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See article on page 427
Chronic infection with hepatitis C virus (HCV) affects 2–15 % of the world's population. In the USA there are more than 4 million chronically HCV infected people and the estimates for Europe are similar. In the European Community chronic hepatitis C is viewed as a major health problem and efforts are being made to develop both preventive and new therapeutic strategies (Key Action 2 of the5th Framework Programme 1998–2002 of Quality of Life and Management of Living Resources).
Treatment of chronic hepatitis C is currently based on interferon α (IFN-α) with limited efficacy, only achieving a sustained virological response in less than 25% of patients with a favourable profile treated for one year.1 To improve the response rate of standard IFN-α monotherapy, several regimens have been tried combining IFN-α three times weekly for six to 12 months with various other agents. These agents include those with antiviral activity like ribavirin, amantadine,2 and azidothymidine; others with immunomodulatory properties such as thymosin; those with liver enzyme lowering activity like ursodeoxycholic acid and ribavirin2; and others with miscellaneous properties such as ofloxacin, N-acetylcysteine, glycyrrhizin, and non-steroidal anti-inflammatory drugs (NSAIDs). The aim of all these efforts was to increase IFN efficacy by decreasing the number of non-responders and relapsed responders as well as to reduce the dose of IFN-α required for a sustained response and consequently its side effects. The most rewarding of all these combinations with IFN was that of ribavirin which in large randomised controlled trials3 4 proved to be far superior to IFN-α monotherapy of six and 12 months duration. In fact, the overall sustained response rate achieved with combination therapy in these two large trials reached 33% and 41% over six and 12 months of treatment, respectively, compared with 6% and 16% achieved with IFN monotherapy over the same time periods. The increase in sustained response was even more dramatic in patients with HCV genotypes 1 and 4–6 than in patients with the more easily eradicable genotypes 2 and 3. The sustained virological response doubled in the latter from 30% to 65% but tripled in the former from 9% to 30%. However, despite these exciting results most treated patients with chronic hepatitis C fail to attain a sustained virological response. This is particularly true for infection with genotypes 1 and 4, with 70% of infected patients failing to respond even to a 12 month combination therapy regimen. It is therefore conceivable that further efforts are needed in order to improve the efficacy of combination therapy. To this end different types of interferon-like consensus IFN, new formulations of IFN-α with attachment of polyethylene glycol, use of daily IFN dosing, higher doses and induction regimens aiming at rapid decrease of HCV replication are being tried. Combination of all these IFN directed efforts with adjuvant drugs is also under evaluation.
NSAIDs combined with IFN has been tried in naive and non-responsive patients with chronic hepatitis C with little or no success.5-7 However, existing evidence suggests that NSAIDs with their cyclooxygenase inhibiting activity possess an IFN potentiating effect by enhancement of 2′,5′-oligosynthetase activity.8 Negative results from the few early clinical studies of combined treatment with NSAIDs and IFN and case reports of NSAID induced hepatotoxicity9 in chronic hepatitis have been discouraging.
In this issue (see page 427), Muñoz et alreport on a prospective randomised controlled trial evaluating the efficacy of combined treatment with IFN and ketoprofen versus IFN alone. The authors have managed to study a fairly large, for a single centre, number of patients with well defined inclusion criteria of chronic hepatitis C. The patients were allocated into three treatment groups receiving either: (1) IFN alone at 3 million units three times weekly for six months; (2) IFN combined with a small dose of the NSAID ketoprofen, 200 mg given three hours before the thrice weekly injections of IFN; or (3) IFN combined with daily ketoprofen at a dose of 200 mg given twice a day. Ketoprofen was administered as a slow-release form. Both groups also received ranitidine (150 mg/day) prophylactically. Ketoprofen was selected over other NSAIDs because it has been used in the past in patients with hepatitis without serious side effects, it has a high bioavailability, its pharmacokinetics are not influenced by cirrhosis, and it inhibits both the cyclooxygenase and lipooxygenase inflammatory pathways. The patients were monitored carefully clinically, biochemically, and virologically. HCV RNA was measured by RT-PCR and negative cases were retested by a nested PCR with a detection limit of 1000 copies/ml. Both doses of ketoprofen were well tolerated with similar side effects to the IFN monotherapy arm except perhaps for a greater drop in haemoglobin concentrations. The virological response rate at the end of follow up (sustained virological response) was significantly higher in the daily ketoprofen group (26%) compared with the small thrice weekly dose and to the IFN monotherapy groups (0% and 10%, respectively, and 2% in the two groups combined, p=0.009). The response rate of the few cirrhotic patients in group 3 was similar. Moreover the 'flu-like side effects of IFN-α were less frequent in the ketoprofen treated patients.
This is the first time that ketoprofen has been given to patients with chronic hepatitis C twice daily in a slow-release form, similar to the doses recommended for the treatment of osteoarthritis and rheumatoid arthritis. This probably explains the major difference in the efficacy of this regimen compared with the lower dose scheme and with the negative results of a similar study using a different ketoprofen dosage.6 Independently of these encouraging results, there are some points of concern in this study that have also been recognised by the authors. Firstly, as expected, the number of patients studied, although large for a single centre study (n=70), is still very small for a three arm study and both type 1 and type 2 errors are possible. In fact the difference between groups 1 and 3 is not statistically significant. Furthermore, because of the small number of patients an intent-to-treat analysis weakens the differences significantly. Secondly, it is difficult to explain the very large discrepancy between the rate of biochemical and virological response at the end of treatment observed in all three groups. Even in the IFN monotherapy group the biochemical response rate was 52% and the virological rate 10%. Thirdly, it is not conceivable how the group on the small ketoprofen dose could have had a response rate below that of the IFN monotherapy group. Fourthly, again as expected, owing to the small number of patients studied, the effect on the efficacy of therapy of several baseline variables such as viral load, HCV genotypes, and extent of liver fibrosis was not evaluated. These and other emerging questions should be answered in future trials of large numbers of patients.
Regardless of the study's limitations, this report of a significant increase in the sustained virological response rate achieved at a small additional financial cost should herald new clinical trials of combined treatment with ketoprofen and IFN. The postulate that NSAIDs may potentiate the action of IFN has received timely independent support from a recent study in hepatoma cell lines, indicating that blockade of arachidonic acid metabolism by NSAIDs, activates a signalling pathway potentiating IFN-α dependent gene activation.10 Clearly the last word on the combination of NSAIDs with IFN has still to be written.
See article on page 427
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