SELECTED HIGHLIGHTS FROM THE DRAFT NIH HCV CONSENSUS STATEMENT

Conference Reports for NATAP


NIH HCV Consensus Development Conference

June 10-12, 2002 Back





SELECTED HIGHLIGHTS FROM THE DRAFT NIH HCV CONSENSUS
STATEMENT

Reported by Jules Levin

Chronic HCV infection is diagnosed by the detection of
HCV RNA at least intermittently in the blood by either qualitative or
quantitative tests for a period of at least 6 months. In general, prospective
studies have shown that the majority of HCV-infected persons develop chronic
infection.

The most important potential bad outcomes of chronic HCV
infection are progressive liver fibrosis leading to cirrhosis, end stage liver
disease (ESLD), and HCC (liver cancer).

Estimates of the proportion of chronically infected
persons who develop cirrhosis 20 years after initial infection have been
substantially higher from retrospective studies (17 to 55 percent) than from
prospective studies (7-16 percent). There is little evidence that the risk of
progression of liver disease is affected significantly by virologic factors,
including viral load, viral genotype, and quasispecies diversity. However, many
host factors are observed to increase this risk, including older age at time of
infection; male gender; and an immunosuppressed state, such as HIV infection.

Alcohol use plays an important role in increasing the
risk of progressive liver disease, with strong evidence for the detrimental
effects of 60 g/day in men (equivalent to six beers, four glasses of wine, or
three mixed drinks) and 40 g/day in women, but there is suggestive evidence that
lower amounts can also increase the risk of liver damage associated with HCV.

In the United States, deaths associated with chronic HCV
are currently more likely to be due to ESLD than to HCC. Data from death
certificates in 1999 found that approximately 4,000 deaths were attributed to
HCV infection, but this is likely to be an underestimate.

The only treatment option for persons who have developed
ESLD (decompensated cirrhosis) is transplantation. Currently, HCV is the primary
reason for liver transplantation in the United States. Little is known about the
clinical course and risks of HCV-related complications in persons who have been
infected longer than two decades.

The incidence of HCV-related HCC is continuing to rise
in United States and worldwide, in part because of the increasing numbers of
persons who have been chronically infected for decades, the presence of comorbid
factors, and the longer survival of persons with advanced liver disease due to
improved management of complications.

Liver biopsy yields information on fibrosis and
histology assessment that is not obtainable by any other means. Various
noninvasive methods based on biochemical or serologic tests have been evaluated
in several studies. Liver enzymes have shown little value in predicting
fibrosis. Extracellular matrix tests do predict severe stages of fibrosis but
cannot consistently classify intermediate stages of fibrosis. Moreover, only
liver biopsy provides information on possible contributions of iron, steatosis,
and concurrent alcoholic liver disease to the progression of chronic hepatitis C
toward cirrhosis.

The highest response rates have been achieved with
PEG-interferon in combination with ribavirin. Genotype determinations now
influence treatment decisions.

Overall, PEG-interferon plus ribavirin is more effective
than standard interferon-ribavirin combination or PEG-interferon alone. SVRs
were similar with both forms of PEG-interferon (alpha 2a and alpha 2b) when used
in combination with ribavirin. Factors associated with successful therapy
include genotypes other than 1, lower baseline viral load, and less fibrosis or
inflammation on liver biopsy. In all three trials, an SVR of 42 to 46 percent
was achieved for genotype 1 using a higher dose of PEG-interferon and ribavirin
for 48 weeks. An SVR of 76 to 82 percent was achieved for patients with
genotypes 2 and 3. It appears that 24 weeks of treatment and a lower dose of
ribavirin is adequate for genotypes 2 and 3. Early viral response (EVR), defined
as a minimum 2 log decrease in viral load during the first 12 to 24 weeks of
treatment, has been identified as predictive of SVR. Those who fail to achieve
an EVR have only a small chance of achieving a SVR even if therapy is continued
for a full year.

Although SVR has not yet been correlated with improved
survival because of the necessity for long-term followup, the absence of a
detectable serum HCV RNA has been correlated with resolution of liver injury,
reduction in hepatic fibrosis, and a very low likelihood of recurrent HCV
infection. Additionally, in two large recent studies from Japan, interferon
treatment was associated with a reduction in the development of hepatocellular
carcinoma, a finding that was more pronounced among patients with SVR.

Re-Treatment

Patients who may benefit from re-treatment include those
whose HCV infection failed to achieve SVR. Decisions regarding re-treatment
should be based upon: (1) previous type of response, (2) the previous therapy
and the difference in potency of the new therapy, (3) the severity of the
underlying liver disease, (4) viral genotype and other predictive factors for
response, and (5) tolerance of previous therapy and adherence.

Relapsers achieve an initial end of treatment response
(ETR) for their HCV disease, but it is not sustained over time (i.e., no SVR).
Nonresponders never achieve an EVR, ETR, or SVR. Among the nonresponders, there
is a subset of persons who have a substantial reduction of HCV RNA (1 to 2 log
units or more) during therapy, and who can be categorized as partial responders.

Even in the absence of SVR, treatment may be associated
with improved histology. Preliminary results suggest that overall only 15 to 20
percent of nonresponders treated with standard interferon/ribavirin combinations
achieved an SVR on re-treatment using PEG- interferon with ribavirin. Patients
with genotypes 2 or 3 have better response rates to re-treatment than genotype
1.

The ability to achieve SVR following re-treatment with
PEG-interferon/ribavirin in patients who relapsed following interferon
monotherapy or standard interferon/ribavirin therapy is currently being
evaluated. However, in cases where the same regimen has been used for re-
treatment, virtually all patients relapse again after treatment is stopped.
Extending the duration of re-treatment without changing the dose or regimen may
reduce the relapse rate, but this has not yet been proven prospectively.

Patients whose HCV infection does not respond to the
current optimal therapy with PEG-interferon and ribavirin present a significant
problem, particularly in the presence of advanced fibrosis or cirrhosis. The
possible role of maintenance therapy with PEG-interferon alone in preventing
further progression of cirrhosis, clinical decompensation, or development of
hepatocellular carcinoma is currently the focus of a large-scale, multicenter
United States trial, HALT-C. Until the results of HALT-C or similar studies are
available, the role of long-term, continuous therapy with PEG-interferon (or
ribavirin or both) for nonresponders must be considered experimental.

Knowledge of the severity of the underlying liver
disease is important in recommending re-treatment. Patients with advanced
fibrosis or cirrhosis are at increased risk for developing hepatic
decompensation and should be considered for re-treatment, especially if they
were originally treated with interferon monotherapy. For the re-treatment of
patients with intermediate degrees of fibrosis and disease activity, clinicians
should consider the factors enumerated above.

WHO SHOULD BE TREATED

All patients with chronic hepatitis C are potential
candidates for antiviral therapy. Treatment is recommended for patients who are
at increased risk for progression to cirrhosis.

These patients are characterized by measurable HCV RNA,
a liver biopsy with portal or bridging fibrosis, and at least moderate
inflammation and necrosis; the majority have persistently elevated ALT values.
In some patient populations, the risks and benefits of therapy are less clear
and should be determined on an individual basis or in the context of clinical
trials. Many patients with chronic HCV have been ineligible for trials because
of injection drug use (IDU), alcohol abuse, age, and a number of comorbid
medical and neuropsychiatric conditions. Efforts should be made to increase
availability of the best current treatment to these patients. Because a large
number of HCV-infected persons in the United States are incarcerated, strategies
should be developed to better prevent, diagnose, and treat these individuals.

In patients with persistent ALT elevations, but with no
fibrosis and minimal necroinflammatory changes, progression to cirrhosis is
likely to be slow; these patients should be monitored periodically.

Data on safety and efficacy of interferon (standard or
pegylated) with or without ribavirin in patients with advanced fibrosis or
compensated cirrhosis have been largely derived from subgroup analyses of larger
trials. SVR is lower in patients with advanced liver disease than in patients
without cirrhosis. An important goal of treatment in advanced liver disease is
to delay histological disease progression, which is being evaluated in the
NIH-sponsored HALT-C trial. Patients with decompensated cirrhosis should be
referred to clinical trials until safety and efficacy data of treatment are
established, or they should be considered for liver transplantation. In patients
with ESLD, the main treatment option is liver transplantation. There are ongoing
studies of antiviral therapy of patients awaiting liver transplantation, but
this approach may be limited by potentially life-threatening side effects of
antivirals.

HIV Coinfection

All HIV infected persons should be screened for HCV.
Patients with chronic hepatitis C and concurrent HIV infection may have an
accelerated course of HCV disease. Therefore, although there are no HCV
therapies specifically approved for patients coinfected with HIV, these patients
should be considered for treatment. Thus far, studies have enrolled only
patients with stable HIV infection and well-compensated liver disease. In
coinfected persons, an SVR can be achieved with HCV treatment. Preliminary data
suggest better responses to PEG-interferon with ribavirin than to standard
interferon with ribavirin. Although treatment of HCV has not jeopardized control
of the HIV infection, additional data are needed.

Injection Drug Users

Recent experience has demonstrated the feasibility and
effectiveness of treating HCV in 20 people who use illicit injection drugs
(known as injection drug users or IDUs). This is important because IDUs comprise
the largest group of hepatitis C patients in the United States, and successful
treatment may reduce transmission. Management of HCV-infected IDUs is enhanced
by linking IDUs to drug-treatment programs. Efforts should be made to promote
collaboration between experts in HCV and substance-abuse providers. HCV therapy
has been successful even when the patients have not been abstinent from
continued drug use or are on daily methadone. Few data are available on HCV
treatment in active IDUs who are not in drug treatment programs.

Alcohol and HCV

Alcohol is an important cofactor in the progression of
HCV liver disease to cirrhosis and HCC. A history of alcohol abuse is not an
absolute contraindication to therapy; however, continued alcohol use during
therapy adversely affects the response to treatment. Treatment of HCV should be
performed in conjunction with efforts to treat alcohol abuse or dependence.
Heavy alcohol consumption of >80 g/day seriously compromises HCV treatment. Safe
levels of alcohol consumption are still unclear.

RECOMMENDATIONS

Educate the American public on the transmission of HCV
in order to better identify afflicted individuals and institute preventive
measures.

Develop reliable, reproducible, and efficient culture
systems for propagating HCV and expand basic research in the pathogenic
mechanisms underlying hepatic fibrosis.

Promote the standardization and wide availability of
diagnostic tests for HCV infection and its complications, leading to early
diagnosis and the implementation of appropriate treatment practices.

Expand the delineation of disease manifestations,
noninvasive tests, and the role of the liver biopsy, so that the application of
current treatment practices may be refined.

Establish a Hepatitis Clinical Research Network for the
purpose of conducting research related to the natural history, prevention, and
treatment of hepatitis C.

Organize RCTs to extend treatment to special populations
not represented in current,clinical trials and to determine the applicability of
accepted antiviral drug combinations to populations such as children and
adolescents, patients with acute hepatitis, hemophiliacs, IDUs in drug treatment
programs, alcohol abusers, patients with stabilized depression, those with
coinfection with HIV, patients with decompensated cirrhosis and HCV infections
in transplant recipients. Such an effort should lead to decreased morbidity and
mortality from the disease, as well as a decrease in thereservoir of disease.

Evaluate strategies to interrupt mother-to-infant
transmission of HCV.

Evaluate new therapies in nonresponders to current
treatments, to include not just antiviral agents but also combinations of
antifibrotic drugs, immunomodulatory agents, and alternative therapies.

Encourage a comprehensive approach to promote the
collaboration between health professionals concerned with management of
addiction with specialists involved in various aspects of HCV and its
complications in order to deal with complex societal, medical, and personal
issues occurring in IDUs afflicted by the disease.

Seek appropriate support from governmental agencies and
the private sector to address urgent research questions concerning epidemiology
and treatment of this disease.









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