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Ipilimumab administration in patients with advanced melanoma and hepatitis B and C.

Introduction Infection with hepatitis B (HBV) and/or C (HCV) represents a challenge for oncologists in treating patients with advanced cancers. Administration of chemotherapy may reactivate HBV and/or HCV, potentially causing severe hepatitis, hepatic decompensation, and even death. Patients and physicians must therefore balance the benefits of disease control with the risks of viral reactivation after systemic therapy. Postchemotherapy HBV reactivation has been reported particularly in patients with lymphoma or patients who receive treatment with rituximab, corticosteroids, anthracyclines, or bone marrow transplantation, a phenomenon that can be reduced by prophylactic antivirals such as lamivudine, entecavir, or tenofovir. Although reports of hepatitis from HCV reactivation exist, the incidence seems to be less frequent. The advent of new targeted therapies that may cause therapy-induced hepatitis reactivation and immunotherapies with unclear effects on viral replication and host immune status introduce even more complexity in treatment planning for these patients. Ipilimumab, a recombinant human immunoglobulin G1 monoclonal antibody that results in increased T-cell activation and proliferation by blocking the inhibitory action of the negative T-cell regulator cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), was the first agent to demonstrate a survival advantage in the treatment of advanced melanoma in a randomized study. This first-in-class drug has a unique adverse effect profile, with its activity manifesting as immune-related events that include enterocolitis, hepatitis, dermatitis, and endocrinopathies. Immune-mediated hepatitis occurred in 2% to 9% of patients in studies of ipilimumab, and 31.6% of patients experienced grade 3 to 4 immune-mediated hepatitis when ipilimumab was combined with dacarbazine. Recommendations for ipilimumab use include monitoring hepatic function tests before each dose, with initiation of corticosteroids for liver function tests (LFTs) and/or total bilirubin of grade 3 or higher that are unrelated to disease progression. Although chemotherapy may have immunosuppressive effects, the effects of ipilimumab in patients with hepatitis are less clear. Polymorphisms of CTLA-4 have been associated with chronic hepatitis B and C infection. CD8 T cells from humans with chronic HBV showed an increased propensity to express CTLA-4 that correlated with viral load and elevated levels of the proapoptotic protein Bim, which is thought to cause depletion of HBV-specific CD8 T-cell responses. Indeed, CTLA-4 blockade in cynomolgus macaques enhanced antibody response to hepatitis B surface antigen. The CTLA-4 pathway is also implicated in virus-specific T-cell exhaustion in patients with HCV. The mechanisms behind these events require further elucidation but imply an existing link between CTLA-4 activity and hepatic viral pathogenesis that could possibly be exploited for therapeutic benefit. Limited, if any, published data exist regarding the safety of ipilimumab in patients with HBV and HCV infection. Such patients were excluded from clinical trials of ipilimumab; therefore, information must be gained through postmarketing experience. Here we describe two patients, one with HBV and one with HCV, who were treated with ipilimumab for metastatic melanoma.