Approach to Managing the Pregnant Woman With Chronic Hepatitis B
Approach to Managing the Pregnant Woman With Chronic Hepatitis B
Should pregnant women with chronic hepatitis B with detectable viral load be treated with antiviral agents during pregnancy to decrease the risk for transmission to the baby?
Let me first frame the question -- what problem are we trying to solve? Infection with hepatitis B virus (HBV) in infancy or early childhood often leads to persistent infection, as evidenced by the fact that in countries with a high prevalence of chronic hepatitis B, perinatal transmission from mother to infant accounts for the majority of cases. Approximately 90% of untreated infants born to mothers positive for hepatitis B e-antigen (HBeAg) will develop "immune tolerance." This is traditionally explained by transplacental transfer of viral antigens, which induces a specific nonresponsiveness of helper T cells to HBeAg and hepatitis B core antigen (HBcAg). Spontaneous HBeAg seroconversion (to anti-HBe positive) may develop with time, but liver damage may occur during the process of immune clearance of HBeAg. Screening for maternal hepatitis B surface antigen (HBsAg), followed by administration of HBV vaccine and hepatitis B-specific immunoglobulin (HBIG) to the newborn within 24 hours of birth, is the most effective way to prevent perinatal HBV infection. The first universal HBV immunization program in the world was launched in Taiwan over 20 years ago; thus, the HBV infection rate and the incidence of hepatocellular carcinoma and fulminant hepatitis in children have been reduced. Current published guidelines state that newborns of HBV-infected mothers should receive passive-active immunoprophylaxis with HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series. This strategy is approximately 95% effective in reducing the risk for HBV transmission, but is less effective in HBeAg-positive mothers with very high serum HBV DNA levels. Maternal serum HBV DNA concentrations >10 IU/mL have been associated with a 5% to 10% failure of immunoprophylaxis.
In highly viremic HBsAg-positive mothers, reduction of viremia in the last month of pregnancy may be an effective and safe measure to decrease the risk for failure of prophylaxis. Two separate strategies have been used to reduce the "viral burden" during pregnancy: prenatal HBIG administration and specific antiviral therapy. However, prophylactic therapy is complex, controversial, and not well studied.
HBIG:
In a prospective randomized controlled trial, Xu and colleagues administered either placebo or HBIG (200 IU intravenously every 4 weeks for 3 times) from the 28th week of gestation in HBsAg-positive mothers. There was a significant difference in the rate of HBeAg and HBV DNA positivity in the newborns (positivity rates: 25% in those born to mothers who received HBIG vs 83% in placebo recipients). In addition, the HBV DNA load of newborns was lower than that of their treated mothers and significantly lower than that of untreated controls.
Specific Antiviral Therapy:
The only oral antiviral agent studied in this setting is lamivudine. When given in the last 4 weeks of pregnancy, lamivudine has been shown to reduce high-level viremia. van Zonneveld and
colleagues treated 8 highly viremic (HBV DNA >1.2 x 10 IU/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. Children (n = 24) born to untreated HBsAg-positive mothers with similar HBV DNA levels served as controls. All children received passive-active immunization with HBIG and HBV vaccine at birth and were followed up for 12 months. Seven of the 8 lamivudine-treated mothers had a decrease in their serum HBV DNA concentrations. One of the 8 children (12.5%) in the lamivudine group remained HBsAg- and HBV DNA-positive at the age of 12 months; all other children seroconverted to anti-HBs. In the untreated control group, perinatal transmission occurred in 7 of 25 children (28%). Other studies have evaluated the efficacy and safety of lamivudine for the treatment of chronic hepatitis B in pregnancy. Li and colleagues investigated the effect of lamivudine vs HBIG on HBV intrauterine transmission. HBsAg-positive pregnant women (n = 56) were given either 200 IU of HBIG intramuscularly every 4 weeks from the 28th week of gestation, or lamivudine (n = 43) 100 mg orally every day from the 28th week of gestation until the 30th day after labor. Subjects in the control group (n = 52) received no specific treatment. The rate of neonatal HBV infection was significantly lower among those patients receiving HBIG (16%) or lamivudine (16%) compared with those in the control group (33%; P < .05). There was no significant difference between HBIG and lamivudine treatment (P > .05). No side effects occurred in the pregnant women or their newborns.
Lamivudine therapy may not prevent perinatal transmission of HBV infection in every newborn. Kazim and colleagues reported the development of chronic HBV infection in a newborn despite suppression of HBV DNA to undetectable levels in the mother by prolonged lamivudine therapy. The newborn received neonatal vaccination and treatment with HBIG, yet had still had increased aminotransferase levels and was persistently positive for HBV DNA. On HBV DNA sequencing, complete sequence homology and a similar precore mutation was found in the mother and child, indicating vertical transmission.
A major question, in addition to efficacy, is, of course, safety. Again, to place the issue in perspective, it is important to remember that hepatitis B during pregnancy does not increase maternal morbidity or mortality or the risk for fetal complications. In addition, the use of lamivudine did not directly lead to adverse events in the infected mothers. However, in one study, when compared with untreated women, there was a significant increase in liver disease activity after delivery in those patients treated with lamivudine. And what about the potential effects of these drugs on the fetus? Lamivudine, adefovir, and entecavir are designated as category C drugs, which indicates that these drugs are capable of exerting teratogenic or embryocidal effects in animals; however, there are no controlled studies in humans. With the emergence of additional nucleos(t)ide analogs (telbivudine and tenofovir [currently undergoing review by the FDA for use in chronic hepatitis B], which are category B drugs), studies are needed to evaluate their role in reducing viral burden during pregnancy.
The bottom line: The strategy of using antiviral therapy to reduce viremia during pregnancy to decrease the risk for transmission of HBV to the baby is reasonable. However, at present, the data are not sufficient to make broad recommendations. The approach should be evaluated in a large controlled trial using new antiviral agents in combination with HBIG to prevent intrauterine HBV infection.
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Question
Should pregnant women with chronic hepatitis B with detectable viral load be treated with antiviral agents during pregnancy to decrease the risk for transmission to the baby?
Response from the Expert
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William F. Balistreri, MD
Dorothy M. M. Kersten Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Medical Director, Liver Transplantation Program, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio |
Let me first frame the question -- what problem are we trying to solve? Infection with hepatitis B virus (HBV) in infancy or early childhood often leads to persistent infection, as evidenced by the fact that in countries with a high prevalence of chronic hepatitis B, perinatal transmission from mother to infant accounts for the majority of cases. Approximately 90% of untreated infants born to mothers positive for hepatitis B e-antigen (HBeAg) will develop "immune tolerance." This is traditionally explained by transplacental transfer of viral antigens, which induces a specific nonresponsiveness of helper T cells to HBeAg and hepatitis B core antigen (HBcAg). Spontaneous HBeAg seroconversion (to anti-HBe positive) may develop with time, but liver damage may occur during the process of immune clearance of HBeAg. Screening for maternal hepatitis B surface antigen (HBsAg), followed by administration of HBV vaccine and hepatitis B-specific immunoglobulin (HBIG) to the newborn within 24 hours of birth, is the most effective way to prevent perinatal HBV infection. The first universal HBV immunization program in the world was launched in Taiwan over 20 years ago; thus, the HBV infection rate and the incidence of hepatocellular carcinoma and fulminant hepatitis in children have been reduced. Current published guidelines state that newborns of HBV-infected mothers should receive passive-active immunoprophylaxis with HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series. This strategy is approximately 95% effective in reducing the risk for HBV transmission, but is less effective in HBeAg-positive mothers with very high serum HBV DNA levels. Maternal serum HBV DNA concentrations >10 IU/mL have been associated with a 5% to 10% failure of immunoprophylaxis.
In highly viremic HBsAg-positive mothers, reduction of viremia in the last month of pregnancy may be an effective and safe measure to decrease the risk for failure of prophylaxis. Two separate strategies have been used to reduce the "viral burden" during pregnancy: prenatal HBIG administration and specific antiviral therapy. However, prophylactic therapy is complex, controversial, and not well studied.
HBIG:
In a prospective randomized controlled trial, Xu and colleagues administered either placebo or HBIG (200 IU intravenously every 4 weeks for 3 times) from the 28th week of gestation in HBsAg-positive mothers. There was a significant difference in the rate of HBeAg and HBV DNA positivity in the newborns (positivity rates: 25% in those born to mothers who received HBIG vs 83% in placebo recipients). In addition, the HBV DNA load of newborns was lower than that of their treated mothers and significantly lower than that of untreated controls.
Specific Antiviral Therapy:
The only oral antiviral agent studied in this setting is lamivudine. When given in the last 4 weeks of pregnancy, lamivudine has been shown to reduce high-level viremia. van Zonneveld and
colleagues treated 8 highly viremic (HBV DNA >1.2 x 10 IU/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. Children (n = 24) born to untreated HBsAg-positive mothers with similar HBV DNA levels served as controls. All children received passive-active immunization with HBIG and HBV vaccine at birth and were followed up for 12 months. Seven of the 8 lamivudine-treated mothers had a decrease in their serum HBV DNA concentrations. One of the 8 children (12.5%) in the lamivudine group remained HBsAg- and HBV DNA-positive at the age of 12 months; all other children seroconverted to anti-HBs. In the untreated control group, perinatal transmission occurred in 7 of 25 children (28%). Other studies have evaluated the efficacy and safety of lamivudine for the treatment of chronic hepatitis B in pregnancy. Li and colleagues investigated the effect of lamivudine vs HBIG on HBV intrauterine transmission. HBsAg-positive pregnant women (n = 56) were given either 200 IU of HBIG intramuscularly every 4 weeks from the 28th week of gestation, or lamivudine (n = 43) 100 mg orally every day from the 28th week of gestation until the 30th day after labor. Subjects in the control group (n = 52) received no specific treatment. The rate of neonatal HBV infection was significantly lower among those patients receiving HBIG (16%) or lamivudine (16%) compared with those in the control group (33%; P < .05). There was no significant difference between HBIG and lamivudine treatment (P > .05). No side effects occurred in the pregnant women or their newborns.
Lamivudine therapy may not prevent perinatal transmission of HBV infection in every newborn. Kazim and colleagues reported the development of chronic HBV infection in a newborn despite suppression of HBV DNA to undetectable levels in the mother by prolonged lamivudine therapy. The newborn received neonatal vaccination and treatment with HBIG, yet had still had increased aminotransferase levels and was persistently positive for HBV DNA. On HBV DNA sequencing, complete sequence homology and a similar precore mutation was found in the mother and child, indicating vertical transmission.
A major question, in addition to efficacy, is, of course, safety. Again, to place the issue in perspective, it is important to remember that hepatitis B during pregnancy does not increase maternal morbidity or mortality or the risk for fetal complications. In addition, the use of lamivudine did not directly lead to adverse events in the infected mothers. However, in one study, when compared with untreated women, there was a significant increase in liver disease activity after delivery in those patients treated with lamivudine. And what about the potential effects of these drugs on the fetus? Lamivudine, adefovir, and entecavir are designated as category C drugs, which indicates that these drugs are capable of exerting teratogenic or embryocidal effects in animals; however, there are no controlled studies in humans. With the emergence of additional nucleos(t)ide analogs (telbivudine and tenofovir [currently undergoing review by the FDA for use in chronic hepatitis B], which are category B drugs), studies are needed to evaluate their role in reducing viral burden during pregnancy.
The bottom line: The strategy of using antiviral therapy to reduce viremia during pregnancy to decrease the risk for transmission of HBV to the baby is reasonable. However, at present, the data are not sufficient to make broad recommendations. The approach should be evaluated in a large controlled trial using new antiviral agents in combination with HBIG to prevent intrauterine HBV infection.
