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.
Summary
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.
References:
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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