy.[3] These data indicate that HIV-infected women identified at any stage of pregnancy should receive zidovudine to decrease the risk of perinatal transmission. However, this approach is suboptimal, and women and infants should minimally receive the full PACTG 076 regimen whenever possible.

The treatment regimen of zidovudine, 100 mg, administered five times daily in the PACTG 076 study was based on the standard dose of zidovudine for adults in 1989. The current recommended dosing for zidovudine of 200 mg three times daily or 300 mg twice daily has been associated with a comparable clinical response and is the recommended dosing schedule for use by pregnant women.

In non–breast-feeding women in Thailand, a short-course regimen of zidovudine consisting of 300 mg twice daily from 36 weeks’ gestation and 300 mg administered every 3 hours during labor decreased transmission to 9%. Another study using a four-arm factorial design compared administration of zidovudine antenatally starting at 28 or 36 weeks’ gestation, orally intrapartum, and to the neonate for 3 days or 6 weeks. The long-long arm (beginning at 28 weeks antenatally and 6 weeks of treatment to the infant) was found to be significantly superior to the other arms of the trial, with a resulting transmission rate of 4%. A third study (performed in Africa) in HIV-infected women of whom 73% breast-fed their infants demonstrated that the combination of zidovudine and lamivudine (3-TC) beginning at 36 weeks gestation, orally intrapartum, and for 1 week postpartum to the mother and infant reduced transmission to 6% for infants at 6 weeks of age. However, with the high rate of breast-feeding, by 18 months of age, 15% of infants were identified as infected, and 19% were infected or had died.

Additional trials have demonstrated that intrapartum and postpartum regimens with either zidovudine and lamivudine or nevirapine are also useful in decreasing transmission when these drugs are administered to an HIV-infected pregnant woman late in pregnancy or while in labor. In an African cohort of women and infants, the intrapartum administration of zidovudine to the mother and postpartum to the breast-feeding mother and infant for 1 week decreased transmission at 6 weeks of age from 17% in the placebo group to 6% in the treated group. In this trial, the administration of zidovudine and lamivudine to the mother alone failed to decrease transmission to the infant. In another study performed in Uganda, the administration of a single 200-mg dose of nevirapine to the mother at onset of labor combined with a single 2 mg/kg dose of nevirapine to her infant at 24 to 72 hours of age reduced transmission at 6 weeks to 12%.[4] The ease of administration and the low cost of single-dose nevirapine given to pregnant women and infants have made this equally good medication[5] the intervention of choice in the developing world for programs targeted at reducing mother-to-child transmission. Recently, concern has been expressed about the risk for the development of HIV strains resistant to nevirapine (and other currently available non-nucleoside reverse transcriptase inhibitors) that may occur in virtually all women who receive single-dose nevirapine. However, most experts currently believe that the risk of resistance is outweighed by the clear benefit of protecting a large proportion of infants from HIV infection. Additionally, preliminary studies suggest that when women or babies are treated with zidovudine in combination with lamivudine for 4 or 7 days, the risk for development of nevirapine-resistant virus can be significantly decreased.

In the United States and other developed countries, combination therapy, usually comprising two nucleoside reverse transcriptase inhibitors and a protease inhibitor, when administered to a woman beginning in the second trimester of pregnancy and combined with intrapartum intravenous zidovudine and 6 weeks of zidovudine administered to the infant, has decreased mother-to-child transmission to less than 2%. The addition of nevirapine was of no further benefit in circumstances in which women receive perinatal care and antenatal antiretroviral therapy and in which cesarean section can be safely performed (PACTG 316).

Optimal medical management of the HIV-infected pregnant woman should include treatment with antiretroviral agents, usually including two nucleoside reverse transcriptase inhibitors and a protease inhibitor, to achieve an HIV plasma RNA load of less than 400 copies/mL. Studies done before the availability of combination antiretroviral therapy generally demonstrated a reduction in HIV mother-to-child transmission when the infant was delivered by cesarean section before rupture of amniotic membranes. More recent data indicate that for women with a plasma HIV RNA load of less than 1000 copies/mL, cesarean section confers no additional benefit. Additionally, nonelective cesarean section performed after the onset of labor or rupture of amniotic membranes has not been associated with a significant reduction in infection in infants when compared with vaginal delivery.

Although the use of antiretroviral agents has been shown to be highly effective in decreasing mother-to-child transmission and in the short term to be safe for both mother and infant, the long-term impact on infants, most of whom are uninfected with HIV, is unknown. Additionally, treatment of women who are likely to become pregnant should take into account the possible consequences to a fetus exposed to these antiretrovirals in utero. For example, efavirenz (Sustiva) was shown in primate studies to be associated with neural tube defects, and several reports have noted babies born with predictable neural tube abnormalities. Because the neural tube closes in the first month of gestation, many women do not know that they are pregnant before the time that damage could occur to the fetus. Another non-nucleoside reverse transcriptase inhibitor, nevirapine, has not been associated with human teratogenicity; however, nevirapine is associated with a rash, as well as an increased risk of symptomatic and potentially fatal liver toxicity. The serious liver toxicity occurs in women with CD4+ lymphocyte counts greater than 250/μL when treatment is first initiated. Thus, nevirapine should be initiated in pregnancy for women with more than 250 cells/μL only if the potential benefits outweigh the risk to the mother. Women who become pregnant while they are receiving nevirapine-containing regimens and who are tolerating the regimen need not discontinue this treatment. Additionally, no toxicity has been observed with the use of single-dose nevirapine to prevent mother-to-child transmission. Thus, a decision to use any antiretroviral therapy during pregnancy should be made by the woman after a thorough discussion of risks and benefits with her health care provider. Infants born to HIV-infected women should be followed by or seen in consultation with health care providers experienced in the care of HIV-infected children. Infants identified as infected should be treated as outlined in the CDC’s “Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection.”

Possible Adjustments to the Standard Care of Women Infected with Human Immunodeficiency Virus

Pregnant Women Infected with Human Immunodeficiency Virus Who Have Not Had Prior Antiretroviral Therapy

The recommendation for antiretroviral therapy should be made after standard clinical, immunologic, and virologic evaluation (see first suggested reading). The three-part zidovudine chemoprophylaxis regimen should be recommended for all pregnant women. If the woman’s HIV plasma RNA load is greater than 1000 copies/mL, combination therapy with an additional nucleoside reverse transcriptase inhibitor and a protease inhibitor is recommended. Decisions regarding combination antiretroviral treatment should be made after a full review of risks and benefits of treatment. At present, most HIV experts recommend combination antiretroviral therapy, including zidovudine, although recent studies indicate that other nucleoside reverse transcriptase inhibitors, including didanosine and stavudine, may also provide benefit. Some HIV experts recommend beginning antiretroviral therapy after the first trimester (the period of organogenesis) in an attempt to minimize risk to the fetus. If a woman’s HIV disease status has not progressed to meet the current guidelines for initiation of antiretroviral therapy (i.e., her CD4+ lymphocyte count is >350 cells/mL and plasma HIV RNA is <100,000 copies/mL), some experts recommend the discontinuation of therapy after delivery. If HIV treatment is to be discontinued, all antiretroviral agents should be stopped at the same time, to minimize the risk for development of antiretroviral resistance.

Women in Late Pregnancy Who Are Infected with Human Immunodeficiency Virus and Who Are Not Receiving Antiretroviral Therapy

A woman who presents late in pregnancy (>∼36 weeks’ gestation) should have her plasma HIV RNA level and CD4+ lymphocyte count evaluated. The woman should be started on antiretroviral therapy including at least zidovudine. However, most experts recommend instituting three antiretroviral agents, including two nucleoside reverse transcriptase inhibitors and a protease inhibitor. If the RNA load around the expected delivery date is not less than 1000 copies/mL, an elective cesarean section should be considered. During delivery and postpartum to the infant, the PACTG 076 regimen is recommended.

Women Infected with Human Immunodeficiency Virus Who Have Viral Loads Greater Than 1000 Copies/Ml Despite Receiving Antiretroviral Therapy at 36 Weeks’ Gestation

If the plasma HIV RNA load is declining at the time of assay, the current antiretroviral therapy should be continued. However, if the viral load is considerably greater than 1000 copies/mL at 36 weeks’ gestation, it is unlikely that it will decline to less than 1000 copies/mL at the time of delivery. The woman should be counseled that elective cesarean section may be of benefit in decreasing the risk of intrapartum transmission. During delivery and postpartum to the infant, the PACTG 076 regimen is recommended.

Pregnant Women Infected with Human Immunodeficiency Virus Who Are Receiving Antiretroviral Therapy

Women receiving antiretroviral therapy and who are identified as being pregnant should continue their current antiretroviral therapy, provided plasma HIV RNA levels are lower than 400 copies/mL. Women who are identified as pregnant during the first trimester should be counseled regarding the potential risks of taking an antiretroviral agent during this period. If therapy is discontinued, all drugs should be stopped and reintroduced at the same time to avoid the development of resistance. If the current antiretroviral regimen does not include zidovudine, substituting zidovudine or adding it to the regimen should be considered after 14 weeks’ gestation. If the previous antiretroviral therapy had not resulted in plasma HIV RNA levels lower than 400 copies/mL, a regimen usually consisting of three drugs of at least two different classes including at least two new drugs should be instituted during pregnancy. If resistance testing is available, pregnant women should be prescribed antiretroviral agents to which their virus is known to be susceptible.

Women Infected with Human Immunodeficiency Virus Who Are in Labor and Who Have Had No Prior Therapy

Several treatment options are available for women who present with HIV infection in labor; however, transplacental infection of the fetus may have already occurred. Treatment regimens include administration of intrapartum intravenous zidovudine, followed by the 6-week zidovudine regimen for the newborn. Some experts also add nevirapine in a single dose before delivery to the pregnant woman and following delivery to the infant. Some experts recommend cesarean section before rupture of amniotic membranes in this situation, to prevent intrapartum transmission. The benefit to the infant must be weighed against the potential risk to the mother of a cesarean section. After delivery, the woman should have a full evaluation of her HIV status and, when appropriate, antiretroviral therapy recommended for her own health.

Infants Born to Mothers Who Received No Antiretroviral Therapy during Pregnancy or Intrapartum

The 6-week neonatal course of zidovudine is recommended as soon after birth as possible for infants born to HIV-infected women. Most HIV experts recommend three-drug combination regimens, including two reverse transcriptase inhibitors and an antiprotease compound for 6 weeks. Following delivery, the woman should have a full evaluation of her HIV status and, when appropriate, antiretroviral therapy recommended for her own health. All pregnant women, regardless of plasma HIV RNA load, should be advised that the use of antiretroviral prophylaxis has been found to provide benefit in preventing perinatal transmission.

FIGURE 260-1  Pediatric AIDS Clinical Trials Group (PACTG 076) zidovudine (ZDV) regimen for prevention of mother-to-infant transmission of human immunodeficiency virus.

Follow-Up

Testing and Supportive Care

After delivery, HIV-infected women should receive comprehensive care and support services required for management of their HIV infection and for care of their family. This care should begin before preg-nancy, with continuity of care ensured throughout pregnancy and postpartum.

Testing for HIV and counseling are essential to any successful plan for identification and treatment of pregnant women. All pregnant women, regardless of their sexual or social history, should be offered HIV antibody testing ( Chapter 408 ). Patients whose test results are negative should be informed that false-negative results may occur because of the latent phase between HIV exposure and development of antibody. The false-negative rate depends on the prevalence of risk-related behavior in the tested population. Patients whose test result is negative should be encouraged to practice low-risk behavior to minimize their risk of infection. A pregnant woman whose test result is positive should have a confirmatory test performed. After confirmation, the patient should have counseling regarding whether to continue the pregnancy, potential risks to the fetus, and benefits of antiretroviral intervention and treatment for herself and her newborn. After identification of HIV infection, care for the infected woman should be the same as for any other person newly identified as HIV positive. Prophylaxis for opportunistic pathogens and treatment of infections should be recommended as for other persons infected with HIV.

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