(Last updated: March 28, 2014; last reviewed: March 28, 2014)
|Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert opinion
For additional information on hepatitis B virus (HBV) and HIV, see HIV/Hepatitis B (HBV) Coinfection in the Adult and Adolescent Antiretroviral Guidelines (http://AIDSInfo.nih.gov)1 and Hepatitis B Virus Infection in the Adult Opportunistic Infections Guidelines.2 The management of HIV/HBV coinfection in pregnancy is complex and consultation with an expert in HIV and HBV infection is strongly recommended.
All HIV-infected women should be screened for HBV and hepatitis C virus (HCV) at entry into general HIV care. Pregnant HIV-infected women should be rescreened for HBV and HCV unless they are known to be coinfected or have already been screened during the current pregnancy. Women who screen negative for HBV (i.e., hepatitis B surface antigen [HBsAg]-negative, hepatitis B core antibody [anti-HBc]-negative, and hepatitis B surface antibody [anti-HBs]-negative) should receive the HBV vaccine series. Data indicate no apparent risk to developing fetuses of adverse events from hepatitis B vaccine, and current vaccines contain noninfectious HBsAg and should cause no risk to fetuses.3 A positive test for anti-HBc alone can be false-positive, or it may signify past exposure with subsequent loss of anti-HBs or “occult” HBV infection, which can be confirmed by detection of HBV DNA.4,5 The clinical significance of isolated anti-HBc is unknown.6,7 Some experts recommend that HIV-infected individuals with anti-HBc alone be tested for HBV DNA before vaccination for HBV or before treatment or prophylaxis with antiretroviral (ARV) drugs is initiated because of the risk of a paradoxical exacerbation of HBV and the occurrence of immune reconstitution inflammatory syndrome (IRIS).2 HIV-infected pregnant women with isolated anti-HBc and occult HBV infection have very low levels of HBV DNA and are thought to be at extremely low risk of transmitting HBV to their infants.8
Because of the added risk of acute infection with hepatitis A virus (HAV) in individuals with chronic HBV, women who are found to have chronic HBV infection should also be screened for HAV. Women with chronic HBV infection who are hepatitis A immunoglobulin G-negative should receive the HAV vaccine series. Although the safety of HAV vaccination during pregnancy has not been determined, HAV vaccine is produced from inactivated HAV and the theoretical risk to the developing fetus is expected to be low.3
An ARV regimen that includes drugs active against both HIV and HBV is recommended for all individuals with HIV/HBV coinfection who require HBV treatment or who are starting ARV drugs, including pregnant women. Initiation of an ARV regimen that does not include anti-HBV drugs may be associated with reactivation of HBV and development of IRIS; IRIS-related flare of HBV activity during pregnancy can occur even in women with relatively high CD4 T lymphocyte (CD4) cell counts at the time of ARV initiation. In addition, use of ARV drugs with anti-HBV activity during pregnancy lowers HBV viremia, potentially increasing the efficacy of neonatal hepatitis B immune globulin (HBIG) and hepatitis B vaccine in prevention of perinatal transmission of HBV. High maternal HBV DNA levels are strongly correlated with perinatal HBV transmission and with failures of HBV passive-active immunoprophylaxis.9-11 Several small studies and a recent meta-analysis suggest that lamivudine or telbivudine may reduce the risk of perinatal transmission of HBV if given during the third trimester to HBV-infected, HIV-seronegative women with high HBV DNA viremia.12-18 Although a high HBV viral load clearly is important, it is not the only factor predisposing to failure of prophylaxis.19
Because lamivudine, tenofovir, and emtricitabine have activity against both HIV and HBV, the recommended dual-nucleoside reverse transcriptase/nucleotide analogue reverse transcriptase inhibitor (NRTI) backbone for HIV/HBV-coinfected individuals, including pregnant women, is tenofovir/emtricitabine or tenofovir/lamivudine. Lamivudine has been extensively studied and is recommended for use in pregnancy (see Table 6). The Antiretroviral Pregnancy Registry includes reports on the outcomes of 4,273 pregnancies that involved administration of lamivudine in the first trimester and there is no indication that the exposure was associated with an increased risk of birth defects.20 Similarly, no increase in birth defects has been noted in 1,230 cases of first-trimester exposure to emtricitabine, which, like lamivudine, is recommended for use in pregnancy (see Table 6). Tenofovir is not teratogenic in animals, but reversible bone changes at high doses have been seen in multiple animal species. A total of 1,800 cases of first-trimester exposure have been reported to the Antiretroviral Pregnancy Registry, with no increase in birth defects noted.20 Tenofovir with emtricitabine or lamivudine is a preferred dual NRTI backbone in women who are HIV-infected or HIV/HBV-coinfected (see Table 6).
Several other antivirals with activity against HBV, including entecavir, adefovir, and telbivudine, have not been well evaluated in pregnancy. Entecavir is associated with skeletal anomalies in rats and rabbits but only at doses high enough to cause toxicity to the mother. Fewer than 52 cases of exposure to each of these drugs during pregnancy have been reported to the Antiretroviral Pregnancy Registry prospectively, with no increased risk of birth defects.20 Telbivudine was given to 135 HBV-positive, HIV-seronegative women during the third trimester and was well tolerated, and perinatal transmission of HBV was lower in telbivudine-treated mothers (0% vs. 8%; P = 0.002).15,21 In a larger meta-analysis of the effects of telbivudine in late pregnancy in women infected with HBV alone, telbivudine was effective in interrupting intrauterine HBV infection without significant adverse effects or complications.16 Each of these anti-HBV drugs should be administered only in addition to a fully suppressive regimen for HIV. Because these other anti-HBV drugs also have weak activity against HIV, they may select for anti-HIV drug resistance in the absence of fully suppressive cART regimen as well as confer the potential for developing cross-resistance to other ARV drugs. (Entecavir, for example, can select for the M184V mutation, which confers HIV resistance to lamivudine and emtricitabine.) Cases of exposure during pregnancy to any of the ARV drugs and HBV drugs listed should be reported to the Antiretroviral Pregnancy Registry (800-258-4263; http://www.apregistry.com).
Interferon alfa and pegylated interferon alfa are not recommended for use in pregnancy and should be used only if the potential benefits outweigh the potential risks. Although interferons are not teratogenic, they are abortifacient at high doses in monkeys and should not be used in pregnant women because of the direct antigrowth and antiproliferative effects of these agents.22
Following initiation of ARV drugs, an elevation in hepatic enzymes can occur in HIV/HBV-coinfected women—particularly those with low CD-cell counts at the time of treatment initiation—as a result of an immune-mediated flare in HBV disease triggered by immune reconstitution with effective HIV therapy. HBV infection also can increase hepatotoxic risk of certain ARV drugs, specifically protease inhibitors and nevirapine. Pregnant women with HIV/HBV coinfection should be counseled about signs and symptoms of liver toxicity, and transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter. If hepatic toxicity occurs, it may be necessary to consider substituting a less hepatotoxic regimen or, if clinical symptoms or significant elevations of transaminases occur, drugs may need to be temporarily discontinued. Differentiating between a flare in HBV disease due to immune reconstitution and drug toxicity often can be difficult, and consultation with an expert in HIV and HBV coinfection is strongly recommended. Because tenofovir has potential to cause renal toxicity, kidney function also should be monitored regularly in women receiving this drug, based on toxicity seen in non-pregnant adults.
Following delivery, considerations regarding continuation of the ARV drug regimen are the same as for other non-pregnant individuals (see General Principles Regarding Use of Antiretroviral Drugs During Pregnancy). Discontinuing agents with anti-HBV activity may be associated with hepatocellular damage resulting from reactivation of HBV. Frequent monitoring of liver function tests for potential HBV flare is recommended in women with HIV/HBV coinfection whose ARV drugs are discontinued postpartum, with prompt re-initiation of treatment for both HIV and HBV if a flare is suspected.
Within 12 hours of birth, all infants who weigh >2,000 g born to mothers with chronic HBV infection should receive HBIG and the first dose of the HBV vaccination series. The second and third doses of vaccine should be administered at ages 1 and 6 months, respectively. This regimen is >95% effective in preventing HBV infection in these infants. Consult the CDC Morbidity and Mortality Weekly Report recommendations for similar infants with birth weights <2,000 g at birth.23
Post-vaccination testing for anti-HBs and HBsAg should be performed after completion of the vaccine series, at age 9 months to 18 months. Testing should not be performed before age 9 months to avoid detection of anti-HBs from HBIG administered during infancy and to maximize the likelihood of detecting late HBV infection. Anti-HBc testing of infants is not recommended because passively acquired maternal anti-HBc might be detected in infants born to HBV-infected mothers up to age 24 months. HBsAg-negative infants with anti-HBs levels >10 mIU/mL are protected and need no further medical management. HBsAg-negative infants with anti-HBs levels <10 mIU/mL should be revaccinated with a second 3-dose series and retested 1–2 months after the final dose of vaccine.