Hepatitis C Treatment and New Drugs in Development
Two review articles published last month offer an overview of the
state-of-the-art in hepatitis C treatment and a look at promising drugs in
Treating Hepatitis C
M.P. Manns, H. Wedemeyer, and M. Cornberg, of the Medical School of Hannover
in Germany, published their review, "Treating viral hepatitis C: efficacy,
side effects, and complications," in the September 2006 issue of Gut.
"The treatment of hepatitis C has dramatically improved over the past
decade. Unlike any other chronic viral infection, a significant proportion
of patients with chronic hepatitis C can be cured," they wrote. "However,
the current standard
therapy -- pegylated interferon alpha and ribavirin -- has its limitations."
The authors provided a brief overview of several drugs in the development
pipeline, including HCV protease and polymerase inhibitors, antisense
oligonucleotides, and small interfering RNAs. Though promising, they
predicted, "Drug resistance may become a problem with these new compounds
and combination therapies may be unavoidable."
In terms of managing acute HCV infection, the authors noted that immediate
treatment of patients with symptomatic acute hepatitis C with conventional
or pegylated interferon monotherapy for 24 weeks produced a high rate of
virological response (about 90%). However, this approach runs the risk of
unnecessarily treating individuals who might spontaneously clear HCV without
therapy, leading to the adoption of a "wait and see" strategy to determine
with patients still have detectable HCV RNA after 12 weeks.
The authors then reviewed current standard therapy with pegylated interferon
plus ribavirin. Among recent advances are the recognition of the importance
of weight-based dosing of ribavirin and the need for individualized therapy
tailored according to factors such as HCV genotype and pre-treatment HCV
viral load. Studies of varying treatment durations -- both shortening
treatment for patients with genotype 2 or 3 and lengthening it for those
with genotype 1 -- are underway, but thus far have yielded mixed results.
Manns and colleagues devoted considerable attention to managing the side
effects of interferon/ribavirin, which can lead to poor adherence, dose
reduction, drug discontinuation, and ultimately treatment failure.
Finally, they included a discussion of hepatitis C treatment in "special
populations," including patients with persistently normal ALT, those
co-infected with HIV or hepatitis B, patients who have received liver
transplants, and those undergoing kidney dialysis.
"The main challenge for the future is to improve the success rates for the
difficult to treat and non-responsive HCV genotype 1 patients," they
Future Therapies for HCV
In the September 2006 issue of Nature Reviews Drug Discovery 5:
715-716, Richard E. T. Smith provided an overview of several experimental
"As with HIV drug development, the first direct antivirals to be developed
for HCV were the nucleoside analogues that inhibit the non-structural
protein 5B (NS5B) polymerase, an essential enzyme required for viral
replication," he wrote.
Ribavirin is a weak inhibitor, but it is effective when used in combination
with interferon. Researchers hoped to circumvent ribavirin-induced anemia
with the prodrug Viramidine (from Valeant), but "efficacy results have been
disappointing so far."
Newer nucleoside analogues now in development include valopicitabine (NM283;
Idenix/Novartis), currently in Phase II trials using lower doses in the
hopes of reducing the occurrence of gastrointestinal side effects; Phase III
trials are expected to start in 2007. Also in development is Roche's R1626,
which recently advanced to a Phase II trial.
Non-nucleoside analogue inhibitors that also target the HCV polymerase are
in earlier stages of development. ViroPharma/Wyeth's HCV-796 is the furthest
along in the pipeline.
"The early development of resistance is not uncommon with this class, as is
evident with non-nucleoside analogue inhibitors for HIV, but like HIV, these
drugs will probably have to be used in combination with other therapies,"
said Smith, echoing Manns and colleagues.
"The HCV NS3-4A serine protease has long been a desirable drug target for
HCV; however, its shallow active binding site has made it difficult to
design small-molecule inhibitors," Smith continued. Boehringer Ingelheim's
BILN 2061 was the HCV protease inhibitor first to enter trials, but was
halted due to cardiac toxicity in animals.
Two other protease inhibitors now undergoing trials are Vertex's VX-950 and
Schering-Plough's SCH-503034. VX-950 has shown "significant potency" in
early studies and is now in Phase II trials. Smith predicted that
InterMune's ITMN-191 would enter clinical trials by the end of this year.
Despite progress with novel antiviral agents, "Most experts agree that for
the foreseeable future, HCV treatment regimens are likely to include an
immunomodulator" such as interferon, Smith wrote.
These included new forms of interferon, such as Albuferon (Human Genome
Sciences/Novartis) and Locteron (Biolex/OctoPlus), which may be able to be
dosed less often than pegylated interferon. Newer immune-based approaches
include toll-like receptor (TLR) agonists such as Coley's Actilon's CPG10101
and Anadys' ANA-975.
"It is evident that the way in which HCV is treated is about to change as
new drugs edge towards the market," Smith concluded. "Sustained virological
response rates need to be improved, the holy grail being an all oral drug
combination that pushes rates into the 80-90% range without the need for
interferon injections. This goal remains some distance away, but in the
meantime the current treatment market for HCV is likely to grow from
approximately US $3 billion per year to more than $8 billion by 2010."
M P Manns, H Wedemeyer and M Cornberg. Treating viral hepatitis C: efficacy,
side effects, and complications. Gut 55(9): 1350-1359. September 2006.
R E T Smith. From the analyst's couch: Hepatitis C virus therapies.
Nature Reviews Drug Discovery 5: 715-716. September 2006.