Hepatitis B virus
Case reports differ in regard to HBV reactivation in patients with chronic HBV being treated with TNF-a. There are abbreviated case reports that have been published describing observed safety with anti-TNF-a in patients with chronic hepatitis B [145,146]. Anelli and colleagues  describe a patient with RA and chronic hepatitis B in which HBV DNA was undetectable after treatment with infliximab. Others, however, describe a growing number of cases of HBV reactivation in patients with rheumatic disease on TNF-a inhibitors leading to serious complications [148-150]. Case reports describe coadministration of lamivudine with an anti-TNF agent is not associated with HBV reactivation [145,148,151]. In regard to rituximab, there have also been several case reports of fulminant hepatitis and subclinical reactivation [152-155]. Case reports suggest tandem use of lamivudine is preventive [156,157].
Calabrese and colleagues  offer guidelines for assessment, prevention, and treatment of HBV-positive patients undergoing anti-TNF-a therapy. These might be well considered for initiation of all immunomodulant therapy. Best practice strongly suggests HBV screening before initiation of any immunosuppressant agent, especially anti-TNF-a agents and rituxi-mab, with serial transaminases and viral load along with consideration of pre-emptive lamivudine if results so indicate [148-150].
Hepatitis C is associated with the development of a wide spectrum of rheumatic diseases. These include various manifestations of vasculitis, arthritis, and connective tissue disorders that are ordinarily treated with immunosuppressive therapy in nonhepatitis patients. Preliminary studies reveal anti-TNF-a to be a safe and effective treatment of co-existing rheumatic disease in patients with chronic HCV without significant side effects, worsening of disease, or increase of HCV markers. [146,151,158,159]. Studies demonstrate significance between etanercept and placebo (P = .04) in achieving negative HCV RNA and normal alanine transaminase in patients being treated for chronic HCV disease with interferon and ribavirin. The etanercept arm experienced fewer side effects . High levels of circulating TNF in HCV are known to be present in patients with HCV who are refractory to standard HCV treatment. This is likely caused by TNF suppressive effects on peripheral T cells resulting in decreases of interferon-g with resultant lack of viral suppression .
Multiple case reports describe successful and safe use of rituximab in patients with HCV cryoglobulinemic vasculitis [160-162]. A prospective study of 20 patients in Italy reported 75% complete response and 75% lasting remission at 1 year in patients treated with adjuvant rituximab in patients who were intolerant or refractory to interferon-a. In patients who had responsive disease, however, the HCV viral load was found progressively to increase and be doubled 1 year later, a potentially harmful outcome suggesting strong consideration of tandem antiviral use in patients with HCV receiving rituximab . Aksoy and colleagues  report a case with a pejorative outcome in a patient with dramatic acceleration of viral load replication after being treated with rituximab for HCV-related non-Hodgkin's lymphoma who died 6 months later because of infiltrative neurologic disease.
Again, best practice with use of immunosuppressant therapy is ascertainment of HCV status, if positive results follow transaminases and viral load closely and strong consideration of a concomitant antiviral, such as ribavirin.
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