Editorial Board: Emmet B. Keeffe, MD (Chair);

Anna Lok, MD; Brian McMahon, MD; Albert Min, MD; Myron Tong, MD; Naoky Tsai, MD; Bruce Tung, MD

HBV Watch™

Timely Information for Practicing Physicians

 

JANUARY 2004

 

TOPIC REVIEW: HEPATITIS B VACCINE NONRESPONSE

Hepatitis B vaccination is highly effective for protection against hepatitis B virus (HBV) infection.  However, approximately 5-10% of adults do not develop protective levels of anti-HBs (> 10 mIU/mL) after the initial 3-dose vaccination series—termed primary vaccine nonresponse.  Several factors that increase the risk of nonresponse to HBV vaccination have been identified: increasing age, male gender, gluteal vaccine administration, obesity, smoking, immunodeficiency, hemodialysis, and decompensated liver disease.  It remains controversial whether compensated chronic hepatitis C or other chronic liver diseases increase the risk of nonresponse.  A recent study showed a 31% HBV vaccine nonresponse rate in patients with chronic hepatitis C, and the response to vaccine was independent of HCV RNA titers or the presence of cirrhosis (Hepatology 2000;31:230).  The precise mechanisms that lead to HBV vaccine nonresponse have not been elucidated.  A genetic predisposition has been demonstrated, with specific HLA-class II haplotypes associated with an increased risk of nonresponse.  Another recent study showed a possible association between HBV vaccine nonresponse and celiac sprue.  These authors postulated a role of HLA-DQ2, which is common in both celiac sprue patients and HBV vaccine nonresponders (Am J Gastroenterol 2003;98:2289).  Routine postvaccination testing for anti-HBs is not recommended in all recipients, based on the high efficacy of the vaccine.  The CDC recommends postvaccination testing 1-2 months after the third vaccine dose only in certain subgroups at high risk of exposure, including infants born to HBsAg-positive mothers, healthcare workers who have contact with blood, sexual partners of persons with chronic HBV infection, and hemodialysis patients. Anti-HBs titers decrease over time and may drop significantly if measured more than 6 months after completing the vaccination series.  However, in most cases immunologic memory confers protection, with an anamnestic immune response with re-exposure to HBV.  In primary nonresponders, protective levels of anti-HBs develop in 10-30% of subjects after a single additional dose of vaccine and in 50-70% after 3 additional doses. Some studies found that higher response rates occur in nonresponders who receive additional doses intradermally.  Thus, it is generally recommended that primary nonresponders receive a second 3-dose vaccination series.  In patients who remain nonresponders after 6 doses of HBV vaccine, further vaccination is not warranted.

 

HBeAg-NEGATIVE CHRONIC HBV INFECTION

Meaning of HBeAg and significance of HBV levels.  A recent article by David Milich and Jake Liang provides a review of the biology of HBeAg.  Although the function of HBeAg is largely unknown, clinical and experimental data suggest that serum HBeAg may serve in an immunoregulatory role, and cytosolic HBeAg may be a target for the inflammatory immune response.  The differentiation of HBeAg-negative chronic hepatitis B from the inactive chronic HBsAg carrier state is often difficult because it typically relies on sequential determinations of ALT levels, which have a fluctuating pattern in 45-65% of cases and may be normal for long periods of time.  Emanuel Manesis and colleagues studied the correlation of a single baseline serum HBV DNA measurement by quantitative PCR assay with HBeAg-negative chronic hepatitis B in 196 consecutive patients (62 inactive carriers and 134 with chronic HBV) seen at the Henry Dunant Hospital in Athens, Greece, from September 1997 to March 1999.  Patients with elevated baseline ALT levels were followed with monthly ALT determinations and underwent liver biopsy when an increase in ALT activity was noted on at least 2 occasions.  Patients with normal ALT levels at baseline were followed for at least 24 months with ALT determinations every 3 months for the first 2 years and every 6 months thereafter.  ALT activity remained normal throughout follow-up in all inactive carriers.  In addition, ALT levels were normal at baseline in 25 of 134 HBeAg-negative chronic HBV patients.  Serum HBV DNA was < 30,000 copies/mL in all inactive carriers.  In HBeAg-negative chronic HBV patients, the baseline serum HBV DNA level was < 30,000 copies/mL in 14 patients (10.5%) and < 100,000 copies/mL in 17 patients (12.9%).  In the 25 HBeAg-negative chronic HBV patients with normal baseline ALT levels, HBV DNA was < 100,000 copies/mL in 8 patients and < 30,000 copies/mL in 5 patients.  HBV DNA cut-off levels of 30,000 and 100,000 copies/mL correctly classified patients with HBeAg-negative chronic HBV in 92.9% and 91.3% of cases, respectively.  These results demonstrate that HBV DNA levels by PCR are able to accurately differentiate most but not all patients with HBeAg-negative chronic hepatitis B from inactive carriers.  (Milich D, Liang TJ. Hepatology 2003;38:1075-1086.  Manesis EK et al. Am J Gastroenterol 2003;98:2261-2267.)

 

LAMIVUDINE THERAPY

Determinants for sustained response.  Rong-Nan Chien and collaborators from the University of Taipei studied 82 patients with HBeAg-positive chronic hepatitis B who had achieved a complete response to lamivudine therapy (normalization of ALT, loss of serum HBV DNA by hybrid capture assay, and HBeAg seroconversion).  The mean duration of lamivudine treatment was 16 months (range, 3-55 mo).  Patients in whom complete response had been sustained for ³ 12 months after the end of lamivudine therapy were classified as sustained responders (n = 43) and the others were classified as relapsers (n = 39).  A stepwise logistic regression model identified HBV genotype (B vs C), patient age (£ 36 y), and duration of additional lamivudine therapy (> 8 mo) to be independent determinants for sustained complete response.  Of 14 patients who had all 3 of these predictive factors, 79% attained sustained complete response; of 13 patients who had none of these factors, 0% had a sustained complete response.  (Chien R-N et al. Hepatology 2003;38:1267-1273.)

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