Tenoxicam, a non-steroid anti-inflammatory drug, is unable to increase the response rate in patients with chronic hepatitis C treated by alpha interferon

Abstract

The purpose of this study is to compare a combination of interferon (IFN)-␣ 2 a (Roferon) ؉ Tenoxicam with IFN-␣ 2 a alone in the treatment of chronic hepatitis C. This prospective, randomized double-blind study included 149 patients, all of whom were diagnosed with active chronic hepatitis C but non-cirrhotic (ALT H 1.5 upper limit of normal, anti-hepatitis C virus (HCV) positive by enzyme-linked immunosorbant assay 2 and RIBA 3 ). The patients were randomized in two groups, as follows: G1 (n ‫؍‬ 76): IFN␣ 2 a 3 million units times per week during 6 months ؉ placebo; and G2 (n ‫؍‬ 73): IFN␣ 2 a 3 million units three times per week ؉ Tenoxicam (20 mg/day) during 6 months. Alanine aminotransferase (ALT) and HCV RNA were determined before and at months 6 and 12 of treatment. 2'5' oligoadenylate synthetase activity (2'5' AS) was dosed in mononuclear cells before and at 3-month treatment intervals in 28 patients. Liver biopsy was performed before and 6 months after the end of therapy. Parameters were similar before therapy for both groups. Biochemical and virological responses were similar for both groups at month 6 (49.3% vs. 42.9% and 43.3% vs. 38.3%, respectively) and month 12 (28.3% vs. 23.8% and 17.2% vs. 17.5%, respectively). HCV RNA level significantly decreased in both groups at month 6, with no difference whatever the therapy; however, the HCV RNA level returned to initial values at month 12 and was the only significant prognostic factor of a sustained response. No peak of 2'5' AS activity was observed during treatment in patients with dual therapy. A histological improvement was also noted in both groups without difference, regardless of therapy. The percentage of adverse events was identical for both groups. Paracetamol intake, assessed in 80 patients, was 49.1 g per 6 months in the G1 group and 22.5 g per 6 months in the G2 group (not significant).In conclusion, the non-steroid anti-inflammatory drug, Tenoxicam, does not increase IFN␣ efficacy in the treatment of chronic hepatitis C. This combination is well tolerated and partially lowers Paracetamol intake, but not preexisting ␣-IFN adverse events. (HEPATOLOGY 1998;27:862-867.)Chronic hepatitis C is a common and worldwide cause of liver cirrhosis and hepatocellular carcinoma. 1 Interferon alpha (IFN␣) is currently used for the treatment of chronic hepatitis C. 2 A common regimen of 3 million units of interferon alpha (IFN␣) three times weekly for 24 weeks can normalize serum alanine aminotransferase (ALT) level in 40% to 50% of the patients during treatment. 3,4 Nevertheless, the sustained ALT and HCV RNA response rates are usually inferior to 25%. 4 Finding the optimal treatment to induce long-term biochemical and virological remission in patients with chronic hepatitis C remains a great challenge. To improve the response rate, several investigators attempted to administer IFN in combination with other drugs. An interesting approach involves inhibition of prostaglandin synthesis and activation of arachidonic acid metabolism. 5 In vitro, the treatment o...

Inhibition of the cyclooxygenase/lipoxygenase pathways to improve interferon alfa efficacy in chronic hepatitis C: A wrong track

“…2 Nevertheless, although it is theoretically possible that the amount of tenoxicam or mesalazine used were not entirely blocking each metabolic pathway, the results of this pilot study do not support a major improvement of the antiviral efficacy of IFN-␣ by the adjunction of both a cyclooxygenase and a lipoxygenase inhibitor. These results are in keeping with those reported with cyclooxygenase inhibitors only in naive patients 3 and in nonresponders to IFN. 5 Overall, modulation of arachidonic acid pathways appears globally to be a wrong track.…”

“…2 Therefore, drugs inhibiting the cyclooxygenase pathway, such as nonstreroidal anti-inflammatory drugs (NSAIDs), might theoretically enhance the antiviral action of IFN by diverting arachidonic acid towards the epoxygenase pathway. In a large series of naive patients with chronic hepatitis C reported last year in HEPATOLOGY, Zarski et al 3 found that neither the activity of the IFN-induced enzyme 2Ј-5Ј oligoadenylate synthetase, nor the ratio of sustained virological response to 6 months of therapy were increased by the adjunction of tenoxicam (an NSAID inhibiting the cyclooxygenase pathway) to IFN-␣. However, it must be stressed that, to date, attempts have been made to block the cyclooxygenase pathway only, so that arachidonic acid could have been diverted principally towards the lipooxygenase pathway, with only a marginal effect on ISRE-related transcription.…”

“…The theoretical basis for immune therapy in chronic HBV infection comes from animal models suggesting the possibility of using hepatitis B surface and core epitopes 2,3 or DNA immunizations 4,5 to stimulate immune responses. Moreover, pilot studies of vaccine-specific therapy in humans with chronic hepatitis B showed encouraging results.…”

Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways

“…Indeed, contradictory results have been reported on the association of interferon-␣ with NSAIDs in treated patients, but they used different pharmacological agents and times of evaluation. [34][35][36][37] Some reports have indicated the failure of NSAIDs and interferon combination therapy in improving interferon-resistant chronic hepatitis C, 34,38 whereas other authors, using ketoprofen plus interferon, have reported an improved virological response in chronic hepatitis C patients. 35 Giambartolomei et al 39,40 reported that indomethacin potentiates the interferon-␣ signaling pathway by increasing signal transducer and activator of transcription 1 phosphorylation in vitro, improving cellular response.…”

Nonsteroidal anti-inflammatory drug metabolism potentiates interferon alfa signaling by increasing STAT1 phosphorylation

“…Indeed, contradictory results have been reported on the association of IFN-␣ with NSAIDs. 8,25,26 It must be noted that the above-mentioned studies used NSAIDs with different biochemical activities and did not include comparable groups of HCV patients, and this may be important for the interpretation of results. Indeed, we showed that, at least in vitro, the effect of indomethacin is more evident when suboptimal concentrations of IFN-␣ are used.…”