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.[,,] In addition, repeat testing should be considered for all women in their third trimester (preferably before week 36) and is recommended for women from high HIV prevalence areas, those with risk behaviors for acquiring HIV, and those who declined testing earlier in the pregnancy. 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 consists of screening with the enzyme-linked immunoassay (ELISA) and confirming any positive test with a Western blot or an immunofluorescence assay (IFA). The new CDC recommended HIV testing algorithm that utilizes a fourth generation antigen-antibody combination assay as the initial screening test provides several advantages over conventional HIV testing pregnant women, including (1) better detection of women with acute or very recent HIV infection and (2) a more rapid turnaround for test results. Any pregnant women that displays symptoms concerning for acute HIV infection should undergo plasma HIV RNA testing in addition to the standard HIV screening test. For women with undocumented HIV status who present at the time of labor, performing a rapid HIV test is recommended.
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%. 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. 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 combination regimens (Figure 1).[,,,,] 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 to 2% of women, in contrast with the transmission rate of 20 to 25% in women who receive no antiretroviral therapy. The use of antiretroviral therapy may provide significant benefit even if the pregnant woman does not achieve an undetectable HIV RNA level. The 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.
General Principles for Use of Antiretroviral Therapy During Pregnancy
When an HIV-infected woman becomes pregnant or is newly diagnosed with HIV in pregnancy, she should promptly undergo clinical evaluation and have testing for CD4 cell count, HIV RNA level, and HIV genotype (if the HIV RNA is greater than 500 to 1,000 copies/ml). The 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 address multiple scenarios involving involving pregnant HIV-infected women. The following discussion will focus on management issues related to (1) HIV-infected pregnant woman who have not received prior antiretroviral therapy and (2) HIV-infected woman who is receiving antiretroviral therapy that was started before the pregnancy. All HIV-infected pregnant women, regardless of CD4 count or HIV RNA level, should receive combination therapy during pregnancy. In general, many of the same principles that guide antiretroviral therapy in the nonpregnant patient apply to treatment of the pregnant HIV-infected women—the patient should receive a combination of at least three medications that result in virologic suppression. The specific choice of regimen will depend on the pregnant woman's prior antiretroviral history and the presence of other comorbid conditions. To maximize the prevention of mother-to-child HIV transmission, antiretroviral therapy in pregnancy should be used in conjunction with intrapartum therapy and infant antiretroviral prophylaxis. In a recent study, investigators followed 671 HIV-infected pregnant women between 2002 and 2011 and found 13.1% of those who received antiretroviral therapy had detectable HIV RNA at the time of delivery; factors associated with detectable HIV RNA at delivery were poor adherence, treatment interruptions, and initiation of antiretroviral therapy during the third trimester.
Initial Regimens for Antiretroviral Therapy-Naive Pregnant Woman
For HIV-infected pregnant women who have never received antiretroviral therapy, the regimen should ideally be selected after receiving results from the antiretroviral drug-resistance assay. Some experts would consider deferring initiation of antiretroviral therapy until after the first trimester, with this decision primarily depending on the mother's CD4 cell count and the severity of first trimester nausea and vomiting. ;For patients that have no evidence of drug-resistant HIV, the recommended combination regimen should consists of a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone plus either a ritonavir-boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (Figure 2). Specifically, the preferred dual NRTI backbone consists of abacavir-lamivudine (Epzicom), tenofovir-emtricitabine (Truvada), or zidovudine-lamivudine (Combivir); abacavir should only be used if the patient has a documented negative HLA-B*5701 test. The preferred protease inhibitor component is either atazanavir (Reyataz) plus ritonavir (Norvir) or lopinavir-ritonavir (Kaltetra). The non-nucleoside reverse transcriptase inhibitor efavirenz is considered a preferred drug, but should only be started if the women is past week 8 in gestation. The HHS perinatal guidelines also include several alternative regimens (Figure 3). Although initiation of nevirapine in women with a CD4 count greater than 250 cells/mm3 is not recommended due to risk of hepatotoxicity, the guidelines allow for continuation of nevirapine (Viramune) in women during pregnancy, regardless of CD4 cell count, assuming the HIV RNA is suppressed to undetectable levels. There are no data or recommendations to support the use of dolutegravir (Tivicay), elvitegravir (Vitekta), maraviroc (Selzentry) in pregnancy.
Approach to Pregnant Woman Currently Receiving Antiretroviral Therapy
In the scenario involving an HIV-infected woman who becomes pregnant while taking antiretroviral therapy, guidelines recommend continuing therapy, if the regimen is not causing adverse effects and the HIV RNA is suppressed to undetectable levels. In the past, guidelines had recommended discontinuing efavirenz due to concern of neural tube adverse effects, but current guidelines recommend continuing efavirenz, even during the first trimester, as long as the patient has undetectable HIV RNA levels. The revision in the efavirenz recommendation is based on a number of reports that have not shown any increased risk of birth defects among infants born to women with first trimester exposure, most notably a large meta-analysis of 1,437 women from 19 studies. In addition, experts have argued that since the neural tube closes between 36 to 39 days after the last menstrual period, most women will not be seeking medical care for pregnancy prior to the closure of the neural tube. Further, studies have shown that antiretroviral changes during pregnancy is a significant risk for patients developing developing detectable HIV RNA levels at the end of pregnancy. If a pregnant women is on antiretroviral therapy and does not have fully suppressed HIV RNA levels, resistance testing should be performed if the HIV RNA level is greater than 1,000 copies/ml (and possibly with greater than 500 copies/ml).
Failure of Virologic Suppression During Pregnancy
In the situation when an HIV-infected woman does not have optimal virologic suppression during pregnancy, the HHS guidelines recommend using a three-pronged approach: (1) evaluate for HIV drug resistance (if the HIV RNA is greater than 500 to 1,000 copies/ml), (2) assess for any problems related to adherence, tolerability, dosing, or absorption, and (3) consider a change in the antiretroviral regimen. When HIV RNA levels are not undetectable level late in pregnancy, such as with emergence of drug resistance or when therapy was started in the second or third trimester, some experts have recommended adding raltegravir (Isentress) to the regimen.[,] Raltegravir causes rapid reduction in HIV RNA levels and thus provides a means to suppress detectable HIV RNA levels late in pregnancy prior to delivery. Enthusiasm for the use of raltegravir in this setting has been dampened by a recent report that showed a 10- to 23-fold increase in hepatic aminotransferase levels in a woman who received raltegravir late in pregnancy; the levels returned to normal after stopping the raltegravir. Currently, the HHS guidelines do not recommend adding raltegravir late in pregnancy in an effort to suppress maternal HIV RNA levels prior to delivery.
Special Considerations with Certain Antiretroviral Medications During Pregnancy
Certain antiretroviral medications have adverse effects that warrant special consideration in pregnancy, either due to enhanced toxicity in the mother or concerns for the fetus. Although there are concerns with maternal toxicity resulting from antiretroviral therapy, in most circumstances, the benefits of therapy in preventing perinatal HIV transmission and improving maternal health usually outweigh the risks. The following list of medications and potential adverse effects is not comprehensive, but rather highlights some medication-related adverse effects that frequently raise clinical concern in this setting for medications considered as recommended or alternative options.
- Nevirapine: 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.[,,,] 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 is not recommended.[,,]
- Efavirenz: As noted above, existing data have suggested that use of efavirenz very early in pregnancy could cause neural tube defects. These concerns have resulted in the recommendation not to start efavirenz in the first 8 weeks of pregnancy. In contrast, since the neural tube closes between 36 to 39 days after the last menstrual period, women already taking efavirenz who become pregnant can usually continue efavirenz, since most women will not be seeking medical care for pregnancy prior to the closure of the neural tube.
- Zidovudine: Among antiretroviral medications used in pregnancy, the most extensive experience exists with zidovudine. Overall, zidovudine has shown an excellent safety profile and there is no evidence that zidovudine causes teratogenicity.
- Tenofovir: Use of tenofovir (Viread) in pregnancy has become common in pregnancy but concerns linger related to the theoretical risk of adversely impacting fetal bone development. Available data have shown no increased risk of birth defects compared with the general population, nor have significant differences been consistently observed in birth weight or growth. Of note, one study has shown lower length and head circumference among infants born to mothers who received tenofovir.
- Protease Inhibitors: Available data suggest that use of HIV protease inhibitors during pregnancy results in a small increased risk of preterm birth. In addition, there have been some concern with the use of atazanavir late in pregnancy, mainly because atazanavir can increase indirect bilirubin levels and thus potentially exacerbate physiologic hyperbilirubinemia in the neonate. For mothers who have received atazanavir during pregnancy, adverse outcomes in newborns related to dangerous or pathological bilirubin elevations have not been reported.
Stopping Antiretroviral Therapy During Pregnancy
In some circumstances, antiretroviral therapy may need to be discontinued during pregnancy, usually due to severe pregnancy-related nausea and vomiting or antiretroviral medication-related adverse effects. If the antiretroviral medications need to be discontinued and the regimen includes a NNRTI (efavirenz or nevirapine), stopping the entire regimen can be problematic due to the very long half life of the NNRTIs compared with the NRTI backbone medications. If the pregnant woman is on an NNRTI-based antiretroviral regimen that needs to be stopped for a non-life-threatening reason, two options have been recommended by experts: (1) stop the NNRTI medication at least 7 days prior to stopping the NRTI backbone or (2) replace the NNRTI with ritonavir-boosted protease inhibitor for 7 to 30 days prior to stopping the entire regimen. For women with severe nausea and vomiting these options may not be possible.
The National Perinatal HIV Hotline
In some circumstances, optimal management of HIV-infected pregnant women and their infants in an attempt to prevent HIV transmission may benefit from expert consultation. The National Perinatal HIV Hotline (888-448-8765) is a federally funded service providing free clinical consultation for medical providers caring for HIV-infected pregnant women and their infants. The perinatal hotline can also assist with referral to local or regional pediatric HIV specialists.