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Flares in HBV DNA, ALT common in pregnant, postpartum women

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August 17, 2016

Pregnant and postpartum women with chronic hepatitis B virus infection can experience severe flares in HBV DNA and alanine aminotransferase, according to recent findings.

“In our multi-center study of pregnant women with chronic hepatitis B, significant increases in hepatitis B DNA and alanine aminotransferase (ALT) were fairly common, mostly during late second trimester and after or shortly after delivery,” Mindie H. Nguyen, MD, MAS, AGAF, FAASLD, director of the hepatology fellowship and hepatology clerkship at Stanford University Medical Center, told Infectious Disease News. “Though rare, a few of these hepatitis flares led to severe hepatic decompensation.”

Nguyen and colleagues, including Christine Y. Chang, BS, division of gastroenterology and hepatology, Stanford University Medical Center, conducted a retrospective study of 113 pregnancies in 101 women with chronic HBV seen during pregnancy at two community gastroenterology clinics and two tertiary medical centers from 1997 to 2015. The researchers sought to examine the onset, severity and resolution of flares in HBV and ALT.

“In contrast to prior studies, our work included women with both low and high viral loads, and focused on maternal outcomes,” Nguyen said.

Mindie H. Nguyen, MD, MAS, AGAF, FAASLD

Mindie H. Nguyen

Women who initiated antiviral therapy for HBV during pregnancy were excluded in the analysis of postpartum flares. Nine percent of women experienced HBV DNA flares during pregnancy (eight of 90), and 4% had flares during postpartum (two of 48). ALT flares — classified as between 99 U/L (minimum 5x upper limit of normal) and 2,522 U/L — were experienced by 6% of women during pregnancy (seven of 112) and 10% of women within 3 months’ postpartum (five of 51).

Antiviral therapy was initiated in 28 pregnancies at 28 weeks of pregnancy. Of the women in both of these groups, two continued treatment during postpartum, and three discontinued treatment at delivery; they all experienced subsequent flares in ALT (between 180 U/L and 1,429 U/L) within the first 3 months’ postpartum.

The researchers noted that most of the women who had increases in HBV DNA during pregnancy and not treated during postpartum returned to baseline HBV DNA levels. Some who remained untreated or discontinued antiviral therapy at delivery, however, sustained HBV DNA levels lower vs. baseline for 3 months to 1 year after delivery.

Christine Y. Chang, BS

Christine Y. Chang

“This suggests that immunological changes during pregnancy, rather than antiviral therapy itself, may stimulate immunoseroclearance, and would support the higher-than-expected rates of HBeAg seroconversion previously reported in [chronic HBV] pregnant women,” the researchers wrote.

Univariate analysis determined that age, hepatitis B e antigen positivity, baseline HBV DNA, baseline ALT, gravida and parity were not significant predictors of flares in this patient population. Nguyen said predictive factors for flares have not been consistently identified, suggesting the need for further research.

“Close monitoring of these patients during late pregnancy and early postpartum should be performed, as flares can be symptomatic and/or warrant antiviral therapy for prevention of hepatic decompensation in mothers as well as prevention of vertical transmission of HBV to infants. Further research is needed to characterize the effects of pregnancy on hepatitis B and help physicians manage the disease during pregnancy,” Nguyen said. – by Melinda Stevens

Disclosure: Nguyen reports receiving research support from Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals and the National Cancer Institute, and serving on the advisory boards at Alnylam Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Intercept Pharmaceuticals, Janssen Pharmaceuticals, and Roche Laboratories. Please see the full study for a list of all other researchers’ relevant financial disclosures.

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PERSPECTIVE

Jamilé Wakim-Fleming

In this study by Chang and colleagues, the authors assessed the rate of flares of HBV DNA and serum ALT levels in pregnant women and postpartum women with chronic HBV.

They conducted a multicenter retrospective review of records of 113 pregnancies in 101 pregnant women. They defined HBV flare as a minimum increase of 2 log IU/mL and an ALT flare as five times the upper limit of normal (ULN > 19 IU/L) or at least three times more than baseline. They excluded women with coinfection with other viruses, those who received treatment during pregnancy and those who had a flare during the pregnancy and continued on it postpartum

They noted that HBV flares occurred in 9%, and ALT flares in 6% during pregnancy, and in 4% and 10%, respectively, in the postpartum period. They also found that antiviral therapy did not affect HBV and ALT recovery during pregnancy or the postpartum period, and most patients recovered spontaneously, although the numbers were low.

These findings are not surprising for the following reasons:

  • Assessment of flares for HBV DNA did not become available until 2008 when the FDA approved the first nucleic acid test for HBV that measures the amount of viral DNA in a patient's blood. Ever since, and due to the ability to measure the viral load, a few but scarce studies have been conducted showing that in pregnant women with HBV infection, flares during the postpartum period can occur. For example, in the studies by Ter-Borg in 2008, Giles in 2015 and Elefsiniotis in 2015, flares were fairly common in the postpartum period reaching about 30% and these rates are much higher than reported by Chang and colleagues.
  • During pregnancy, screening for hepatitis B in the second trimester and close follow-up for HBV viral load and liver enzymes have been recommended by the American Association for the Study of Liver Diseases and other major medical societies in order to detect HBV infection that may require therapy in the mother if HBV viral load is elevated and also to provide HBV immune-prophylaxis for the newborn.
  • Outside of pregnancy, flares may appear spontaneously in people who carry HBV infection, and they may be caused by an immune-deficient state or following the intake of immunosuppressive therapy. Also, flares can be seen in people who stop antiviral therapy.
  • The pregnancy state is an immune-tolerant state that favors replication of the virus and can precipitate flares in women with HBV infection
  • The reported spontaneous resolution of the flares in this study and in other studies with an overall favorable outcome in both treated and untreated women, can be partially explained by the fact that antiviral therapy was given to pregnant women who had the highest viral load (> 5.6 log IU/mL). One pregnant woman, however, developed liver failure and required therapy.

We would expect that future larger studies may reveal a high level of flares in the pregnancy and the postpartum period.

In conclusion, clinicians should remain vigilant in screening HBV infections in pregnant women and in following them up very closely for many months after delivery.


Jamilé Wakim-Fleming
Hepatologist, department of gastroenterology and hepatology, Cleveland Clinic

References:

Elefsiniotis I, et al. World J Gastroenterol. 2015;doi:10.3748/wjg.v21.i4.1261.
Giles M, et al. Gut. 2015;doi:10.1136/gutjnl-2014-308211.
Ter Borg MJ, et al. J Viral Hepat. 2008;doi: 10.1111/j.1365-2893.2007.00894.x.

Disclosure: Wakim-Fleming reports no relevant financial disclosures.