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Managing HBV Infection During Pregnancy
— Posting 7
LEARNING OBJECTIVE: Manage HBV infection during pregnancy to reduce the risk of maternal transmission.
DISCLOSURE: Robert G. Gish, MD
A 35-year-old Caucasian woman was seen by her internist for an appointment due to elevated liver enzymes. An elevated alanine aminotransferase (ALT) of 70 IU/L and normal liver synthetic tests prompted the physician to evaluate the patient for viral hepatitis. At the same visit, the woman stated she had missed her last two periods. A positive urine pregnancy test indicated she was pregnant. Subsequent testing led to the following findings: elevated alpha fetoprotein (AFP) consistent with pregnancy; platelet count, 220,000/mm3; HBsAg positive; HBV DNA 3x109 IU/L; HBeAg positive; anti-HBe negative; HDV negative; and HCV negative. The patient had a normal spleen size of 9 cm. The physician and the patient had a prolonged discussion on whether to start oral antiviral therapy.
DECISION POINT 1: What would you recommend?
| a. | Start anti-HBV therapy immediately |
| b. | Wait until the third trimester to start anti-HBV therapy |
Discussion
(b) The patient's high HBV DNA levels indicate that anti-HBV therapy should be initiated prior to delivery. Although, historically, HBeAg status has been a surrogate for infection transmission risk, the current standard is to consider serum HBV DNA levels indicative of the viral replication, and thus, the risk for HBV transmission. To minimize medication exposure to the fetus, however, the safest course is to withhold therapy until the pregnancy is more developed, preferably in the third trimester. The teratogenic period of pregnancy is considered to be from days 31 through 71 after the last menstrual period.1
The risk of vertical transmission of HBV from mother to infant is from 10% to 85%, depending on the mother's hepatitis HBV DNA levels and B e antigen (HBeAg) status.2-5 Approximately 90% of infants who become infected by perinatal transmission will develop chronic infection. More than 90% of these infections can be prevented, however, with the administration of HBV vaccine and hepatitis B immune globulin (HBIG) soon after birth. High HBV DNA levels are associated with an increased risk of vertical infection due to infant vaccination failure, as well as failure of passive immunization with HBIG. Reducing HBV DNA levels prior to delivery has been shown to reduce the risk of breakthrough infection and vaccination failure.6-8
Appropriate therapy could include any oral anti-HBV agent as all have a theoretic pregnancy safety level of B or C. (See Tables 19 and 210-17). Lamivudine, however, has the largest database in terms of safety in pregnancy.11
Table 1. Drug Labeling Categories in Pregnancy9| Category | Description |
| A | Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities. |
| B |
Animal studies have revealed no evidence of harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women.
Or Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. |
| C |
Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women.
Or No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women. |
| D | Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk. |
| X |
Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. The use of the product is contraindicated in women who are or may become pregnant. |
Table 2. Drug Pregnancy Safety Data10-17
| Drug |
Pregnancy Category |
Animal Studies |
Human Experience |
Approved for HBV |
| Adefovir10,11 | C | No harm to fetus in rats at 23 times the human dose or in rabbits at 40 times the human dose; harm to fetus in rats at 38 times the human dose | No adequate and well-controlled studies in pregnant women; 16 women in Pregnancy Registry | Yes |
| Entecavir12 | C | No harm to fetus in rats or rabbits at 28 to 212 times the human dose; harm to fetus in rats and rabbits at 3100 and 883 times the human dose, respectively | No adequate and well-controlled studies in pregnant women | Yes |
| Lamivudine11,13 | C | No teratogenicity in rats or rabbits at 35 times the human dose; embryotoxic at human doses in rabbits, but not in rats | >2000 | Yes |
| Telbivudine14 | B | No harm to fetus in rats or rabbits at doses of 6 and 37 times the human dose, respectively | No adequate and well-controlled studies in pregnant women | Yes |
| Tenofovir11,15 | B | No harm to fetus in rats or rabbits at 14 to 19 times the human dose | No adequate and well-controlled studies in pregnant women; 7 women followed in Pregnancy Registry | No |
| Emtricitibine16 | B | No harm to fetus in mice or rabbits at doses of 60 and 120 times the human dose, respectively | No adequate and well-controlled studies in pregnant women | No |
|
Tenofovir plus emtricitabine17 |
B | For emtricitabine, no harm to fetus in mice or rabbits at doses of 60 and 120 times the human dose, respectively. For tenofovir, no harm to fetus in rats or rabbits at 14 to 19 times the human dose | No adequate and well-controlled studies in pregnant women | No |
Case Continues
Lamivudine was on the formulary of the local health plan and the patient was started on lamivudine at 100 mg/day at the beginning of the last trimester. Within 24 hours of birth, the baby received HBV vaccination and HBIG prophylaxis. The patient was followed with laboratory tests at delivery and over the next 3 months. At 6 months of treatment, the patient presented with an HBV DNA level of 4x104 IU/L. Since the patient had delivered a normal term infant it was decided to perform a blood test for biochemical markers of fibrosis. The test had a score of 0.7, consistent with advanced fibrosis.
DECISION POINT 2: What would you recommend?
| a. | Switch to an anti-HBV agent with a lower rate of resistance |
| b. | Continue with lamivudine 100 mg/day monotherapy |
Discussion
(a) Lamivudine is now considered second-line therapy because of its high rate of resistance, 70% at 4 years18,19 although it remains useful in the setting of pregnancy due to the short-term use and its known safety profile. In light of the patient's present HBV DNA level and evidence of advanced fibrosis, switching to an anti-HBV agent with a lower rate of resistance, such as entecavir, or adding an agent with a lower risk of resistance when used with lamivudine, such as adefovir, would improve the efficacy of therapy. Recent findings from a 3-year study of entecavir showed the incidence of resistance to be 1% among nucleoside-naive patients and 15% among patients with lamivudine-resistant disease during year 3, with a cumulative risk of 32% at year 3 for lamivudine-resistant disease.20 Emerging expert opinion suggests that lamivudine-resistant patients who are changed to entecavir may also need to have the addition of a nucleotide such as adefovir or tenofovir. Adefovir also has a lower rate of resistance: 0% for nucleos(t)ide-naive patients and up to 18% for lamivudine-resistant patients after 48 weeks of adefovir therapy when adefovir is used as monotherapy.21
In October 2006, telbivudine was approved by the Food and Drug Administration for the treatment of chronic hepatitis B. Resistance data from the GLOBE trial shows the rate of breakthrough and resistance with telbivudine to be 3% and 2.5%, respectively, at 1 year in treatment-naive patients and 21.6% and 8.6 % at 2 years in HBeAg positive and HBeAg negative disease, respectively, when using genotypic testing of those patients who had a 1-log breakthrough on therapy.22-24 It is important to note that patients who develop the 204 mutation in the polymerase of the HBV virus while being treated with other nucleoside analogs will have cross resistance if they are placed on telbivudine therapy.14 Thus, telbivudine monotherapy is not a first-line therapy for patients with lamivudine resistance.
References
- Konchak PS. Preconception care: "VITAL MOM"—a guide for the primary care provider. J Am Osteopath Assoc. 2001;101(2 Suppl):S1-9.
- Centers for Disease Control and Prevention. Hepatitis B virus: a comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR. 1991;40(RR-13);1-19.
- del Canho R, Grosheide PM, Mazel JA, et al. Ten-year neonatal hepatitis B vaccination program, The Netherlands, 1982-1992: protective efficacy and long-term immunogenicity. Vaccine. 1997;15:1624-1630.
- del Canho R, Grosheide PM, Schalm SW, de Vries RR, Heijtink RA. Failure of neonatal hepatitis B vaccination: the role of HBV-DNA levels in hepatitis B carrier mothers and HLA antigens in neonates. J Hepatol. 1994;20:483-486.
- Ngui SL, Andrews NJ, Underhill GS, Heptonstall J, Teo CG. Failed postnatal immunoprophylaxis for hepatitis B: characteristics of maternal hepatitis B virus as risk factors. Clin Infect Dis. 1998;27:100-106.
- van Zonneveld M, van Nunen AB, Niesters HG, De Man RA, Schalm SW, Janssen HL. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat. 2003;10:294-97.
- van Nunen AB, De Man RA, Heijtink RA, Niesters HG, Schalm SW. Lamivudine in the last 4 weeks of pregnancy to prevent perinatal transmission in highly viremic chronic hepatitis B patients. J Hepatol. 2000;32:1040-1041.
- Su GG, Pan KH, Zhao NF, Fang SH, Yang DH, Zhou Y. Efficacy and safety of lamivudine treatment for chronic hepatitis B in pregnancy. World J Gastroenterol. 2004;10:910-912.
- Food and Drug Administration (FDA). Current categories for drug use in pregnancy. Available at: http://www.fda.gov/fdac/features/2001/301_preg.html#categories. Accessed on: November 14, 2006.
- Hepsera® (adefovir dipivoxil). Product Information. Foster City, CA: Gilead Sciences, Inc; 2006.
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry Interim Report for 1 January 1989 through 31 January 2006. Wilmington, NC: Registry Coordinating Center; 2006. Available at: http://www.apregistry.com/forms/apr_report_106.pdf. Accessed on: November 14, 2006.
- Baraclude™ (entcavir). Product Information. Princeton, NJ: Bristol-Myers Squibb Company; 2005.
- Epivir® (lamivudine). Product Information. Research Triangle Park, NC: GlaxoSmithKline; 2006.
- Tyzeka™ (telbivudine). Product Information. Cambridge, MA: Idenix Pharmaceuticals, Inc; 2006.
- Viread (tenofovir disoproxil fumarate). Product Information. Foster City, CA: Gilead Sciences, Inc; 2006.
- Emtriva® (emtricitabine). Product Information. Foster City, CA: Gilead Sciences, Inc; 2005.
- Truvada® (emtricitabine and tenofovir disoproxil fumarate). Product Information. Foster City, CA: Gilead Sciences, Inc; 2006.
- Lai C-L, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687-696.
- Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962.
- Colonno RJ, Rose RE, Pokornowski K, et al. Assessment at three years shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients. Hepatology. 2006;44:532A.
- Lee YS, Suh DJ, Lim YS, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43:1385-1391.
- Standring DN, Seifer M, Patty A, et al. HBV resistance determination from the telbivudine GLOBE registration trial. Abstract 514. Presented at: 41st Annual Meeting of the European Association for the Study of the Liver; April 26–30, 2006. Paris, France.
- Lai C-L, Gane E, Liaw Y-F, et al. Telbivudine (LDT) vs. lamivudine for chronic hepatitis B: first-year results from the international phase III Globe trial. Hepatology. 2005;42(suppl 1):748A.
- Lai C-L, Gane E, Hsu C-W, et al. Two-year results from the Globe trial in patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine (LDT) vs. lamivudine. Hepatology. 2006;44(suppl 1):222A.