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Other Options for Treatment of Hepatitis C

NIH Consensus Development Conference on Management of Hepatitis C

Other Options for Treatment of Hepatitis C Herbert L. Bonkovsky, M.D.

Introduction: Need for More Effective Therapy

The continuing search for more effective modes of therapy for hepatitis C viral (HCV) infection bears witness to the imperfection of current therapy. Although the ultimate therapeutic goal continues to be eradication of all detectable virus, there is a grudging, growing realization that in many patients, this goal is difficult or impossible to achieve. Accordingly, other important and useful goals are being pursued, including, (1) diminution of virus levels in the blood and risk of infectivity, (2) diminution in the activity of hepatic inflammation, (3) diminution of the rate of progression of hepatic fibrosis, and prevention or delay in the development of cirrhosis and hepatocellular carcinoma.

Several approaches to management of chronic hepatitis C, beyond interferons or ribavirin, have been tested, and the current status of the major approaches is summarized below.

Iron Reduction

It has been known for many years that iron is an element required for replication of virtually all organisms, including virulent microorganisms. Patients with infections or other inflammatory conditions have decreases in serum iron concentrations, due largely to the effects of interleukin-1, an important mediator of the inflammatory response. (1) This hypoferremia is a host defense mechanism that helps to limit infection. Although the effects of iron and limitation of its availability have been studied mainly in bacterial and fungal infections, there is evidence for similar effects in viral infections as well. (2) A role for iron influencing the natural history of viral hepatitis was emphasized by Blumberg and colleagues more than 15 years ago. (3) They observed that patients with hepatitis B viral infection with higher serum iron or ferritin levels had greater likelihood of development of chronic infections than those with lower levels, who more often resolved their infections spontaneously. Several other groups have reported that larger stores of hepatic iron are positively associated with progression of hepatic fibrosis/cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B.

Increases in levels of serum ferritin, iron, and transferrin saturation also have been noted with high frequencies in patients with chronic hepatitis C,2 and the higher levels have, in general, been associated with lesser likelihood of response to interferon (IFN) therapy. For example, in nine different studies involving 434 patients, the levels of serum ferritin have been lower in complete responders to IFN than in noncomplete responders. Elevations of serum ferritin or transferrin saturation in such patients is not usually associated with hepatic iron overload. Nonetheless, complete responders to IFN have, on average, lower hepatic iron concentrations than do noncomplete responders. In addition, lack of stainable iron in nonparenchymal cells (especially endothelial cells in portal tracts) has been associated with greater likelihood of complete response of chronic hepatitis C to therapy with IFN. (2) Indeed, the presence of portal iron deposits was as strong a discriminator of response as viral genotype or the level of viral RNA in serum. (4)

Hayashi and colleagues(5) reported that iron reduction alone, by repeated venesection, led to significant improvement in serum alanine aminotransferase (ALT) levels in chronic hepatitis C. Indeed, the levels became norrnal in 5 of 10 subjects studied. This was confirmed in 12 additional studies involving a total of 306 patients. (2) In addition, in some, iron reduction alone led to a modest, albeit usually not statistically significant, decrease in serum levels of HCV RNA. Addition of IFN after iron reduction led to further and larger decreases in serum HCV RNA levels and to significant improvement in biochemical and virological responses. Of particular interest is a recent study in which previously untreated patients received IFN alone or IFN after iron reduction. A total of 29 percent (6/21 ) of the former but 59 percent ( 10/17) of the latter had a complete biochemical response, and this was sustained in 29 percent (5/17) versus 5 percent (1/21) for more than 6 months after therapy was discontinued. Clearly, these results need confirmation in a large multicenter trial. Although the mechanisms underlying a beneficial effect of iron on chronic hepatitis C remain unclear, there is experimental evidence for the following. ( 1 ) nonspecific effects of iron to increase oxidative stress enhance peroxidation of lipids and oxidative damage of other cellular components, perhaps with depletion of thiols or other antioxidant protective factors; (2) adverse effects of iron on host immunity, including impairment of function of antigen-presenting cells, impairment of cloning efficiency of T helper- 1 and cytotoxic T Iymphocyte subsets, impairment of T Iymphocyte proliferation and maturation, impairment of proinflammatory T cell responses, and impairment of natural killer cell-dependent Iysis of infected cells; and (3) impairment of humoral immunity.

Antioxidants and Anti-inflammatory Agents

Other approaches to treatment, such as the use of N-acetyl cysteine (NAC), or other -SH donors, are based upon the knowledge that, in chronic hepatitis C (as in other liver diseases), oxidative stress increases and plasma and liver GSH concentrations decrease. Oral NAC ( 1800 mg/d), although having little effect alone, enhanced the response to IFN. (6) Favorable effects of vitamin E alpha-tocopherol) on oxidative stress and activation of the cascade of fibrogenesis were reported recently. In a few small studies, similar effects have been reported for aspirin, other nonsteroidal anti-inflammatory drugs, pentoxyfylline, and colchicine. Similar nonspecific effects probably account for the improvements in serum ALT levels reported in chronic hepatitis C patients treated with many other concoctions, including traditional Chinese remedies and extract of snap cucumber. Whether such improvements in blood tests will be associated with diminution in the rate of progression to bridging fibrosis, cirrhosis, or hepatocellular carcinoma is currently unknown but is clearly an important issue.

Hydrophilic Bile Salts

Supplemental (tauro-) ursodeoxycholic acid has led to improvements in serum ALT levels, in both the absence and the presence of IFN. (7) These effects seem to be related to the beneficent effect of hydrophilic bile salts on many chronic inflammatory conditions involving the liver.

Cytokines and Other Immunomodulating Agents

Cytokines and other immunomodulating agents have also undergone limited trials in chronic hepatitis C. Effects of granulocyte/monocyte colony stimulating factor (GM-CSF) have generally been disappointing: it is expensive, poorly tolerated, and without beneficial effect except perhaps in a rare patient who develops severe neutropenia due to IFN, in whom GM-CSF may permit continuation of higher doses of IFN. In one reasonably large (110 patients), doubly masked, randomized trial, thymosin alpha- I plus IFN was compared with placebo and IFN alone. (8) A complete serum ALT response was reported in 42 percent of those treated with the combination, compared with 3 percent in those treated with placebos and 17 percent in those treated with IFN alone. The reason for the unusually low latter percentage was not clear, nor were long-terrn followup data available.

Other antiviral agents recently studied have included amantadine(9) and isoprinosine. (10) The forrner showed promise (and is currently the subject of further trials), whereas the latter did not. Several inhibitors of the HCV protease and RNA polymerase are under development by pharmaceutical companies. Results of their use are awaited with much interest.


In summary, several therapies, in addition to IFN and ribavirin, have beneficial effects in chronic hepatitis C. It seems likely that, as has been the case for HIV infection, combinations of these treatments will prove to be superior to monotherapy of chronic hepatitis C. Additional organized, controlled trials of therapy are urgently needed.

1.Dinarello CA. Interleukin-l. Rev lnfect Dis 1984;87:1372-4.
2.Bonkovsky HL, Banner BF, Rothman AL. Iron and chronic viral hepatitis. Hepatology. In press.
3.Blumberg BS, Lustbader ED, Whitford PL. Changes in serum iron levels due to infection with hepatitis B virus. ProcNatlAcadSciUSA 1981;78:3222-4.
4.Ikura Y, Morimot H, Johmura H, Fukui M, Sakurai M. Relationship between hepatic iron deposits and response to interferon in chronic hepatitis C. Am J Gastroenterol 1996;91:1367-73.
5.Hayashi H, Takikawa T, Nishimura N, Yano M, Isomura T, Sakamoto N. Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron. Am J Gastroenterol 1994;89:986-8.
6.Beloqui 0, Prieto J, Suarez M, Gil B, Qian CH, Garcia N, Civeira MP. N-acetyl cysteine enhances the response to interferon-alpha in chronic hepatitis C: a pilot study. J Interferon Res 1993;13:279-82.
7.Angelico M, Gandin C, Pescarmona E, Rapicetta M, del'Vecchio C, Bim A, Spada E, Baroni CD, Capocaccia L. Recombinant interferon-a and ursodeoxycholic acid versus interferon-a alone in the treatment of chronic hepatitis C: a randomized clinical trial with long-term follow-up. Am J Gastroenterol 1995;90:263-9.
8.Sherman KE, Sjogren MH, Creager RL, Freeman S, Lewey S, Root S, Davis D, Weber FL, Ishak K, Goodman ZB. Thymosin a I +interferon combination therapy for chronic hepatitis C: results of a randomized controlled trial [abstract]. Hepatology 1996;24:402A.
9.Smith JP. Treatment of chronic hepatitis C with amantadine-hydrochloride [abstract]. Gastroenterology 1996;1 IO:A1330.
10.Par A, Bero T, Brasch G, Gogl A, Lamaras G, Mehesfalvi E, Ozsvar Z, Paal M, Szipocs 1, Telegdy L. Isoprinosine therapy in chronic hepatitis C (multi-center placebo-controlled double-blind prospective study) [Hungarian]. Orvosi Hetilap 1993;134:1015-9.

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