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By Marion Peters, M.D.

July 9-14, 2000

This TAG report on hepatitis C virus (HCV) is comprehensive and will bring you completely up to date. It runs the gamut of HCV infection with areas of interest for the clinician, allied health care worker and educated patient. It contains information about epidemiology, natural history, diagnosis, pathogenesis and treatment. It is certainly an enormous task to undertake but the authors have been largely very successful. Many of the chapters contain the earliest literature in the area and are current to last month's abstracts. It may be difficult for some of us to read an abstract with the same conviction of fact, as abstracts have not been peer reviewed rigorously, nor is all the data usually available at the time presentation. However, in a fast moving field such as HCV, it allows the reader to know what is "hot" and where the field is heading. We are clearly told what data and trials are peer reviewed, which are confirmed by other investigators and which appear to be "outside the envelope" but interesting none the less. This report is generally superbly referenced and will be of great value to you.

The natural history chapter reminds us that not all patients inexorably deteriorate to end-stage liver disease, liver transplantation or death. It is clear that for the large number of years that we have been following patients, some clinicians see the slowest rates of progression whilst others see HCV as "the evil empire". Patients need to know the facts, not colored by drug company hype, or physician preference and this report provides these facts. Only by knowing that not all patients progress, can individuals patients decide whether treatment for them is now or in the future. The epidemiology, risk factors and modes of transmission are well outlined with perhaps an overabundance of information. You can skim it or dive in for the total immersion, whichever is your preference. This is an excellent chapter with clear tables, explaining the high rate of transmission in IVDU patients and the low sexual transmission rate.

The diagnosis of HCV is often complex with multiple tests and the confusion of liver biopsy evaluation. Once again the authors have used excellent available reviews and references to present readable current state-of-the-art information. The reader must be cautioned that this area is not well regulated and HCV RNA tests are changing rapidly. In addition, when tests are performed in the hospital setting or the community, often a different laboratory is used at different times (the pressures of managed care). In these cases, one cannot extrapolate from one bDNA to another PCR or even from one PCR to another. Therefore, it is critical that patients and clinicians not put excessive weight on small (less than one log) changes. HCV RNA will change little from patient to patient but a lot from test to test.

The area of co-infection with HIV is the youngest in the field and is a moving target. Large cohort studies are lacking and treatment trials are small in number and patient size. This is an area that is receiving a large amount of attention; treatment trials are underway and more hepatologists are becoming involved working side-by-side with infectious disease specialists. The role of HCV in response to HIV therapy is largely unknown. Viral dynamics of HCV is in its infancy, compared to that of HIV. Markers of response to HCV have included genotype, age of acquisition, gender, viral load and amount of fibrosis on liver biopsy. Early studies suggest that these may be superceded by viral dynamics: those with rapid response to interferon therapy are more likely to achieve a sustained response versus those who are slow responders. Only time will tell if this sweeping statement is correct.

The chapters on experimental therapies and current treatment are excellent. Once again we are reminded that at best only half of HCV patients respond to current therapies. But only half may need therapy in the long term. Unfortunately clinicians cannot determine which patients will progress to fibrosis and end-stage liver disease and so most patients are treated especially if they have some scarring without cirrhosis. This is an area that requires intensive research from clinical, epidemiological and immunological aspects. Interferon remains the mainstay of therapy with pegylated IFNs providing exciting new advances. By combining IFN to polyethylene glycol, IFN remains in the circulation longer and thus only weekly dosing is required. This results in ease of treatment as well as an apparent higher response rate, including a surprisingly high rate in cirrhotics (<10% in all studies before pegylated IFN). We may need to look carefully at these studies when they are published but early reports are very encouraging. Side effects are not much different from those of daily dose interferon although there may be some populations in whom dose finding is necessary before putting patients on long- acting weekly IFN. Newer therapies aimed at the virus itself have been slow in coming but are clearly the next line of drugs. In particular, ribozymes may be the next "breakthrough" in this area. Immunomodulators have been generally less promising with the exception of IL-10 as an anti-fibrotic.

I would recommend this report highly to those who want to be fully informed about the area. Those who need full references; those who may not have the time or inclination to gather the oldest and the latest information; and those who need to delve more deeply into particular areas of this fascinating field will find this report useful. Many scientists and clinicians have worked with Michael Marco to address specific areas of their expertise. It is a testament to them and to Michael that he has produced this informative but easily readable document. Not all of the statements in this report have been validated. You will not agree with all of them. But you will be stimulated to learn more and to keep abreast of new developments after reading these all encompassing chapters. You may not concur with all of the TAG policy recommendations but you will be forced to re-evaluate and think about many important issues surrounding HCV. Good luck and enjoy.

Marion Peters is Professor of Medicine and Chief of Hepatology Research, at the University of California, San Francisco.

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