1. Management of Chronic Hepatitis B Virus Infection in Women of Reproductive Age
Anna S. F. Lok, MD
Professor of Internal Medicine and Director of Clinical Hepatology University of Michigan, Ann Arbor Ann Arbor, Michigan
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3. Disclosures
Anna S. F. Lok, MD, has disclosed that she has received consulting fees from Gilead Sciences, GlaxoSmithKline, and Novartis and funds for research support from Bristol-Myers Squibb, Gilead Sciences, and Merck. The following PIM clinical content reviewers, Linda Graham, RN, BSN, BA; Jan Hixon, RN, BSN, MA; Trace Hutchison, PharmD; Julia Kirkwood, RN, BSN; and Jan Schultz, RN, MSN, CCMEP, hereby state that they or their spouse/life partner have not had any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.
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4. Chronic HBV Infection in Women of Reproductive Age
Women who contemplate starting a family in the foreseeable future
Women who become pregnant while receiving antiviral therapy
Women who are pregnant, have high HBV DNA, and not currently on treatment
Women with newly diagnosed HBV infection during pregnancy
HBV, hepatitis B virus.
There are 4 major populations of patients to address regarding the management and treatment of chronic hepatitis B virus (HBV) infection in women of reproductive age. The first is women who are contemplating becoming pregnant in the near future. The second situation is women who become pregnant while receiving antiviral therapy. The third scenario is women who are pregnant, have high HBV DNA, and are not currently receiving treatment. The fourth condition is women who have newly diagnosed HBV infection discovered during pregnancy.

5. Chronic HBV Infection in Women Considering Starting a Family
Should plans to start a family influence management decisions?
Depends on immediacy of plan to become pregnant
Uncertainty regarding safety of antiviral medications in pregnancy
Careful discussion with patient and spouse regarding benefits vs risks
Indications for treatment
Start now: advanced fibrosis/cirrhosis, severe flares/persistently high ALT
Defer: no/mild fibrosis, normal/minimally elevated ALT
ALT, alanine aminotransferase; HBV, hepatitis B virus.
The first group of patients to consider is women who are planning to become pregnant. The goal of a patient’s HBV treatment plan depends in part on the immediacy of her plans to become pregnant: whether it is in the next year or 2 or in a more distant future, such as 5 years or longer. The safety of antiviral medications during pregnancy is of crucial importance, and it is critical to discuss the benefits vs risks of treatment with both the patient as well as her partner. In women with advanced fibrosis or cirrhosis, a severe flare, or persistently high alanine aminotransferase (ALT), treatment should be started immediately regardless of plans to become pregnant. For women with no or mild fibrosis and normal or minimally elevated ALT, treatment for HBV can potentially be deferred.

6. HBV Infection in Women Considering Starting a Family: Which Drug?
FDA classification: based on in vitro and animal studies
Pregnancy class B: telbivudine and tenofovir DF
Pregnancy class C: interferon, adefovir, entecavir, and lamivudine
Human data:
Antiretroviral pregnancy registry: safety established for lamivudine and tenofovir, including exposure in first trimester[1]
Clinical studies of antiviral therapy to prevent perinatal transmission: safety established for lamivudine and telbivudine, mainly exposure in third trimester[2-5]
FDA, US Food and Drug Administration; HBV, hepatitis B virus.
Certainly, these discussions would not be necessary if the available treatments were known to be safe when used in pregnancy. The US Food and Drug Administration (FDA) classifies medications regarding safety for use in pregnancy largely based on in vitro and animal studies. Class A agents are the safest, and class D includes drugs that are not to be used during pregnancy. Among the currently available hepatitis B drugs, telbivudine and tenofovir are considered to be class B, meaning there are no data from animal studies or in vitro studies to suggest teratogenicity. Others, including interferon, adefovir, entecavir, and lamivudine, are considered to be class C, meaning the available data suggest possible risks to the fetus.
There are, however, some human data on the safety of these drugs. The first comes from the Antiretroviral Pregnancy Registry, where safety has been established, including during the first trimester, for lamivudine and tenofovir, which are commonly used in HIV treatment. There are also clinical studies of antiviral therapy specifically to prevent perinatal transmission, and these studies provide safety data for lamivudine and telbivudine, although these drugs are mainly used in third trimester in the context of these clinical trials.
1. Antiretroviral Pregnancy Registry. December Xu WM, et al. J Viral Hepat. 2009;16: Shi Z, et al. Obstet Gynecol. 2010;116: Han GR, et al. J Hepatology. 2011;55: Pan CQ, et al. Clin Gastroenterol Hepatol. 2012;10:

7. Second or Third Trimester
Incidence of Birth Defects With in Utero Exposure to HBV Nucleos(t)ide Analogues
Data derived from Antiretroviral Pregnancy Registry, 1/ /2012[6]
International, voluntary, prospective, exposure-registration cohort
Data on exposure in HBV-monoinfected mothers began in 1/2003
Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance program administered by CDC[6,7]
Overall birth defects: 2.72% (95% CI: )
Regimen Containing
First Trimester
Second or Third Trimester
Exposed, n
Birth Defects,
% (95% CI)
Lamivudine
4185
3.2 ( )
6843
2.8 ( )
Tenofovir
1612
2.4 ( )
838
2.3 ( )
CDC, Centers for Disease Control and Prevention; CI, confidence interval; HBV, hepatitis B virus.
These data, derived from the Antiretroviral Pregnancy Registry from January 1989 to July 2012, are international and based on voluntary reporting. The study began by reporting on HIV drugs, and data were also collected on HBV‑monoinfected mothers beginning in January Because much of this study focused on HIV treatment, the greatest available data are for lamivudine and tenofovir. Several thousand pregnancies were recorded in which these drugs were used, both in the first trimester and in the second and third trimesters. The incidence of birth defects is similar between treated and control populations, ranging from approximately 2.4% to 3.2%. Based on a Centers for Disease Control and Prevention report, the overall rate of birth defects in a control population at large is 2.7%.
6. Antiretroviral Pregnancy Registry. December Correa A, et al. Birth Defects Res A Clin Mol Teratol. 2007;79:

8. Limitations of the Antiretroviral Pregnancy Registry
Depends on voluntary reporting
Information is reviewed but not verified
Long-term follow-up is limited
Data available for live births only
No data on miscarriages or subsequent developmental delay
Limited data on antivirals used for HBV monoinfection
< 100 pregnancies reported for exposure to adefovir, entecavir, or telbivudine
HBV, hepatitis B virus.
A major limitation of the Antiretroviral Pregnancy Registry is that it depends on voluntary reporting and, therefore, is unlikely to be complete. The information is reviewed but not verified—there is no long-term follow-up, so there is no record of whether these children have any developmental delays. The data are also collected only for live births, so there is no information on miscarriages. Furthermore, there are very few data on antivirals that are used for hepatitis B only: specifically for adefovir, entecavir or telbivudine, there are fewer than 100 pregnancies included in this Registry.
8. Antiretroviral Pregnancy Registry. December 2012.

9. Antiviral Therapy for Chronic HBV Infection in Women Starting a Family in Near Future
Moderate-severe inflammation; advanced fibrosis/cirrhosis?
Yes No
Finite treatment with pegIFN before pregnancy*
If possible, delay therapy until completion of family
HBV, hepatitis B virus; NUC, nucleos(t)ide; pegIFN, peginterferon.
What treatment is recommended for a woman who might become pregnant in the near future? One important factor is the patient’s liver disease. If the woman has moderate to severe inflammation, advanced fibrosis, or cirrhosis, then treatment should be started immediately. If the patient is hoping to become pregnant in the next year or 2, then peginterferon is worthwhile because treatment would be a finite duration. If the woman responds with suppression of virus and HBeAg seroconversion, then treatment may be stopped before she becomes pregnant.
On the other hand, interferon treatment is not always successful. There are also some women for whom peginterferon is contraindicated to or who do not wish to start interferon therapy. In these cases, nucleos(t)ide analogues should be started. If, however, a woman does not have active inflammation or advanced fibrosis, then treatment can be deferred until the woman has completed her pregnancy.
Treatment failure/ pegIFN not possible
Success
Initiate NUC
*Effective contraception indicated.

10. Antiviral Therapy for Chronic HBV Infection in Women Considering Starting a Family
Which nucleos(t)ide analogue?
Safety to fetus, including exposure during first trimester
Lamivudine, tenofovir, telbivudine
Risk of drug resistance
Lamivudine > telbivudine > tenofovir
Preferred drug: tenofovir
Established safety; potent; low risk of drug resistance
Benefit vs risk discussed with patient and spouse
Inform if become pregnant
HBV, hepatitis B virus.
There are some data to support the safety of lamivudine, tenofovir, and telbivudine during pregnancy. However, it is important to consider safety of the fetus, as well as the risk of drug resistance, as most of these mothers may have high HBV DNA levels and might need long‑term treatment. The risk of drug resistance is highest with lamivudine, followed by telbivudine and then tenofovir. The preferred drug would be tenofovir because there are available safety data, it is potent, and there is a low risk of drug resistance.
Regardless, it is very important to discuss the benefits vs the risks both with the patient as well as her partner, and it is crucial to ensure the couple informs you when the patient becomes pregnant, as a decision must be made regarding continuation of treatment during pregnancy.

11. Women Who Become Pregnant While Receiving Antiviral Therapy
Continue, switch, or stop?
Review indications for treatment
Advanced fibrosis or cirrhosis: continue
Early/mild disease or uncertain indications: stop?
Assess whether therapeutic endpoint has been reached
HBeAg seroconversion: stop?
Discuss potential risks/benefits to mother and fetus
HBeAg, hepatitis B e antigen.
The decision of whether to continue or switch treatment in women who become pregnant while receiving antiviral therapy depends on the indications for treatment. If the original indication was advanced fibrosis or cirrhosis, then treatment should continue. If the original indication was milder disease, then treatment may be stopped.
Treatment duration in this scenario would be similar to women who are not pregnant. For a patient who was HBeAg positive initially, treatment should continue until the standard therapeutic endpoint, that is, HBV DNA suppression with HBeAg seroconversion. If the patient was HBeAg negative, treatment should continue until hepatitis B surface antigen (HBsAg) loss. Again, it is very important to discuss the potential risks and benefits of treatment to both the mother and the fetus with the patient and her partner.

12. Women Who Become Pregnant While Receiving Antiviral Therapy
When continuing treatment, evaluate for safety
Tenofovir: continue
Lamivudine or telbivudine: continue if HBV DNA is undetectable
Consider switching to tenofovir if HBV DNA remains detectable to prevent breakthrough during pregnancy
Adefovir, entecavir, or pegIFN: stop and switch to tenofovir
When stopping or switching, monitor for hepatic flares
HBV, hepatitis B virus; pegIFN, peginterferon.
When a decision is made to continue treatment, the safety of the patient’s current regimen must be considered. If the patient is currently receiving tenofovir, then treatment may be continued. If the patient is receiving lamivudine or telbivudine, then treatment may continue with the same drug if HBV DNA is undetectable. If the virus is not fully suppressed, then switching to tenofovir is recommended to prevent breakthrough during pregnancy. Adefovir, entecavir, and peginterferon are pregnancy class C drugs with limited safety data in vivo, and if the patient is currently receiving one of these drugs, then it is best to switch therapy to tenofovir.
When treatment is altered or stopped, it is important to monitor for hepatitis flares, as this could compromise the health of both the mother and the baby.

13. Women Receiving Antiviral Therapy Who Desire to Breast-feed
Breast-feeding generally not recommended while receiving antivirals
Nucleos(t)ide analogues present in breast milk
Tenofovir: a prodrug with low oral bioavailability
Nursing rhesus macaques administered tenofovir (n = 2): peak concentration in breast milk 2% to 4% of that in serum; AUCmilk is ~ 20% AUCserum[9]
HIV-infected women (n = 5): median concentration of tenofovir in breast milk 0.03% of proposed oral infant doses[10]
Existing data suggest tenofovir is safe
AUC, area under the curve.
A question that is frequently asked is whether it is safe to continue antiviral therapy if a woman decides to breast-feed. Breast-feeding is, in general, not recommended while receiving antivirals because nucleos(t)ide analogues may be present in breast milk. Tenofovir, however, may be used during breast-feeding because it is a prodrug that results in very low drug concentrations in breast milk. This has been demonstrated in rhesus macaques that have been administered tenofovir; the peak concentration in the breast milk is only 2% to 4% of that in serum. Limited studies in HIV‑infected women suggested that the median concentration of tenofovir in human breast milk is extremely low, at 0.03% of the proposed oral infant doses. Thus, the existing data suggest that tenofovir may be safe in women who are breast-feeding.
9. Van Rompay K, et al. Antimicrob Agents Chemother. 2005;49: Benaboud S, et al. Antimicrob Agents Chemother. 2011;55:1315.

14. Preventing Perinatal HBV Transmission: Why Is It So Important?
Risk of progression to chronic infection is inversely related to age at infection
100 80 60
Progression to Chronic Infection (%) 40
HBV, hepatitis B virus.
One reason why preventing perinatal HBV transmission is so important is that the risk of progression to chronic HBV infection is inversely related to the age at infection. If an immunocompetent adult is infected, the risk of progressing to chronic infection is less than 5%. By contrast, a newborn exposed at the time of birth, has a 90% chance of progressing to chronic infection. 20
Newborns
Infants/Children
Immunocompetent Adults
11. Lok AS, et al. Hepatology. 2009;50:

15. Prevention of Perinatal HBV Transmission
Cornerstone: HBIG + HBV vaccine
HBIG + first dose vaccine within 12 hrs of birth, different sites
Efficacy: ~ 95%
Reasons for failure
Delay in administration of HBIG and first dose of vaccine
Failure to complete vaccine series
Mother HBeAg positive and/or high HBV DNA
HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin; HBV, hepatitis B virus.
The most important measure to prevent perinatal transmission is the administration of hepatitis B immunoglobulin (HBIG) as well as the hepatitis B vaccine to newborns of HBV-infected mothers. The first dose of hepatitis B vaccine and HBIG should be administered within 12 hours of birth, at different sites of administration. Following these guidelines, the efficacy of preventing perinatal transmission is approximately 95%. This approach is not 100% successful for several reasons, including a delay in the administration of HBIG and/or the first dose of vaccine, a failure to complete the vaccine series, or if the mother is HBeAg positive with a very high HBV DNA level during labor and delivery.
12. Lok AS, et al. Hepatology. 2009;50: Mast EE, et al. MMWR Recomm Rep ;54(RR-16):1-31.

16. Perinatal HBV Transmission Is Related to Maternal HBV DNA Level
All infants received HBIG + first dose HBV vaccine within 12 hrs of birth and additional doses of HBV vaccine at 2, 4, and 6 mos 20
P = .039
P = .031 15
Perinatal Transmission*
Rate (%) 10
8.5
6.6
HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
Several studies have shown that, despite proper administration of passive/active prophylaxis in infants, HBV transmission can occur, and this is largely due to mothers having very high HBV DNA levels. One study from Australia assessed more than 100 pregnant women. All of the babies received HBIG and the first dose of hepatitis B vaccine within 12 hours of birth, and all of them completed the vaccine series. No HBV transmission was observed if the mother’s HBV DNA level was ≤ 108 copies/mL. However, among the mothers with HBV DNA > 108 copies/mL, 4 out of 47 infants were infected. These data corroborate other studies that have shown that high maternal HBV DNA level increases the risk of perinatal transmission. 5
n/N =
4/61
4/47
0/77
0/73
0/18
HBeAg+
HBeAg-
< 5 log
5-8 log
> 8 log
Maternal HBeAg Status
Maternal HBV DNA (copies/mL)
*Perinatal transmission = HBsAg positive at Mo 9.
14. Wiseman E, et al. Med J Aust. 2009;190:

17. Pregnant Women With High HBV DNA and Not Currently on Antiviral Therapy
Should antiviral therapy be recommended to reduce risk of perinatal transmission?
What should be the cutoff maternal HBV DNA level for initiation of antiviral therapy?
When to start?
Which antiviral drug?
When to stop?
What is the risk of posttreatment flares?
HBV, hepatitis B virus.
What is the best course of treatment for pregnant women who present with high HBV DNA and are not currently receiving antiviral therapy? Should antiviral therapy be recommended in an attempt to reduce the risk of perinatal transmission, and what should be the cutoff maternal HBV DNA level for initiation of antiviral therapy? When should treatment begin and end? Which antiviral drug should be used? What is the risk of posttreatment flares? The reason these questions must be addressed is: 1) high maternal HBV DNA is associated with increased risk of perinatal transmission, despite passive/active prophylaxis, and 2) there are some data to show that administration of antiviral therapy in the third trimester does reduce that risk.

18. Lamivudine in Late Pregnancy May Reduce HBV Transmission in High Viremic Mothers
Randomized, double-blind, placebo-controlled trial
All mothers HBV DNA > 109 copies/mL prior to starting lamivudine at Wk 32 of pregnancy
All infants received HBIG + HBV vaccine
100
Lamivudine (n = 56)
Placebo (n = 59) 80 60
P = .014
Infants HBsAg Positive at 1 Yr (%)
HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
In a randomized, double‑blind, placebo-controlled study conducted in China, pregnant women with HBV DNA >109 copies/mL received either lamivudine or placebo starting at Week 32, and all the infants received HBIG and hepatitis B vaccine at birth. Based on the intent‑to‑treat analysis, the infection rate among the infants at 1 year was lower in the lamivudine-treated group compared with the control group (18% vs 39%, respectively; P = .014).
Unfortunately, in this study, many infants did not return for follow‑up testing at 1 year, and intent‑to‑treat analysis assumes all of these are infected, which may not necessarily be correct. When the results were analyzed based on the last available result, the infection rate was 7% in the lamivudine-treated group and 18% in the placebo group. Although this analysis failed to reach statistical significance (P = .15), overall, the study does suggest that antiviral treatment may reduce the risk of infection. 39 40
P = .15
7 infants in lamivudine group and 18 in placebo group did not return for HBsAg test at 1 yr 18 18 20 7
Missing = Failure
Last Observation Carried Forward for Missing Values
15. Xu WM, et al. J Viral Hepat. 2009;16:

19. Antiviral Treatment During Pregnancy: TBV Starting Wk 20-32
HBeAg-positive Chinese mothers with HBV DNA > 107 copies/mL received TBV mg/day beginning in Wk of gestation or served as untreated controls
Not randomized; controls chose not to receive treatment
P = .001
100
100
TBV (n = 135)
100
TBV + HBIG + Vac (n = 132) 92
Control (n = 94) 80 80
HBIG + Vac (n = 88) 60 60
Undetectable HBV DNA (%)
P = .001
Proportion of Patients, %
anti-HBs, antibody to hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; TBV, telbivudine; Vac, HBV vaccine.
In a nonrandomized trial of telbivudine also conducted in China, HBeAg‑positive mothers with HBV DNA > 107 copies/mL were recommended to receive telbivudine 600 mg/day, starting between Week of gestation. Mothers who opted not to start treatment served as untreated controls. The study included more than 200 women, and telbivudine treatment did result in HBV DNA suppression: 33% of the mothers who received treatment had HBV DNA of < 500 copies/mL at delivery compared with 0% in the untreated group. More importantly, none of the infants of mothers who received telbivudine was infected compared with 8% of infants born to mothers who did not receive treatment. This further supports the idea that antiviral therapy administered in late second or early third trimester of pregnancy to mothers with high HBV DNA might reduce maternal–infant HBV transmission. 40 33 40
P = .001 20 20 8
Maternal HBV DNA < 500 c/mL at Delivery
HBsAg+ at 7 Mos
Anti-HBs Detectable at Wk 28
16. Han GR, et al. J Hepatol. 2011;55:

20. Meta-analysis of Lamivudine to Interrupt Perinatal Transmission of HBV
Infant HBsAg Seropositive
Lamivudine,
Events/N
Control ,
Risk Ratio
(95% CI)*
Han 2005
0/43
5/35
0.07 ( )
Li 2006
1/36
7/44
0.17 ( )
Feng 2007
7/48
16/42
0.38 ( )
Guo 2008
4/70
12/40
0.19 ( )
Xu 2009
10/56
23/59
0.46 ( )
Zhang 2010
1/50
8/50
0.13 ( )
Total
23/303
71/270
0.33 ( )
Risk Ratio (95% CI)*
0.01
0.1 1 10
100
Favors Lamivudine
Favors Control
Infant HBV DNA Seropositive
Lamivudine,
Events/N
Control ,
Risk Ratio
(95% CI)*
Feng 2007
7/48
16/42
0.38 ( )
Guo 2008
6/70
18/40
0.19 ( )
Xu 2009
11/56
27/59
0.43 ( )
Zhang 2010
1/50
8/50
0.13 ( )
Total
25/224
69/191
0.32 ( )
Risk Ratio (95% CI)*
CI, confidence interval; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.
Additional support for prenatal antiviral treatment comes from a meta‑analysis that included several studies using different endpoints. In the top panel, the endpoint was based on detection of HBsAg in the infant, and in the bottom panel, the endpoint was based on detection of HBV DNA in the infant. In all of these studies, the risk ratio favored lamivudine, thereby indicating that despite variability in the size of the study, all of the data show a very consistent result: Antiviral treatment is associated with decreased risk of perinatal transmission.
*Risk ratio calculated using the Mantel-Haenszel random-effects model.
0.01
0.1 1 10
100
Favors Lamivudine
Favors Control
17. Han L, et al. World J Gastroenterol. 2011;17:

21. All Women With Newly Diagnosed HBV Infection During Pregnancy
Register HBV status in OB record
HBIG + first dose of vaccine to baby within 12 hrs of birth
Complete full course of vaccine
Check baby for HBsAg and anti-HBs at 9-15 mos
Counseling on precautions to prevent HBV transmission
Screening and vaccination of family members
anti-HBs, antibody to hepatitis B surface antigen; HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; OB, obstetrics.
If a woman presents with newly diagnosed HBV infection during pregnancy, the first step is to ensure that the diagnosis is in the patient’s obstetrical records so that when the baby is born, all healthcare providers know that the mother has hepatitis B and that HBIG and the first dose of vaccine should be administered within 12 hours of birth. It is also important to remind the mother to complete her baby’s full course of vaccination and to ensure the baby is checked for HBsAg and anti-HBs between the ages of 9 and 15 months to verify that the baby is indeed protected against HBV infection.
The mother should also be counseled on precautions to prevent HBV transmission to other people, not just the baby, and this is a good time to recommend that other family members and household members be screened for hepatitis B and vaccinated if they test negative.
18. Lok AS, et al. Hepatology. 2009;50:

22. All Women With Newly Diagnosed HBV Infection During Pregnancy
Refer for further evaluation
Assess HBV replication and liver disease
HBeAg/anti-HBe, HBV DNA
Blood counts, liver panel ± ultrasound
Evaluate need for antiviral therapy
For control of liver disease in mother
For prevention of transmission to baby
Emphasize importance of long-term follow-up
anti-HBe, antibody to hepatitis B e antigen; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus.
It is important to focus on the mother’s disease and treatment as well as preventing transmission to the infant because, for many patients, this is their initial diagnosis with hepatitis B, and they need to be fully evaluated.
Patients should be referred to a specialist and assessed for the level of HBV replication and liver disease. This is accomplished through blood testing for HBeAg and anti‑HBe, as well as HBV DNA. Additional testing should include complete blood counts, including platelets, a liver panel, and, if necessary, an ultrasound. An ultrasound is frequently not necessary for young women, but if there is any concern about cirrhosis, an ultrasound would be advisable.
The patient should then be evaluated to determine the need for antiviral therapy. This depends on whether antiviral therapy is needed to treat liver disease in the mother or if antiviral therapy is needed simply to reduce the risk of HBV transmission to the baby. It is also important to emphasize to the patient that even if no HBV treatment is required at this stage, she should continue with long-term follow-up because chronic HBV infection is well known to undergo fluctuations during its natural course of infection.

23. Pregnant Women With High HBV DNA and Not Currently on Antiviral Therapy
Should antiviral be recommended to reduce risk of perinatal transmission?
Yes; although quality of evidence is low, all studies showed benefit and no harm
What should be the cutoff maternal HBV DNA level for initiation of antiviral therapy?
> 8 log10 IU/mL: Yes
6-8 log10 IU/mL: Maybe
< 6 log10 IU/mL: No
As mentioned previously, antiviral therapy should be recommended to reduce the risks of perinatal HBV transmission if the patient has high HBV DNA. Although the quality of the evidence is low due to small and nonrandomized studies, a meta‑analysis of the available data shows a consistent result that there is decreased transmission to infants and no evidence of harm with antiviral treatment in the third trimester.
Different studies have used different HBV DNA thresholds for the initiation of antiviral therapy, but it seems clear that if the mother’s HBV DNA level is > 108 IU/mL, then antiviral therapy should be recommended. However, if the mother’s HBV DNA is < 106 IU/mL, there is no obvious benefit with recommending antiviral therapy, as HBIG and vaccination alone would likely prevent perinatal transmission. It is less clear if antiviral therapy is beneficial if the mother’s HBV DNA level is between 106 and 108 IU/mL.

24. Pregnant Women With High HBV DNA and Not Currently on Antiviral Therapy
When to start antiviral?
Late second/early third trimester
Allow at least 4-6 wks for an effect
Which antiviral drug?
Lamivudine, telbivudine, or tenofovir
Tenofovir preferred: low risk of drug resistance, baseline HBV DNA high, and some mothers may need treatment for their liver disease in the future
Ideally, antiviral treatment should be started in the late second or early third trimester, to allow at least 4-6 weeks for therapy to reduce HBV DNA levels.
Lamivudine, telbivudine, and tenofovir all have some safety data in humans. Telbivudine and tenofovir are pregnancy class B and lamivudine is class C. However, because of the high HBV DNA in many of these women and the possibility of treatment for liver disease in the future, tenofovir is recommended in this patient population due to the low risk of resistance to this agent.

25. Pregnant Women With High HBV DNA and Not Initially on Antiviral Therapy
When to stop antiviral after delivery?
To prevent perinatal transmission: immediately, especially if mother plans to breast-feed, or up to 3 mos postdelivery
To treat liver disease: continue until therapeutic endpoint
What is the risk of posttreatment flare?
Seemingly rare, but mild ALT elevation common; also seen in postpartum period for women not receiving antiviral
Decompensation not reported in clinical trials; likelihood low because most pregnant women have early-stage liver disease
Important to closely monitor ALT after antiviral therapy is discontinued (eg, 1, 3, and 6 mos posttreatment)
ALT, alanine aminotransferase.
This decision to discontinue antiviral therapy in women following pregnancy mainly depends on the purpose of the treatment. If the purpose were purely to prevent perinatal HBV transmission, treatment can be stopped immediately upon delivery, especially if the mother plans to breast-feed. Alternatively, antiviral therapy may be continued for a few months postdelivery; however, there is no need to continue treatment for an extended time, particularly if therapy with a low barrier to resistance such as lamivudine or telbivudine were selected. If there has been evidence of active disease or advanced liver disease in the mother and therapy was indicated to treat the mother’s liver disease, then treatment should be continued until the appropriate therapeutic endpoint is achieved.
An important consideration when discontinuing treatment is the risk of posttreatment flare. The available data, although limited, suggest that this is an extremely rare event. Although it is not uncommon to see a mild ALT elevation, such an ALT elevation is generally very well tolerated in this patient population, with no increase in bilirubin and no decompensation—possibly because most of these patients are young women with minimal initial liver disease.
Clinical trials of antiviral therapy to prevent perinatal transmission have not reported decompensation, but again, most of these trials have very limited long‑term follow‑up. Therefore, it is extremely important to monitor ALT after antiviral therapy is discontinued, at 1, 3, and 6 months posttreatment.
19. Ter Borg MJ, et al. J Viral Hepat. 2008;15:37-41.

26. Algorithm for HBV Management in Women During Pregnancy
Pregnant women with HBV infection
Active disease/suspected cirrhosis: consider initiating treatment with tenofovir
1st trimester: assess HBV replication and liver disease
End of 2nd trimester: quantitative HBV DNA and ALT levels
HBV DNA < 106 IU/mL*
HBV DNA > 106 IU/mL*
Consider initiating treatment with tenofovir, lamivudine, or telbivudine at wks†
Monitor; infant receives HBIG + vaccine at birth
ALT, alanine aminotransferase; HBIG, hepatitis B immunoglobulin; HBV, hepatitis B virus.
This algorithm summarizes the management of HBV during pregnancy.
If a woman presents with HBV infection in the first trimester, she should be assessed for HBV replication and liver disease. If the patient has active disease or suspected cirrhosis or advanced fibrosis, immediate treatment should be considered, with the preferred drug being tenofovir. Tenofovir is preferred for these patients because it is safe for use in pregnancy, and as these women will likely need an extended course of treatment, a drug with low risk of resistance is preferred.
If, however, the woman has normal liver enzymes or mild disease, she can be monitored and rechecked for HBV DNA in the second trimester. If the HBV DNA is low (< 106 IU/mL), then the mother can continue to be monitored without therapeutic intervention, and the infant should receive HBIG and vaccination at birth. However, if the mother has HBV DNA > 108 IU/mL, then treatment with tenofovir, lamivudine, or telbivudine in the late second or early third trimester should be considered, with tenofovir being the preferred drug for the reasons previously stated. In addition, the infant should receive HBIG and HBV vaccine at birth. If the mother’s HBV DNA is between 106 and 108 IU/mL, then the course of treatment depends on the patient’s specific circumstances.
At all points in care, it is important to discuss the benefit vs risk of treatment options with both the mother and her partner.
Infant receives HBIG + vaccine at birth
*The cut-off level of maternal HBV DNA level for initiation of therapy is unclear, and HBV DNA from 6-8 log10 IU/mL can be considered for therapy based on physician and patient preference.
†Tenofovir is preferred if treatment is expected to be > 12 weeks or if treatment is expected to continue while breastfeeding.

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