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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
HIV/Hepatitis C Virus Coinfection
(Last updated: March 28, 2014; last reviewed: March 28, 2014)
All HIV-infected pregnant women should be screened during pregnancy for hepatitis B virus (HBV) and hepatitis C virus (HCV), unless they are known to be coinfected or have already been screened during the current pregnancy (see HIV/Hepatitis B Virus Coinfection section) (AIII).
Screening for HCV infection should use the most sensitive immunoassays licensed for detection of antibody to HCV (anti-HCV) in blood (AIII).
All pregnant women who screen negative for HBV (i.e., HBV surface antigen negative, HBV core antibody negative, and HBV surface antibody negative) should receive the HBV vaccine series (AII).
Women with chronic HCV infection should also be screened for hepatitis A virus (HAV) because they are at increased risk of complications from coinfection with other viral hepatitis infections (AIII).
Women with chronic HCV who are negative for hepatitis A immunoglobulin G should receive the HAV vaccine series (AII).
The management of HIV/HCV coinfection in pregnancy is complex, given currently approved medications for HCV. If considering treatment of HCV in an HIV coinfected pregnant woman, consultation with an expert in HIV and HCV is strongly recommended (AIII).
Interferon alfa and pegylated interferon alfa are not recommended and ribavirin is contraindicated during pregnancy (AII).
Recommendations for antiretroviral (ARV) drug use during pregnancy are the same for HIV-infected women who have chronic HCV as for those without HCV coinfection (BIII).
Pregnant women with HIV/HCV coinfection receiving ARV drugs should be counseled about signs and symptoms of liver toxicity, and liver transaminases should be assessed 1 month following initiation of ARV drugs and at least every 3 months thereafter during pregnancy (BIII).
Decisions concerning mode of delivery in HIV/HCV-coinfected pregnant women should be based on standard obstetric and HIV-related indications alone (see Intrapartum Care) (BIII).
Infants born to women with HIV/HCV coinfection should be evaluated for HCV infection with anti-HCV antibody testing after age 18 months (AII). Infants who screen positive should undergo confirmatory HCV RNA testing. HCV RNA virologic testing can be done after age 2 months, if earlier diagnosis is indicated (AIII). Because HCV viremia can be intermittent, two negative HCV RNA tests at or after age 2 months, including one at or after age 12 months, are needed to definitively exclude HCV infection (BIII). Children are considered to be HCV-infected if they have two or more positive HCV RNA results or are HCV antibody-positive beyond age 18 months (AII).
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
All HIV-infected women should be screened for hepatitis B virus (HBV) and HCV at entry into general HIV care. Pregnant HIV-infected women should be re-screened for HBV and HCV unless they are known to be coinfected or have already been screened during the current pregnancy. HCV coinfection is not uncommon in HIV-infected women, particularly those infected via parenteral use of drugs; among HIV-infected pregnant women, the HCV seroprevalence rate ranges from 17% to 54%.3 Screening for chronic HCV infection using a sensitive immunoassay for HCV antibody is recommended for all HIV-infected individuals, including pregnant women. False-negative anti-HCV immunoassay results can occur in HIV-infected individuals, particularly those with very low CD4 T lymphocyte (CD4) cell counts, but it is uncommon with the most sensitive immunoassays. Individuals who have a positive HCV antibody test should undergo confirmatory testing for plasma HCV RNA using a commercially available quantitative diagnostic assay. Testing for HCV RNA also should be performed on individuals whose serologic test results are indeterminate or negative but in whom HCV infection is suspected because of elevated aminotransaminase levels or risk factors such as a history of intravenous drug use.
Women who screen negative for HBV (i.e., hepatitis B surface antigen (HBsAg)-negative, hepatitis B core antibody-negative, and hepatitis B surface antibody-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.4
Because of the added risk of acute infection with hepatitis A virus (HAV) in individuals with chronic HCV, women who are found to have chronic HCV infection should also be screened for HAV. Women with chronic HCV 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.4
Few data exist on the optimal management of HIV-infected pregnant women with HCV coinfection. Recommendations for antiretroviral (ARV) drug use during pregnancy for treatment of HIV and/or prevention of perinatal transmission are the same for women who have HCV coinfection as for those with HIV alone (see HIV/Hepatitis C Coinfection in the Adult and Adolescent Antiretroviral Guidelines). However, currently available anti-HCV treatments are not recommended during pregnancy. Interferons are not recommended for use in pregnancy because they are abortifacient at high doses in monkeys and have direct antigrowth and antiproliferative effects,5 and ribavirin is contraindicated (Food and Drug Administration [FDA] Pregnancy Category X) because of teratogenicity at low doses in multiple animal species. Ribavirin-associated defects in animals include limb abnormalities, craniofacial defects, anencephaly, and anophthalmia. Concerns have been raised about potential mutagenic effects of ribavirin in the offspring of men taking ribavirin before conception because of possible accumulation of ribavirin in spermatozoa. However, in a small number of inadvertent pregnancies occurring in partners of men receiving ribavirin therapy, no adverse outcomes were reported.6 Pregnancies that occur in women taking ribavirin should be reported to the Ribavirin Pregnancy Registry (800-593-2214 or http://www.ribavirinpregnancyregistry.com). There are no data in pregnancy on telaprevir or boceprevir, both approved in 2011 by the FDA for treatment of HCV, or simeprevir or sofosbuvir, also approved for HCV treatment by the FDA in 2013. Telaprevir, boceprevir, and sofosbuvir are Pregnancy Category B agents and simeprevir is a Pregnancy Category C agent; however, these agents currently must be used in combination with pegylated inteferon and ribavirin, which should not be used in pregnancy. In addition, potential drug interactions between these newer anti-HCV drugs and ARV drugs, particularly certain ritonavir-boosted protease inhibitor (PI) regimens, may reduce the effectiveness of these medications if used together (for more detailed information see Adult and Adolescent Antiretroviral Guidelines).7 Pregnancy does not appear to influence the course of HCV infection and women with chronic HCV generally do quite well during pregnancy, provided that their infections have not progressed to decompensated cirrhosis.8
In a majority of studies, the incidence of perinatal HCV transmission increases if the mother is coinfected with HIV, with transmission rates between 10% and 20%.9-12 These higher transmission rates are likely related to an increase in HCV viremia and/or other HIV-related impact on HCV disease activity.13 A European study of perinatal transmission of HCV found that use of effective combination antiretroviral therapy (cART) for HIV was associated with a strong trend toward reduction in HCV transmission (odds ratio 0.26, 95% confidence interval, 0.07–1.01).14 Maternal HIV/HCV coinfection also may increase the risk of perinatal transmission of HIV.15 Therefore, potent cART with at least three drugs is recommended for all HIV/HCV-coinfected pregnant women, regardless of CD4 cell count or HIV viral load.
As with chronic HBV infection, an elevation in hepatic enzymes following initiation of cART can occur in HIV/HCV-coinfected women—particularly in those with low CD4 cell counts at treatment initiation—as a result of an immune-mediated flare in HCV disease triggered by immune reconstitution with effective cART. Like HBV, HCV infection may increase the hepatotoxic risk of certain ARV agents, specifically PIs and nevirapine. Pregnant women with HIV/HCV coinfection should be counseled about signs and symptoms of liver toxicity, and transaminase levels should be assessed 1 month after initiation of ARV drugs and then every 3 months thereafter. If hepatic toxicity occurs, consideration may need to be given to substituting a less hepatotoxic drug regimen, and if clinical symptoms or significant elevations of transaminases occur, drugs may need to be temporarily discontinued. Differentiating between a flare in HCV disease associated with immune reconstitution and drug toxicity often can be difficult; therefore, consultation with an expert in HIV and HCV coinfection is strongly recommended.
As with transmission of HIV, risk of perinatal transmission of HCV may be increased by use of internal fetal monitoring, amniocentesis, and rupture of membranes for more than 6 hours.11,16 The majority of studies of elective cesarean delivery that have included HIV-infected women have found that the procedure does not reduce the risk of perinatal transmission of HCV.14,17-19 Thus, the general recommendations for intrapartum management are the same in women with HIV/HCV coinfection as in those with HIV infection alone (see Intrapartum Care).
Infants born to women with HIV/HCV coinfection should be assessed for HCV infection with anti-HCV antibody testing after age 18 months. Infants who screen positive should undergo confirmatory HCV RNA testing. HCV RNA virologic testing can be done after age 2 months, if earlier diagnosis is indicated or desirable.20,21 Because HCV viremia can be intermittent, 2 negative HCV RNA tests at or after age 2 months, including 1 at or after age 12 months, are needed to definitively exclude HCV infection. Children are considered to be HCV-infected if they have 2 or more positive HCV RNA polymerase chain reaction results or are HCV antibody-positive beyond age 18 months.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2013. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. 2013. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.
Thomas SL, Newell ML, Peckham CS, Ades AE, Hall AJ. A review of hepatitis C virus (HCV) vertical transmission: risks of transmission to infants born to mothers with and without HCV viraemia or human immunodeficiency virus infection. Int J Epidemiol. 1998;27(1):108-117. Available at http://www.ncbi.nlm.nih.gov/pubmed/9563703.
Centers for Disease Control and Prevention. Guidelines for vaccinating pregnant women, hepatitis A. Available at http://www.cdc.gov/vaccines/pubs/preg-guide.htm#hepa. 2013. Accessed February 14, 2014.
Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G. The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Neurology. 2005;65(6):807-811. Available at http://www.ncbi.nlm.nih.gov/pubmed/16186517.
Hegenbarth K, Maurer U, Kroisel PM, Fickert P, Trauner M, Stauber, RE. No evidence for mutagenic effects of ribavirin: report of two normal pregnancies. Am J Gastroenterol.; 2001; 96(7):2286-7. 2001. Available at http://www.ncbi.nlm.nih.gov/pubmed/11467687
Food and Drug Administration. Victrelis (boceprevir) and ritonavir-boosted HIV protease inhibitor drugs–drug interactions. Available at http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm291389.htm. 2012. Accessed March 5, 2014.
Sookoian S. Effect of pregnancy on pre-existing liver disease: chronic viral hepatitis. Ann Hepatol. 2006;5(3):190-197. Available at http://www.ncbi.nlm.nih.gov/pubmed/17060881.
Tovo PA, Palomba E, Ferraris G, et al. Increased risk of maternal-infant hepatitis C virus transmission for women coinfected with human immunodeficiency virus type 1. Italian Study Group for HCV Infection in Children. Clin Infect Dis. 1997;25(5):1121-1124. Available at http://www.ncbi.nlm.nih.gov/pubmed/9402369.
Gibb DM, Goodall RL, Dunn DT, et al. Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission. Lancet. 2000;356(9233):904-907. Available at http://www.ncbi.nlm.nih.gov/pubmed/11036896.
Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis. 2005;192(11):1880-1889. Available at http://www.ncbi.nlm.nih.gov/pubmed/16267758.
Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006l; 44(1 Suppl):S6-S9. 2006. Available at http://www.ncbi.nlm.nih.gov/pubmed/16352363
Polis CB, Shah SN, Johnson KE, Gupta A. Impact of maternal HIV coinfection on the vertical transmission of hepatitis C virus: a meta-analysis. Clin Infect Dis. 2007;44(8):1123-1131. Available at http://www.ncbi.nlm.nih.gov/pubmed/17366462.
European Paediatric Hepatitis CVN. A significant sex—but not elective cesarean section—effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis. 2005;192(11):1872-1879. Available at http://www.ncbi.nlm.nih.gov/pubmed/16267757.
Hershow RC, Riester KA, Lew J, et al. Increased vertical transmission of human immunodeficiency virus from hepatitis C virus-coinfected mothers. Women and Infants Transmission Study. J Infect Dis. 1997;176(2):414-420. Available at http://www.ncbi.nlm.nih.gov/pubmed/9237706.
Valladares G, Chacaltana A, Sjogren MH. The management of HCV-infected pregnant women. Ann Hepatol. 2010;9 Suppl:92-97. Available at http://www.ncbi.nlm.nih.gov/pubmed/20714003.
Ghamar Chehreh ME, Tabatabaei SV, Khazanehdari S, Alavian SM. Effect of cesarean section on the risk of perinatal transmission of hepatitis C virus from HCV-RNA+/HIV- mothers: a meta-analysis. Arch Gynecol Obstet. 2011;283(2):255-260. Available at http://www.ncbi.nlm.nih.gov/pubmed/20652289.
Marine-Barjoan E, Berrebi A, Giordanengo V, et al. HCV/HIV co-infection, HCV viral load and mode of delivery: risk factors for mother-to-child transmission of hepatitis C virus? AIDS. 2007;21(13):1811-1815. Available at http://www.ncbi.nlm.nih.gov/pubmed/17690581.
McMenamin MB, Jackson AD, Lambert J, et al. Obstetric management of hepatitis C-positive mothers: analysis of vertical transmission in 559 mother-infant pairs. Am J Obstet Gynecol. 2008;199(3):315 e311-315. Available at http://www.ncbi.nlm.nih.gov/pubmed/18771997.
Indolfi G, Resti M. Perinatal transmission of hepatitis C virus infection. J Med Virol. 2009;81(5):836-843. Available at http://www.ncbi.nlm.nih.gov/pubmed/19319981.
Polywka S, Pembrey L, Tovo PA, Newell ML. Accuracy of HCV-RNA PCR tests for diagnosis or exclusion of vertically acquired HCV infection. J Med Virol. 2006;78(2):305-310. Available at http://www.ncbi.nlm.nih.gov/pubmed/16372293.