ARCH GASTROENTEROHEPATOL 2002; 21 ( N0 3 – 4 ):
U.S. National Institute of
Health: Consensus development conference statement on hepatitis C
Nacionalni Institut za Zdravlje SAD: Saoštenje sa konferencije o konsenzusu o hepatitisu
C
Institute
for Infectious Diseases, Clinical Center of Serbia,
Belgrade.
Address
correspondence to: Professor Dr Neda Švirtlih,MD,PhD.
Institute
for Infective Diseases,
Clinical Center of Serbia,
16 Bulevar JA Str.,
YU-11000
Belgrade, Serbia,
Yugoslavia
FAX
+381 11 684 272
.....................................................................................................
After discovering in 1998, Hepatitis
C Virus (HCV) was recognized as the leading course of known liver
disease worldwide. Moreover, it is well confirmed that this virus often
produces chronic liver disease (CLD) with severe consequences, such as liver
cirrhosis (LC), end-stage of liver
disease (ESLD), and eventually, hepatocellular carcinoma (HCC). Because of
serious sequelae of its persistence and difficulties in attaining an effective
antiviral treatment response, late complications of HCV infections are
the most common indications for liver transplantation in U.S.
Five years after Consensus
Statement had been held by National Institute of Health (NIH) in March 1997,
large number experimental and clinical studies on HCV were done (1). In
2001, hepatology experts
......................
........................................
NIH consensus on HCV Gastroenterološka sekcija SLD-
01735,2002.
on behalf of the Royal College
of Physicians,London (UK) and the British Society of Gastroenterology, directed
clinical guidelines on the management of hepatitis C (2). In spite of
these recommendations, further needs for reexamination to the approach and
management of HCV were neccessary.
The latest NIH Consensus
conference on Hepatitis C convened was held in 2002, from June 10-12.
During two-and-a-half day, the 12-member consensus panel discussed the current
state of knowledge of HCV. They reviewed researches regarding the
natural history and epidemiology of HCV, appropriate diagnostic
procedures and monitoring of patients, treatment strategies, preventive
measures of virus transmission and the
most important areas for future
investigations. After weighing all scientific evidences, the panel drafted a
“preliminary statement”, pending review of comments. The consensus panel’s
Statement was posted to the Consensus Program Web site:
http:// consensus.nih.gov&emdash, on Wensday, June 12, 2002 (3).
Briefly, the Statement presents
HCV as a member of the Flaviviridae family with 6 genotypes and
more than 50 subtypes. Genotype 1 accounts for 70%- 75% of all HCV
infection in U.S., and is associated with poorer response to antiviral therapy.
Viral heterogeneity and its high propensity of mutation with lack of a vigorous
T-lymphocyte response, promotes chronic infection and also, difficulties in
vaccine development. The virus replicates primarily in hepatocytes without producing
directly damage of cells. The level of viral genome (HCV RNA) is very
variable from person to person and from acute to chronic infection. But, within
the same individual with chronic infection, viral shedding is relatively
stable.
Extensive epidemiological
studies estimated that approximately 4 million of Americans are infected with
the virus, and 2.7 million of them have chronic infection. Majority of them are
persons aged 40 to 59 years. The HCV is yet the most common blood-borne
virus in U.S., although transmission by blood and blood products sharply
declined after application of diagnostic tests. Its prevalence is at least
1.8%, with 35.000 acute infections per year. The most important risk for
acquiring infection is intravenous drug use (IDU), following with blood
transfusion, organ transplantation, high sexual practices, maternal
transmission, etc. It is important from the clinical point of view, that a high
rate of persistent infection are expected likely to produce a fourfold increase
in the number of persons with CLD up to 2015.
An acute hepatitis develops
after infection with the virus mostly without clinical manifestations or
symptoms. It appears 2 to 8 weeks after exposure to the virus with elevation of
ALT. Rarely, it can be severe and fulminant in its course. HCV RNA can
be detected in blood in 1 to 3 weeks after infection, while in that time,
antibodies to HCV (anti-HCV) detected by enzyme immunoassay (EIA)
are present only in 50%-70% of patients. After 3 months of initial exposure,
antibodies can be detected almost in 90% of patients.
Diagnosis of chronic HCV
infection in immune competent persons requires presence of antibodies to the
virus and confirmation by constantly or intermittently positive HCV RNA
in the blood for a period of 6 months.
Recent analysis evaluated the
actual risk of chronically infected persons for progressive disease to
cirrhosis and confirmed that it was less that had been estimated from
retrospective studies. Actual data indicate that cirrhosis develops in less
than 20% of patients within 20 years. It is accepted that not the virus itself,
but many host and behavioral factors have important role in disease
progression, e.g., older age, male gender, alcohol abuse, hepatotoxic
medications, iron overload, immune suppressive state, co-infection with hepatitis
B virus (HBV), etc. Approximately 4.000 deaths were attributed to HCV
infection in U.S., associated more to ESLD than HCC, although the incidence
of HCV-related HCC continues to rise. Unfortunately, liver transplantation
is the only suggested treatment option in advanced liver disease.
Clinically, many extrahepatic manifestations based on immune origin are associated with chronic HCV infection such as: rheumatoid symptoms, keratoconjuctivitis sicca, lichen planus, glomerulonephritis, essential mixed cryoglobulinemia and porphyria tarda.
Currently, various tests are
available for diagnosis and monitoring of HCV infection. Both, enzyme
immunoassay (EIA) and confirmatory recombinant immunoblot assay (RIBA), detect
antibodies against viral structural and non-structural antigens. These tests
are reproducible and inexpensive. EIA is suitable for screening persons at high
risk and is recommended as initial test for patients with clinical liver
disease. With its high sensitivity and specificity, EIA is sufficient to
exclude or confirm HCV infection in immune competent patients. In
patients with immune deficiencies or patients with autoimmune disorders, EIA
can be rarely falsely negative or positive, requiring assays for HCV
RNA. Confirmatory RIBA is useful as a supplemental assay in screening of blood
products.
Persistent HCV infection
positive by EIA is mandatory to confirm in all patients by a qualitative HCV
RNA assay. The U.S. Food and Drug Administration (FDA) approved qualitative HCV
polymerase chain reaction (PCR) test with lower limit of detection of 50 IU/ml.
Yet not approved, an alternative test, transcription-mediated amplification
assay (TMA), is recently developed. If HCV RNA is positive, it confirms
active viral replication and does not require repeating in untreated patients.
As negative detection does not exclude decline or transient absence of viral
replication, this test should be repeated to confirm absence of viral
replication in follow-up patients.
Quantitative determination of
viral load by different assays for HCV RNA level (PCR or branched DNA
signal amplification), provides important information for response to
treatment. Recently developed standard for HCV RNA, currently enables
expressing viral titer in international unit per milliliter (IU/ml), although
between available assays significant variability can exist. Because of that,
using the same specific initial assay is requiring for serial determination.
However, nor viral load, neither serum ALT level are in correlation with
disease severity, progression or histological findings.
Various liver-associated
laboratory tests and imaging methods are only important in assessing liver
function in advanced liver cirrhosis but not hepatic fibrosis and early
cirrhosis. Liver biopsy is a method which actually provide important
information of disease progression based on liver fibrosis. Moreover, it allows
choice of patient for treatment and evaluation of treatment response, estimates
contribution of iron, steatosis and concurrent alcohol liver disease, but is
not specific to be used in discovering HCV etiology.
As HCC can complicate cirrhosis
secondary to HCV in 0%- 3% per year, screening for alpha-fetoprotein
(AFP) level and ultrasound examination every 6 months can help in detecting
ongoing liver cancer. More specific
tumor markers is needed in the future.
Advances in therapy have
occurred in last few years: monotherapy with alpha-interferon (alpha-IFN),
e.g., combination treatment of alpha-IFN plus ribavirin (Rbv), pegylated
interferon (PEG-IFN) or particularly, combination PEG-IFN plus Rbv, all which
resulted in better treatment response than monotherapy with interferon alone.
Genotype of the virus determinated by PCR technique or by serotyping assay is
definitively established as the factor that has influence on treatment, its
duration and response rates. A sustained viral response (SVR) is considered the
best indicator of treatment response, and is defined as the absence of
detectable qualitative HCV RNA in serum by RT-PCR 24 weeks after the end
of treatment. Early viral response (EVR) is defined as minimum 2 log decrease
in viral load during first 12-24 weeks of therapy and is predictive of SVR,
while early treatment response (ETR) relates to absence of viral detection at
the end of therapy.
Clinical trials excluding
patients with decompensated cirrhosis and co-morbid conditions, suggest that
the most effective treatment of naive patients is combination with PEG-IFN and
Rbv. Better treatment response can be achieved in patients with genotypes other
than 1, low baseline viral load and less fibrosis and inflammation. In patients
with genotype 1, treatment with larger doses PEG-IFN and Rbv for 48 weeks and
with genotype 2 and 3, SVR were 42%-46% and 76%-82%, respectively. The effect
of therapy was evidently in correlation with resolution of liver injury,
reduction of fibrosis and low likelihood recurrence of HCV infection.
Chances of development of HCC or improving survival are not still convincing.
Some patients with ETR do not achieve SVR. In that situation, they are defined as relapsers. Moreover, if patients do not achieve EVR, ETR or SVR, they are defined as non-responders. Re-treatment of these patients could be attempted with combination (PEG-IFN plus Rbv) therapy and these trials are currently under investigation. Re-treatment with same therapy they received (monotherapy with IFN, PEG-IFN or IFN plus Rbv), usually gives relapse. With prolongation and higher dose regiment of therapy, these patients can benefit, but it is not yet proven. Particularl problem are patients previously treated with PEG-IFN plus Rbv but with no SVR. Generally, decision to re-treat these groups of patients depends on many factors such as: presence the severity of liver disease with advanced fibrosis or cirrhosis, previous type of therapy and response, difference in the potency of the new therapy and tolerance of previous therapy. However, in some patients who achieved partial response (substantial reduction of HCV RNA 1 to 2 log units or more, but not SVR), treatment may be associated with improved histology.
Side effects of combination
treatment (PEG-IFN plus Rbv) were noted in approximately 20% of patients,
requiring its discontinuation in some of them. Obviously, careful education of
patients and management of side effects are integral parts of treatment.
Carefully considering possible
treatment response and general opinion that all patients with chronic hepatitis
C are potentially candidates for treatment, therapy is primarily recommended
for patients who are in increased risk for progression to cirrhosis. Evaluation
of disease progression is based on measurable viral RNA, histology findings of
portal and bridging necrosis and at least moderate inflammation and necrosis,
and as well, on elevated ALT values. When the risks or benefits are less clear,
decision must be determined on an individual basis or in clinical trials. In
patients ineligible for treatment (IDUs, alcohol abusers, children or older
age, patients with co-morbid medical and neuropsychiatric conditions, advanced
cirrhosis, etc.), patients with acute hepatitis or viral recurrence after liver
transplantation, additional efforts should be done for their best treatment
regiment. These groups of patients are currently in open label therapeutic
studies.
Prevention measures for HCV
transmission must be primarily referred to IDUs, which present 2/3 of all new
infections. Infection after transfusion and transplantation are rare in U.S.
Also, sexual transmission or occupational exposure is estimated as low risk of
infection. Perinatal transmission is low also, but it is higher with
concurrently mother`s high viral load, HIV infection or drug use. It is
generally accepted that breast -feeding does not appear to transmit the virus.
At the end, the most important
areas for future researches are discussed in this Statement. Several
suggestions and finally recommendations are given. Among them are different
fundamental and clinical needs that are necessary to be solved. Developing
adequate culture system for viral growth and investigations of the role of
genetic and immune factors in the pathogenesis of HCV infection are
definitively obligatory. Discovering less toxic therapies and other antiviral
agents, new and precise therapeutic strategies for special groups, resolving
more efficient measures in prevention of infection, standardization of
diagnostic tests, designation of liver biopsy criteria for pre-treatment
outcomes, are also stressed as problems with invaluable importance.
REFERENCES:
1.Management of Hepatitis
C. NIH Consensus Statement 1997, Mar 24-26; 15: 1-41.
2.Booth JCL, O'Grady J and J
Neuberger J. Clinical guidelines on the management of hepatitis C. Gut 2001;
49(Suppl I):1-21.
3- National Institute of
Health. Consensus Development Conference Statement. Management of Hepatitis
C: 2002, June 10-12,2002. Preliminary Draft Statement. June 12, 2002.