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To the Editor:

In September 2004 we reported 3 cases of chronic hepatitis B in Crohn's disease (CD) patients from a cohort of 80 patients treated with infliximab.1 Two patients showed severe reactivation, 1 of whom died. Based on the American Association for the Study of Liver Disease (AASLD) and European guidelines,2, 3 preemptive lamividune was administered to the third patient, and no flare-up of hepatitis B virus (HBV) infection was detected 6 months after first infliximab infusion, when the article was accepted for publication. Lamivudine resistance can be detected in 14% to 32% after 1 year and 60% to 70% after 5 years of treatment. Thus, we suggested in a previous article1 that adefovir dipivoxil could be a better option for patients requiring long-term immunosuppressive therapy because resistance occurs at a slower rate compared to with lamivudine.4 However, the patient was maintained on lamivudine because of a good sustained response and based on widely accepted recommendations at that time.

We report here long-term follow-up of this patient, who showed severe reactivation of HBV infection 5 years after lamivudine initiation and 2 years after infliximab induction treatment and subsequent retreatment infusions.

A 29-year-old man was diagnosed with ileocolic and perianal CD in 1995. In 1999 mild, persistent hypertransaminasemia was found, and chronic B hepatitis (HBeAg and HBV DNA positive) was diagnosed. A liver biopsy performed in February 2000 showed mild portal and lobular activity without fibrosis. Lamivudine 100 mg daily started in April 2000 showed a good response, with HBeAg seroconversion, HBV/DNA clearance, aminotransferase normalization, and persistence of HBsAg positivity. In November 2001 the patient experienced a CD relapse with worsening of his perianal fistula, and he was treated with azathioprine 2.5 mg/kg per day. In July 2003 infliximab was added because of a lack of response to azathioprine. Three doses of infliximab were administered, followed by an 8-week maintenance treatment, resulting in a complete and sustained response. Lamivudine was also maintained, and no flare-up of HBV infection was observed until May 2005, when a slight increase in aminotransferase levels was detected. Two months later the patient experienced asthenia, malaise, and nausea. Blood analysis disclosed increased levels of serum ALT (289 IU/L), AST (225 IU/L), alkaline phosphatase (68 IU/L), GGT (35 IU/L), and total bilirubin (1.8 mg/dL). Hypoalbuminemia (29 g/L) and a decrease prothrombin rate (56%) were also found. The liver appeared normal on abdominal ultrasonography, and there was no ascites. Serum markers of hepatitis A virus, hepatitis C virus, cytomegalovirus, Epstein-Barr virus, and herpes virus were negative. IgM anti-HBc antibodies and high serum HBV DNA polymerase levels were detected (13,763 IU/mL). A test for HBeAg, previously positive, was negative at this time, suggesting the emergence of lamividune resistance with reactivation of a mutant B virus. Infliximab was stopped, and adefovir dipivoxil (added to lamivudine) was started in August 2005. The patient's status ameliorated in the next weeks, and he was totally asymptomatic in October 2005. A progressive improvement in the hepatic profile was detected, with normalization occurring in April 2006. A slow decrease in HBV DNA polymerase levels was detected in the next months. However, detectable HBV DNA persisted until November 2006 (59 IU/mL). A hepatic biopsy performed in June 2006 showed clear progression of liver damage compared to a previous biopsy, with septal fibrosis and two well-defined nodules suggesting incomplete cirrhosis. His CD remained in clinical, analytical, and endoscopic remission with azathioprine until the last control in March 2007. Immunomodulatory therapy with anti-TNF has not been necessary during follow-up. The viral and biochemical profile is shown in Figure 1.

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Figure 1. Biochemical profile related to Hepatitis B exacerbation.

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The recently published new AASLD practice guidelines suggest that adefovir or entecavir could be used as an alternate option to lamivudine when long-term immunosuppressive therapy (more than 12 months) is foreseen.5 Some CD patients, mainly those with a fistulizing pattern, require long-term infliximab therapy to maintain remission.6 In this setting, preemptive antiviral therapy with entecavir, which will soon be commercially available, is preferred to adefovir because of the rapid onset of action and lack of nephrotoxicity. In addition, this case and previously reported cases from a cohort of 80 CD patients1 demonstrate that severe reactivation in HBV-infected patients related to infliximab seems to be the rule. Based on this limited but relevant experience, the following recommendations for HBV-infected patients requiring anti-TNF therapies may be provided: (1) screening for HBV markers including HBsAg and anti-HBc (to detect occult hepatitis B) is mandatory; (2) HBV DNA should be determined in HBsAg- and anti-HBc-positive patients; (3) entecavir or adefovir should be administered to all HBsAg-positive and/or HBV DNA–positive patients during anti-TNF therapy and at least 6 months after withdrawal, with antiviral prophylaxis also recommended to all HBV-infected inflammatory bowel disease patients requiring immunosuppressives; and (4) anti-TNF therapy should be judiciously administered to HBV-infected patients and the risks and benefits cautiously weighed.

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Maria Esteve*, Carme Loras*, Ferran González-Huix†, * Department of Gastroenterology Hospital Mútua de Terrassa University of Barcelona Terrassa, Catalonia Spain, † Department of Gastroenterology Hospital Josep Trueta Girona, Catalonia, Spain.