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Quadrennial review - Treatment of chronic viral hepatitis
Professor J Hoofnagle, Bethesda, Maryland, USA, presented his second
quadrennial review on the treatment of chronic viral hepatitis, having
previously done so at the WCOG meeting in Sydney, Australia. Professor
Hoofnagle’s eminence in the field of hepatitis diseases was acknowledged
in his introduction, which noted his many significant publications in
this area of medicine.
Although hepatitis B, C, and Delta, are clinically similar, they are,
in fact, very different diseases, and respond differently to treatment.
Due to limitations of time, Prof Hoofnagle restricted his discussion to
hepatitis B and C, saying Delta hepatitis was too complex an issue to
be covered as well.
Around five per cent of the world’s population have hepatitis B,
but there is wide geographical variation of prevalence, with 5-10 per
cent in Asia and sub-Saharan Africa, but only 1 million people are infected
in the USA. Although there are excellent vaccines for this disease, therapy
is problematic. Typically, IFN is used at 5 MU per day, or 10 MU TIW,
as treatment, for 4-6 months. Clearance of HBeAg is 30-40 per cent in
typical patients with such regimens. However, therapy is expensive and
poorly tolerated.
The end points used to measure treatment efficacy are loss of HBeAg and
HBV DNA, normalisation of ALT, and improved histology. IFN causes a one
(1) log fall in HBV DNA during the first three months of treatment, and
then it suddenly disappears. There is also a flare of hepatic disease,
due to increased enzyme activity, with eventual clearance of HBeAg, fall
in enzyme activity, and development of anti-HBeAg. HbeAg is still present
in one-third of patients at therapy end, but eventually disappears, as
does HBsAg (surface antigen).
A long term follow-up (3-10 years) study of 103 patients has shown that
loss of HBeAg is sustained, with only two of 31 responders redeveloping
it, and these had serious underlying disease. Also, 86 per cent of the
responders ultimately lost HBsAg. However, therapy does not cure hepatitis
B. The strongest evidence for this comes from liver transplantation studies,
where livers from people free of surface antigen have incurred hepatitis
B subsequently in 78 per cent of the recipients. In addition, hepatitis
B may become re-activated in AIDS patients, and those receiving cancer
chemotherapy.
Several types of patient do not qualify for hepatitis B therapy, including
children, people with HIV/AIDS, and those with end stage liver disease.
However, there are a number of new treatments evolving, based on second
generation nucleoside analogue drugs. These are lamivudine, famciclovir,
lobucavir, adefovir dipivoxil, and clevudine.
A recently published study of 25 and 100 mg lamivudine daily in 300 Chinese
patients has shown good results, with 98 and 93 per cent HBV DNA disappearance
during therapy. Treatment lasted for one year, and resistance developed
in 14 per cent of patients. Also, relapse occurred once therapy ended.
These results underline problems relating to the length of time needed
to ensure effective treatment, since it is unknown how long lamivudine
treatment may be used successfully. However, new and promising therapies
are forthcoming, which may include combinations of antivirals, and possibly
immune modulators such as cytokinins.
Turning to hepatitis C, Prof Hoofnagle said this affects approximately
1-2 per cent of US citizens, which is the same rate in the PRC. Unlike
hepatitis B, there is no vaccine for hepatitis C, but he went on to explain
that therapy may well offer a cure. Recommended treatment for hepatitis
C is 3 MU TIW of IFN for 12 months. A sustained response with clearance
of HCV RNA and normalisation of ALT levels, is achieved in only 15-20
per cent of patients, and 40-50 per cent of patients do not respond to
therapy.
Although virological, biochemical, and histological endpoints are used
in assessing treatment, Prof Hoofnagle maintained that sustained virological
response was the best measurement of efficacy. The reliability of this
endpoint was illustrated by a small study of 10 patients who had been
followed up for 10 to 12 years. Five of these had had a sustained virological
response to treatment, and all of these are still free of HCV RNA and
have normal ALT levels now. Also their liver biopsies show that cirrhosis
has disappeared, suggesting that hepatitis C can be cured. However, therapy
is expensive.
NIH recommendations for patients to be treated for hepatitis C include
adults of 18-60 years, with elevated ALT levels, and HCV RNA in their
serum. However, the situation is less clear cut for children, old people,
patients with cirrhosis, and those with only mild disease. In fact, IFN
treatment in those with hepatitis C and normal levels of ALT may be harmful.
Treatment is contraindicated in children, transplant recipients, patients
with renal failure, and those with HIV, as well as drug and alcohol abusers,
in the USA.
The highest response to IFN treatment of hepatitis C is found in Asians,
and the lowest in African Americans. Women respond better than men do,
and shorter duration of disease also predicts favourable treatment outcome.
However, virological factors of HCV genotype and viral load are the strongest
predictors for treatment outcome. Every one log (ten-fold) drop in viral
load equates to a doubling of response rate. There are six HCV genotypes,
of which genotype 1 is most difficult to treat, whereas genotypes 2 and
3 are much more responsive.
Prof Hoofnagle reviewed possible methods to improve treatment response
rates in hepatitis C. He did not recommend higher does of IFN, and was
not convinced whether there are any differences between the various forms
of IFN available. He did mention the newest form of IFN, which is covalently
linked to a molecule of polyethyleneglycol (PEG). This form has a longer
duration of action, better pharmacokinetics, fewer side effects, and is
injected once weekly. He considered induction therapies to be an improvement
only during the treatment time. Combination therapy with IFN plus ribavirin,
a nucleoside analogue, was most promising.
In a trial conducted by McCutcheson involving 1700 therapy naïve
patients in four treatment arms, the combination of ribavirin plus IFN
was shown to significantly improve response rates, reaching up to 50 per
cent, in terms of patients becoming HCV RNA negative. It also decreased
the number of patients who suffered relapse at treatment end. Genotypes
2 and 3 responded well to combination therapy, and although there was
only a 17 per cent response rate amongst patients with HCV genotype 1,
this was a vast improvement on the two per cent measured with IFN monotherapy.
Side effects are an issue for both IFN and ribavirin. The psychological
effects of IFN are well known, and ribavirin produces dose dependent haemolysis,
which can be dangerous in coronary artery and cerebrovascular disease.
Ribavirin is also teratogenic and is contraindicated in renal failure.
Despite all these problems, this combination treatment with IFN and ribavirin
probably represent the best future treatment.
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