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IL-12 Not Useful

Hepatology, June 2003, Vol 37, number 6 Paul Pockros et al. Division of Gastroenterology and Hepatology, Scripps Clinic, La Jolla, CA.

About two years ago small pilot studies suggested IL-12 might be an effective treatment for HCV nonresponders. The poor results from the latest study discussed below were presented at a conference last year so we knew IL-12 was not effective and here is the final published report.

IL-12 given alone for the treatment of chronic hepatitis C is not efficacious and is poorly tolerated. The antiviral efficacy and histologic benefits of the newer pegylated IFNs in combination with ribavirin suggest that immunomodulation through IL-12 should not be developed as future therapy for chronic hepatitis C. This large, multicenter, randomized, double-blind, placebo-controlled trial evaluated recombinant IL-12 therapy in patients with chronic hepatitis C who had previously failed to achieve sustained viral clearance with IFN- alone or IFN- plus ribavirin. The results show an end-of-treatment virologic response in 7 of 160 (4.4%) and sustained virologic response in 2 of 160 (1%) for patients who received at least 8 weeks of IL-12 therapy. However, 7 of 225 (3%) developed severe adverse events probably related to therapy; as a result, this study was terminated early. The low efficacy in terms of virologic or histologic response compared with conventional IFN- and ribavirin therapy in this prior treatment failure group, combined with the significant toxicity observed in this study, suggests that IL-12 as monotherapy probably has no further role in the treatment of chronic hepatitis C.

Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States; it affects 3.8 million people, 2.7 million (70%) of whom have developed chronic HCV infection characterized by variable degrees of liver inflammation and hepatocyte injury.1 Chronic HCV infection is now the most frequent indication for liver transplantation in developed nations.2 Predictions of disease burden over the next few years suggest that the incidence of HCV-related cirrhosis and hepatocellular carcinoma will increase by 60% to 70%, along with an approximate 2-fold increase in liver-related mortality.

The most effective currently available therapy for chronic hepatitis C is the combination of pegylated interferon (IFN) and ribavirin, which results in a sustained viral response (defined as absence of serum HCV RNA 6 months after the end of treatment) in more than one half of treated patients. However, therapy is costly, may be associated with significant adverse effects, and is not suitable for all patients. Thus, newer approaches to treatment are required.

An inadequate immune T-helper cell response may lead to persistent infection and the development of chronic hepatitis C,6 whereas a strong and polyclonal cytotoxic T-lymphocyte response is associated with lower levels of viremia in this disease.7 Th1 cells stimulate cytotoxic T-lymphocyte responses by producing proinflammatory cytokines such as interleukin 2 (IL-2) and IFN-. Th2 cells mediate humoral immunity through IL-4, IL-5, and IL-10 and may restrict cell-mediated responses.

Recombinant human IL-12 is a 70-kilodalton heterodimeric cytokine that facilitates a Th1 immune response, enhances cytotoxic T-lymphocyte and natural killer cell activity, and stimulates IFN- production.8,9 IL-12 secretion may be reduced in patients with chronic HCV with deficient cytotoxic T-lymphocyte responses, and administration of IL-12 to these patients has been associated with enhanced cellular immune responses to HCV antigens.

A 12-week pilot trial of IL-12 in 24 nonresponders to IFN- indicated that 3 of 6 patients randomized to the 300-ng/kg dosing regimen had complete loss of detectable HCV RNA during therapy.12 However, all 3 patients experienced a relapse after treatment. The drug seemed to be well tolerated at doses of 30 to 300 ng/kg subcutaneously twice weekly in this study. Another dose-escalation phase 1/2 study using a different formulation of IL-12 (at 0.03-0.5 µg/kg subcutaneously once per week for 10 weeks) indicated a greater than 50% decline from baseline HCV RNA in some patients but no loss of detectable virus. Given the drawbacks and shortfalls of our current therapies as well as these preliminary findings, the investigators who designed and planned this study carefully discussed these issues and believed there was a sufficient need and rationale to proceed with this study. The pertinent negative results of this dose-escalation phase 1/2 trial were taken into account when the decision was made to prematurely terminate our study.

The aim of this study was to determine the safety and efficacy of a 48-week regimen of IL-12 in patients with chronic hepatitis C who had previously failed to respond to standard therapy with IFN- alone or in combination with ribavirin.

Recombinant human interleukin 12 (IL-12) is an immunomodulatory cytokine that is active against several viruses. Treatment options in patients with chronic hepatitis C with nonresponse to interferon (IFN)-based therapy are limited. Prior dose-ranging studies have indicated drug tolerability and transient suppression of hepatitis C virus (HCV) RNA by IL-12. The aim of this study was to determine the safety and efficacy of prolonged IL-12 therapy in patients who have failed treatment with IFN- ± ribavirin. A total of 225 patients at 21 U.S. sites who had a history of nonresponse to IFN- or combination IFN- plus ribavirin for treatment of HCV were randomized to 500 ng/kg IL-12 or placebo subcutaneously twice weekly for 12 weeks. The groups were then unblinded; patients receiving IL-12 continued for another 36 weeks, and the placebo group received 48 weeks of treatment with IL-12 in an open-label fashion. HCV RNA, serum alanine aminotransferase (ALT) level, and a repeat liver biopsy were assessed at 24 weeks following therapy. Approximately 1% (2 of 160) of nonresponsive patients enrolled for treatment had a sustained virologic response to IL-12 therapy, but 3% (7 of 225) developed severe adverse events probably related to treatment, resulting in early termination of the trial. Common adverse effects reported by most patients included chills, fever, fatigue, headache, and arthralgia. At termination of the study, 160 patients had received at least 8 weeks of treatment with IL-12. Paired liver biopsy specimens were available for evaluation in 54 patients, but there were no significant changes in Knodell fibrosis or histologic activity index (HAI) scores. In conclusion, IL-12 as monotherapy at the doses used in this trial for chronic hepatitis C has low efficacy, was poorly tolerated, and is unlikely to provide an alternative to conventional IFN-based therapy.

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