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  NIH HCV Consensus Development Conference
June 10-12, 2002
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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 not.
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 website:http://consensus.nih.gov
Many of the subjects for discussion this morning are clearly not well understand and many questions remain needing research.