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Case 1: Discussion

Recommendations for HIV Testing in Pregnancy

The Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists (ACOG) recommend offering HIV testing to all pregnant women as part of routine antenatal laboratory testing, using an "opt-out" approach, meaning that pregnant women will undergo testing for HIV as part of the routine prenatal laboratory evaluation unless they refuse the test[1,2,3]. The ACOG also recommends offering repeat testing in the third trimester to women from high HIV prevalence areas, those with risk behaviors for acquiring HIV, and those who declined testing earlier in the pregnancy[3]. If the pregnant woman refuses HIV testing, the clinician should document this refusal in the medical record. The conventional HIV testing algorithm used for women during pregnancy involves screening with the enzyme-linked immunoassay (ELISA) and confirming any positive test with a Western blot or an immunofluorescence assay (IFA). Because this conventional process of HIV testing can require several days, or even several weeks in some centers, it is not acceptable to use conventional HIV tests for women with undocumented HIV status who present at the time of labor; in this setting, rapid HIV testing is the appropriate testing method.

Impact of Antiretroviral Therapy on HIV Transmission

Antiretroviral therapy and avoidance of breastfeeding are the primary interventions that reduce the risk of mother-to-child HIV transmission. In 1994, results from the Pediatric AIDS Clinical Trials Group (PACTG) 076 trial were published showing a multi-component zidovudine (Retrovir) regimen reduced mother-to-child HIV transmission by nearly 70%[4]. Later that year, the U.S. Public Health Service (USPHS) issued guidelines for the use of zidovudine to reduce perinatal HIV transmission. The PACTG 076 study and the subsequent USPHS recommendations spurred a dramatic decline in the number of perinatal AIDS cases in the late 1990's[1]. Clinical trials and observational studies in the United States, as well as clinical trials of shorter course regimens in low resource settings, have demonstrated that a variety of antiretroviral regimens reduce the risk of maternal-child HIV transmission, with the greatest risk reductions seen with longer duration and more complex regimens (Figure 1)[1,4,5,6,7]. With the use of combination antiretroviral therapy during pregnancy and the achievement of very low or undetectable maternal HIV RNA levels (at the time of delivery or near delivery), perinatal transmission of HIV occurs in fewer than 1-2% of women, in contrast with the transmission rate of 20-25% in women who receive no antiretroviral therapy (Figure 2)[1]. The use of antiretroviral therapy may provide significant benefit even if the pregnant woman does not achieve an undetectable HIV RNA level. Among women with comparable low-level detectable HIV RNA (less than 1,000 copies/ml) at the time of delivery, those who received antiretroviral therapy (during pregnancy, at the time of delivery, or both) had a significantly lower rate of HIV transmission compared with those who received no antiretroviral therapy[8]. Thus, it appears that antiretroviral therapy decreases maternal-child HIV transmission via multiple mechanisms, including those dependent and independent of HIV RNA levels. Taken together, available data clearly show that antiretroviral therapy significantly reduces the risk of maternal to child HIV transmission, and these data justify recommendations to use antiretroviral therapy for all HIV-infected pregnant women during pregnancy.

Guidelines for Use of Antiretroviral Therapy in Pregnancy

The USPHS guidelines discuss four major clinical scenarios in which antiretroviral therapy can be used to reduce maternal to child transmission of HIV: (1) an HIV-infected pregnant woman has not received prior antiretroviral therapy; (2) an HIV-infected woman is receiving antiretroviral therapy that was started before she became pregnant; (3) an HIV-infected woman is in labor and has not received prior antiretroviral therapy; and (4) an infant is born to an HIV-infected woman who has received no antiretroviral therapy during pregnancy or in the intrapartum period. The following discussion will focus on management issues related to the first two scenarios that involve the use of antiretroviral therapy during pregnancy. All HIV-infected pregnant women, regardless of what regimen they receive during pregnancy, should receive intravenous zidovudine during labor, and the newborn should receive zidovudine by oral suspension for the first 6 weeks of life[1].

Approach to Antiretroviral Therapy-Na?ve Pregnant Woman

When an antiretroviral therapy-na?ve HIV-infected woman becomes pregnant or is newly diagnosed with HIV in pregnancy, she should promptly undergo clinical, immunologic, and virologic evaluation. In this scenario, many experts would recommend deferring initiation of antiretroviral therapy until after the first trimester to minimize fetal exposure at the most vulnerable period of development. If, however, the clinical or immunologic condition of the woman indicates the need for more immediate initiation of therapy, effective combination antiretroviral therapy should be started, using agents as recommended in the 2005 US Public Health Service (USPHS) Task Force document (discussed below in Specific Drug Recommendations for Use in Pregnancy)[1]. In addition, some experts would recommend obtaining baseline genotypic resistance testing prior to selecting an antiretroviral regimen. When the pre-antiretroviral therapy HIV RNA level exceeds 1000 copies/ml, combination antiretroviral therapy is recommended, regardless of the patient's CD4 cell count or clinical status. In addition, the pregnant woman should receive combination antiretroviral therapy if she has an indication for antiretroviral therapy based on her immunologic status. Although zidovudine monotherapy with the three-part regimen used in the PACTG 076 study would be considered acceptable in women who have a CD4 count greater than 350 cells/mm3 and HIV RNA less than 1000 copies/ml, data from PACTG 367 suggest that combination therapy achieves an even lower rate of HIV transmission[9]. In addition, the use of zidovudine monotherapy during pregnancy can result in the development of resistance to zidovudine and can thus negatively affect future antiretroviral therapy options.

Approach to Pregnant Woman Receiving Antiretroviral Therapy

In the second scenario involving an HIV-infected woman who becomes pregnant while taking antiretroviral therapy, most experts would recommend continuing therapy, especially if the woman has already entered the second or third trimester of pregnancy. If, however, the woman is still in the first trimester, the risks and benefits of continuing therapy should be discussed in detail with her[1]. In some instances, antiretroviral therapy may need to be interrupted in the first trimester if the woman has significant nausea and vomiting, a situation that may create problems with adherence and proper absorption. If, for whatever reason, antiretroviral therapy is discontinued during the first trimester, all antiretroviral medications should be stopped to avoid the development of resistance and then restarted at the onset of the second trimester. If the regimen includes efavirenz (Sustiva) or nevirapine (Viramune), most experts would recommend discontinuing these drugs several days prior to other medications in the regimen because of their very long half-life and low genetic barrier to developing resistance[1]; in this situation, the clinician should ideally consult with an expert in antiretroviral therapy. If the decision is made to continue antiretroviral therapy during the first trimester, and the woman's existing regimen contains efavirenz, another effective agent should replace efavirenz, because of the increased risk of neural tube defects associated with first trimester exposure to this drug[10,11]. Some experts would consider the use of efavirenz in the second or third trimester acceptable if no other effective antiretroviral option existed. In addition, if therapy is to be continued, but the existing regimen does not include zidovudine, many experts would recommend substituting zidovudine for one of the nucleoside (or nucleotide) reverse transcriptase inhibitors (if this would be likely to maintain optimal effectiveness) or adding zidovudine to an existing regimen, mainly because of the extensive data with zidovudine in preventing maternal-child HIV transmission.

Specific Drug Recommendations for Use in Pregnancy

Most of the same general principles exist when choosing antiretroviral regimens for use during pregnancy as when choosing regimens for HIV-infected adults and adolescents who are not pregnant. The 2005 USPHS Task Force recommended antiretroviral therapy for HIV-infected pregnant women consists of combination therapy with three or more antiretroviral medications, typically two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI). These guidelines categorize antiretroviral drugs in pregnancy as either recommended, alternative, those for which insufficient data exists, and those not recommended (Figure 3)[1]. These categorizations are based on experience (or lack of experience) and available data with these medications related to safety and effectiveness in reducing perinatal HIV transmission. Any decision regarding regimen selection should also include consideration of effectiveness for maternal treatment. The preferred dual NRTI backbone consists of zidovudine combined with lamivudine (Epivir), most often given as the fixed-drug preparation Combivir. The preferred PIs include either nelfinavir (Viracept) or saquinavir SGC (Fortovase) boosted with ritonavir (Norvir). As noted above, the use of efavirenz should be avoided during pregnancy. Although the use of single or dual NRTIs alone is not recommended for treatment of HIV infection, zidovudine monotherapy is considered acceptable for prophylaxis of perinatal transmission in pregnant women who have a baseline HIV RNA less than 1,000 copies/mL and who do not meet CD4 criteria for initiating antiretroviral treatment. The clinician should also be aware of several special considerations when using antiretroviral agents in pregnancy: (1) pharmacokinetics may be altered during pregnancy; (2) antiretroviral therapy toxicity and side effects may be altered in pregnancy, or may be more easily overlooked; and (3) potential fetal and newborn toxicity, such as birth defects, carcinogenicity, anemia, and mitochondrial toxicity, must be considered, since these could potentially occur with babies exposed to these drugs in utero, irrespective of their HIV status.

Special Risk with Antiretroviral Therapy During Pregnancy

Women initiating nevirapine with a CD4 greater than 250 cells/mm3 have a 10-fold increased risk of developing symptomatic, often rash-associated hepatotoxicity and hepatic failure, usually within the first 18 weeks after starting nevirapine[1,12,13,14]. These adverse reactions to nevirapine have included several deaths among pregnant patients. Although women who enter pregnancy on a well-tolerated nevirapine-containing regimen may continue on this regimen, initiating nevirapine-containing combination therapy in women with a CD4 count greater than 250 cells/mm3 should be avoided. Although it is recommended that whenever possible antenatal antiretroviral therapy should include zidovudine as part of the regimen, zidovudine is associated with bone marrow suppression and pregnant women are more likely to be anemic. Accordingly, severe anemia constitutes a relative contraindication for using zidovudine, unless a transfusion is given. Stavudine (Zerit) is considered an alternative NRTI in pregnancy and can substitute for zidovudine, as in the patient in this case. The combination of stavudine and didanosine (Videx EC) has been associated with several cases of lactic acidosis, some fatal, in pregnancy and should not be used unless no other options are available[15,16]. Sparse data exist regarding the use of tenofovir DF (Viread), abacavir (Ziagen), or emtricitabine (Emtriva) during pregnancy. Tenofovir DF has become a very commonly used agent for non-pregnant HIV-infected persons, but its use in pregnancy remains limited because of concern regarding potential fetal bone effects. Among the protease inhibitors, there are some concerns with indinavir (Crixivan) and atazanavir (Reyataz) use late in pregnancy, mainly because these drugs can increase indirect bilirubin levels and thus theoretically exacerbate physiologic hyperbilirubinemia in the neonate. Although there are concerns with maternal toxicity resulting from antiretroviral therapy, the benefits of therapy in preventing perinatal transmission and improving maternal health when maternal treatment is indicated far outweigh the risks.

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    Figure 1 - Trends in Mother to Infant Transmission Rate and Maternal Antiretroviral Therapy: 1990-1999 Figure 1
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    Figure 2 - Perinatal HIV Transmission According to Last Maternal HIV RNA and Last Maternal Antiretroviral Therapy Figure 2
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    Figure 3 - Recommendations and Rationale for the Use of Antiretroviral Drugs in Pregnant HIV-Infected Women Figure 3