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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

Special Populations

HIV/Hepatitis C Virus Coinfection

(Last updated: August 6, 2015; last reviewed: August 6, 2015)

Panel's Recommendations

Panel's Recommendations

  • All HIV-infected pregnant women should be screened during the current pregnancy for hepatitis B virus (HBV) and hepatitis C virus (HCV), unless they are known to be coinfected (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 HIV-infected 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 HBV or 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 if they have never received it (AII)
  • The management of HIV/HCV coinfection in pregnancy is complex because currently approved medications for HCV are not recommended during pregnancy, and no safety data exist for use of the recently approved HCV oral medications in pregnant women (AIII). 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 drug use during pregnancy are the same for HIV-infected women whether or not they have chronic HCV (BIII).
  • Pregnant women with HIV/HCV coinfection receiving antiretroviral drugs should be counseled about signs and symptoms of liver toxicity, and liver transaminases should be assessed 1 month following initiation of antiretroviral 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; HCV coinfection does not necessitate cesarean delivery, if not otherwise indicated (see Intrapartum Care) (AIII).
  • 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. If earlier diagnosis is desired, HCV RNA virologic testing can be done after age 2 months (AIII). 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 (BIII). Children are considered to be HCV-infected if they have two or more positive HCV RNA results at any age, 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

For additional information on hepatitis C virus (HCV) and HIV, see HIV/Hepatitis C Coinfection in the Adult and Adolescent Antiretroviral Guidelines1 and Hepatitis C Virus Infection in the Adult Opportunistic Infections Guidelines.2 The American Association for the Study of Liver Diseases, the Infectious Diseases Society of America, and International Antiviral Society-USA recently updated their HCV treatment guidelines to add newly approved interferon-free direct-acting antiviral regimens and to provide more information about treating patients with HIV/HCV coinfection and decompensated liver disease. The guidelines are available online at HCVguidelines.org. The management of HIV/HCV coinfection in pregnancy is complex and consultation with an expert in HIV and HCV infection is strongly recommended, particularly if treatment of HCV infection during pregnancy is being considered.

Screening and Vaccination

All HIV-infected women should be screened for hepatitis B virus (HBV) and HCV at entry into general HIV care. HIV-infected women should be rescreened for HBV and HCV during each pregnancy, unless they are known to be coinfected. HCV coinfection is not uncommon in HIV-infected women, particularly those infected via parenteral use of drugs; among HIV-infected pregnant women in a European cohort, the observed HCV seroprevalence rate was 12%.3 The male partners of all HIV/HCV-coinfected patients should be referred for both HIV and hepatitis counseling and testing to prevent horizontal transmission of HIV as well as HCV from woman to their male partners.  

Althought current HCV treatment guidelines recommend therapy for all HCV-infected patients with estimated life expectancies >12 months, currently available anti-HCV treatments lack sufficient safety data to be recommended during pregnancy. In addition, the risks of perinatal HCV transmission are much lower than of perinatal HIV transmission, and many infected children will clear HCV infection spontaneously, making the balance of risks and benefits for treating HCV in pregnancy very different than for treating HIV in pregnancy. 

The primary reasons for HCV testing during pregnancy, therefore, are: 

  1. To identify HCV-infected women at a time when they are engaged with the health system, so that HCV treatment can be offered after delivery (ideally before a subsequent pregnancy, if planned); 
  2. To be aware of increased risk of HCV-related hepatotoxicity related to antiretroviral (ARV) use in HIV/HCV coinfected women; 
  3. To ensure vaccination against other viral hepatitides (hepatitis A virus [HAV] and HBV) when needed; and 
  4. To ensure appropriate follow-up and evaluation of HCV-exposed infants.

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 or very recent infection, but it is uncommon with the more sensitive immunoassays. If HCV infection is suspected despite a negative HCV antibody screen, a quantitative HCV RNA assay can be performed. 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 injection drug use.

HIV/HCV-coinfected 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 vaccination, and current vaccines contain noninfectious HBsAg and should cause no risk to fetuses.4

Because of the added risk of hepatic decompensation from acute infection with HAV in individuals with chronic HCV, women with HCV infection should also be screened for HAV, using antibody testing for immunoglobulin G (IgG). If HAV IgG is negative, and if the HAV vaccine was not given previously, HIV/HCV-coinfected women should receive the HAV vaccine series. Post-vaccination serologic testing is not indicated because many commercially available HAV antibody assays do not have the sensitivity to detect low HAV antibody concentrations after vaccination.5 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

Impact of Hepatitis C Virus on HIV Management 

Few data exist on the optimal management of HIV-infected pregnant women with HCV coinfection. Recommendations for ARV drug use during pregnancy for treatment of HIV and prevention of perinatal transmission are the same for women who have HIV/HCV co-infection as for those infected only with HIV (see HIV/Hepatitis C Coinfection in the Adult and Adolescent Antiretroviral Guidelines). 

Hepatitis C Virus-Specific Therapy in Pregnancy 

Currently available anti-HCV treatments—both oral and parenteral—lack sufficient safety data to be recommended during pregnancy. Until recently, most anti-HCV therapy included both interferon and ribavirin. Interferons are not recommended for use in pregnancy because they are abortifacient at high doses in monkeys and have direct antigrowth and antiproliferative effects.6 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.7 Pregnancies that occur in women taking ribavirin should be reported to the Ribavirin Pregnancy Registry (800-593-2214 or http://www.ribavirinpregnancyregistry.com). 

Newer interferon-free and ribavirin-free regimens have recently been approved for treatment of HCV. As of June 2015, these regimens included the protease inhibitor (PI) simepravir (Pregnancy Category C), the nucleotide analogue NS5B polymerase inhibitor sofosbuvir (Pregnancy Category B), the NS5A inhibitor ledipasvir (Pregnancy Category B), and a fixed-dose combination (Pregnancy Category B) of both ledipasvir/sofosbuvir and paritaprevir (NS3/4A PI)/ritonavir/ombitasvir (HS5A PI) plus twice-daily dasabuvir (NS5B polymerase inhibitor), given with and without ribavirin, depending on HCV genotype. However, these medications are not yet recommended for use in pregnancy because of the lack of data on their use in pregnancy. In addition, potential drug interactions between these newer anti-HCV drugs and ARV drugs, particularly certain protease inhibitor (PI) regimens and non-nucleoside reverse transcriptase inhibitors, may reduce the effectiveness of these medications if used together or increase exposure to tenofovir disoproxil fumarate if included in the regimen. For more detailed information on drug interactions and newly approved medications, see Adult and Adolescent Antiretroviral Guidelines, Adult Opportunistic Infections Guidelines and the HCV treatment guidelines (http://www.hcvguidelines.org)

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.8,9 

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% reported primarily among women not treated with combination antiretroviral therapy (cART).10-13 These higher transmission rates are likely related to an increase in HCV viremia and/or other HIV-related impact on HCV disease activity.14 However, early and sustained control of HIV viremia with cART may reduce HCV transmission to infants.9,15,16 A European study of perinatal transmission of HCV found that use of effective 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).15 

Maternal HIV/HCV coinfection also may increase the risk of perinatal transmission of HIV.17 Therefore, cART is recommended for all HIV/HCV-coinfected pregnant women, regardless of CD4 cell count or HIV viral load.

Monitoring of HIV/ Hepatitis C Virus-Infected Women during Pregnancy 

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. 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. 

Mode of Delivery 

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.12,18 The majority of studies of elective cesarean delivery in HCV-infected women with or without HIV coinfection have found that the procedure does not reduce the risk of perinatal transmission of HCV.15,19-21 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). 

Evaluation of HCV-Exposed Infants 

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.22,23 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. Children are considered to be HCV-infected if they have two or more positive HCV RNA polymerase chain reaction results at any age, or are HCV antibody-positive beyond age 18 months.

References

  1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2014. Available at http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed June 6, 2015.
  2. 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. 2015. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed July 7, 2015.
  3. Landes M, Newell ML, Barlow P, et al. Hepatitis B or hepatitis C coinfection in HIV-infected pregnant women in Europe. HIV Med. 2008;9(7):526-534. Available at http://www.ncbi.nlm.nih.gov/pubmed/18554310.
  4. Centers for Disease Control and Prevention. Guidelines for vaccinating pregnant women, hepatitis A. 2014. Available at http://www.cdc.gov/vaccines/pubs/preg-guide.htm#hepa. Accessed March 8, 2015.
  5. Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization. MMWR. 2006;55(RR-7). Available at http://www.cdc.gov/mmwr/PDF/rr/rr5507.pdf.
  6. 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.
  7. 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):2286-2287. Available at http://www.ncbi.nlm.nih.gov/pubmed/11467687.
  8. 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.
  9. Benova L, Mohamoud YA, Calvert C, Abu-Raddad LJ. Vertical transmission of hepatitis C virus: systematic review and meta-analysis. Clin Infect Dis. 2014;59(6):765-773. Available at http://www.ncbi.nlm.nih.gov/pubmed/24928290.
  10. 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.
  11. 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.
  12. 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.
  13. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. 2006;44(1 Suppl):S6-9. Available at http://www.ncbi.nlm.nih.gov/pubmed/16352363.
  14. 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.
  15. 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.
  16. Checa Cabo CA, Stoszek SJ, Quarleri J, et al. Mother-to-child transmission of hepatitis C virus (HCV) among HIV/HCV-coinfected women. J Ped Infect Dis. 2013;2(2):126-135. Available at http://jpids.oxfordjournals.org/content/2/2/126.full
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.

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