Report 1, Morning Session, June 10
Reported by Jules Levin
I'm reporting from the NIH Consensus Development Conference in Bethesda , MD
taking place at the NIH Natcher Conference Center. After welcoming comments,
James Boyer, MD, is making opening comments. This is a public meeting where
professional experts will review the currently available data and evidence.
At the conclusion of the meeting the Panel will make recommendations
including research ideas. A few of the panelists are HIV specialists
uncluding Judith Feinberg, MD an ACTG researcher at the University of
Cincinnati. Also on the panel is Steven Spector, MD, an HIV researcher at
UCSD. A consensus panel was held 5 years ago. This Panel was convened to
discuss new information and make new recommendations. Presentations will take
place today and Tuesday.
The panel will discuss and make recommendations on such subjects as who
should be treated, what are the recommended treatment approaches.
Presentations will include epidemiology, the role of biopsy, therapy, special
situations, side effects, special patient groups. The final document of
recommendations will be made available. Oftentimes people use these
recommendations in making treatment related decisions and in discussing
possible transmission routes.
Individual presentations will be 15 minutes in length. Discussion and Q&A
take place after several speakers on a particular topic.
Jay Hoofnagle, MD, from the NIH, opened today's talk by disicussing the high
replication rates of HCV, high mutation rates, and high heterogenocity of
this virus. About 75% of Americans are infected with Genotype 1. About 13%
with Genotype 2. There is new vaccine because we don't have cell cultures and
poor animal models in which to study the virus. After acute HCV infection ALT
are ususually elevated 1-5 fold in chronically infected patients. But
sometimes ALT can be normal. Chronicity rate has been reported to be 74% in
the USA. Rates can vary and reported rates may not be completely accurate. In
children & young women it can be 55%. In African-Americans the rate can be
95%. Hoofnagle suggested the chronicity rate may be lower than has been
reported. It's suggested that patients able to clear HCV have better CD4/CD8
immune responses (stronger & broader responses).
Fatigue and neuropathy can be experienced by persons with chronic HCV.
W Ray Kim, MD, from the Division of GI & Hepatology at the Mayo Clinic was
the next to speak. 3.9 million Americans have Anti-HCV. 2.7 million Americans
have ongoing infection. 71% have genotype 1 and 22% have genotype 2/3.
Overall prevalence is 1.8% of Americans. HCV is the most prevalent
blood-borne disease in the USA. 18% in an outpatient VA clinic had HCV in a
study of 1000 persons. Among homeless vets the rate in a study was 40%. 39%
had HCV in a prison study in California, and it was 55% among young women.
Many patients are not diagnosed because they don't enter the healthcare
system. Prevalence appears to be on the decline since the mid 90's but since
many people have had HCV for years people will be increasingly getting sick
as their disease progresses. Decline in prevalence could be due to less IVDU
or safer IVDU. There has been a dramatic increase in hospitaliztions due to
HCV. This is accompanied by increasing hospitaliztion and direct health care
costs has increased and it was estimated to be 1.8 billion dollars in 1998.
The majority of people who die of HCV is 44-54 years of age. The lost to
wages is significant. Direct and indirect costs are great & increasing. There
is a remarkable increase in impact of HCV. The upslope in the impact should
increase for another 10 years.
Leonard Seef, MD, from the NIH, was the next speaker & discussed the Natural
History of HCV. Evolution of the disease often occurs without symptoms. Seef
reported that the percentages of the evolution to cirrhosis seem to be
variable among studies and oftentimes appears to be relatively low; and Seef
reported it can vary by the way in which infection occurred. Host-related
factors play a role in who progresses and who doesn't. Seef and others
suggested rates of 11-15% can progress to dying of liver disease or progress
to cirrhosis in HCV monoinfection. Others have suggested slightly higher
rates of progression, such as 20% or perhaps higher in certain circumstances
depending on risk factors. Drinking alcohol is an important factor in leading
to progression of HCV. Seef said there are a lot of unanswered questions
about who progresses and the reasons for progression. Perhaps race, smoking,
and environmental toxins are factors.
Patrick Marcellin, MD, was next speaker and discussed fibrosis. He said the
Ishak system can be more sensitive. He said sampling error can occur.
Cirrhosis can be missed or underestimated. In 20% or more you may
underestimate disease. Factors associated include age, alcohol, steatosis,
immune deficiency, gender while viral load & genotype are not. He suggested
many additional factors are not known or well understood. Progression to
cirrhosis varies from one person to another and depends on their risk
factors. Progression is fibrosis is probably not linear. Source of infection
may not be associated with fibrosis. Progression may accelerate as person
gets older. Progression can take 30-40 years. Patients infected after 50
years of age can experience faster rate of acceleration. Marcellin suggests
that a person infected at young age can experience slow progression, but
acceleration appears to occur at certain age which he suggests may be after
age 50. HIV probably affects appears to increase progression.
There are no good predictors of progression of fibrosis. Bur Serum ALT,
inflammation and stage of fibrosis can help. He said normal ALT indicates
good prognosis. (editorial note: However, many would disagree with this.
Several studies have suggested you could have normal ALT and moderate disease
or worse). In most patients, progression is slow. Alcohol & weight and
metabolic disorders are important factors in progression. Liver biopsy
remains best method to assess progression. A liver biopsy ought to be done
3-5 years after the first biopsy. There is not much data on this but appears
to be generally accepted practice. More research is needed on this question,
how often to perform biopsy. In general risk for severe progression from
first to second biopsy is low. Evidence suggests if person is antibody
positive but PCR negative they may not be infectious.
Quality of life is lower in HCV-infection, but knowing you have HCV may
affect your perception of quality of life.
Chronicity rate in black men has been greater than in black women in limited
studies. Studies that have been conducted suggest whites experience quicker
progression but African-Americans have lower rates of cirrhosis. There is
much controversy about this and disagreement about whether this is true or
Anne Spaulding and Jackie Walker (ACLU) raised the questions surrounding HCV
in prisons. Walker recommended consideration in finalizing recommendations.
Spaulding suggested the overall prevalence rates may be underestimated due to
an underestimated rate in prisons.
Anna Lok, MD, from the Division of Gastroenterology at the University of
Michigan, talked about non-invasive monitoring of HCV. She started by saying
there are few answers to this question although there are possibilities.
There is a need for a reliable non-invasive way to assess liver disease.
Progressive decline in platelet count may reflect disease progression. Using
several variables including AST/ALT ratio, platelet count and others are not
completely reliable. She reviewed a number of lab markers (blood tests)
including quantitative tests of liver function that may have correlation with
disease progression. She said radiologic imaging (ultrasound, MRI, etc) are
not reliable in predicting or diagnosing cirrhosis. She said we need more
research to identify a non-invasive way to diagnose liver disease.
Jean-Michel Pawlotsky, MD, from France, talked about HCV markers: genotype,
HCV RNA, antibody testing. When severe immunosuppression is present the
antibody test may not be reliable. He reviewed the various HCV RNA viral load
tests, and the use of international units rather than copies/ml. There are
sensitive tests able to test if viral load is below 5-10 IU/ml: TMA, LabCorp.
He talked about study results suggesting that measuring viral load results at
week 12 after starting HCV therapy may predict well who will or will not
achieve an antiviral response (2 log viral load reduction). Based on these
preliminary study results, Pawlotsky suggested that therapy can be stopped in
certain circumstances if patient has inadequate viral response at week 12.
Observers in the audience commented during Q&A that these study results are
preliminary and based on retrospective analysis. Pawlotsky and the commenters
agreed that follow-up prospective studies need to be done to confirm these
preliminary observations. He also referred to the study of pegylated
inteferon 2a at the EASL conference which showed that 24 weeks therapy with
Pegasys/RBV provided equal response rates to patients who received 48 weeks
therapy in patients with non-1 genotype.
Hesham El-Serag, MD, from the Houston VA Medical Center discussed increased
rates in hepatocellular carcinoma (liver cancers). It has doubled in the last
decades across all ethnic groups. HCC usually occurs in cirrhosis and
advanced fibrosis. The increased rates may be due to the longer periods of
times of people having HCV. HCV accounts for a high proportion of the
increases. HBV does not appear to contribute as much. Diabetes can be a risk
factor for HCC. Heavy alcohol consumption can also contribute to HCC. Based
on a model HCC may significantly increase the number of patients with HCC and
the number with HCC may double in the next 10 years to 5000. In Q&A El-Serag
said he does not think genotype 1 is related to HCC. Although most studies
are retrospective interferon appears to slow progression. Since these studies
are retrospective and have other limitations they are not adequate to
reliably predict if interferon will slow progression. He referred to the
ongoing HALT-C study where we can expect to see more reliably if interferon
slows disease. In HALT-C patients with advanced disease are receiving
pegylated interferon 2a (Pegasys) at half dose (90 mcg/once per week), but
results are not expected for perhaps 4 years. (editorial note: ACTG
researchers are trying to plan studies to try to obtain reliable information
on this question in less time than 4 years).
Kelly Gebo, MD, from the Division of Infectious Diseases at Johns Hopkins
University School of Medicine, discussed screening for HCC. She reviewed the
various ways to test for screening for HCV. I will not get into her talk here.
After lunchbreak the discussion should get more interesting. Prevention,
sexual transmission, maternal-fetal transmission, therapy for HCV, optimal
therapy for HCV, retreatment of HCV, and a review by Mark Sulkowski will take
place. As well, the role of the biopsy and monitoring HCV RNA during therapy
will be discussed. Tomorrow morning therapy in special populations and
special patient situations will be discussed, including HIV, cirrhosis, acute
HCV, patients with normal ALT, children with HCV, IVDUs, alcohol, and other
special populations. As well, side effects of therapy and management of side
effects, and future therapies will be discussed. The meeting will adjourn at
12:30 tomorrow. Panelists will convene and the following day the consensus
statement will be presented. The statement will be made available on the NIH
Many of the subjects for discussion this morning are clearly not well
understand and many questions remain needing research.