to treat or not..M.D. views

[Guest guest]

Medical Crossfire Vol. 4 No. 2, February 2002

Watchful Waiting and an Individualized Approach

by A. Levine, MD

Dr. Levine is Professor of Medicine in the Division of Gastroenterology at State University of New York Upstate Medical University in Syracuse, New York.

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The Argument for Immediate Antiviral Therapy

by D. Mullen, MD

Dr. Mullen is Professor of Medicine at Case Western Reserve University and Consultant Hepatologist at MetroHealth Medical Center in Cleveland, Ohio.

The debate over how patients with histologically mild chronic hepatitis C should be managed continues. Some physicians advocate immediate empirical therapy; others advocate watchful waiting with periodic liver biopsy. To gain further insight into this debate, Medical Crossfire recently asked experts from both sides to share their thoughts on this issue.

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Watchful Waiting and an Individualized Approach

by A. Levine, MD

Chronic hepatitis C occurs in 85% of patients who are exposed to the hepatitis C virus (HCV-RNA), and 20% of these patients develop cirrhosis within 20 to 50 years.(1) The long-term natural history of this disease is unknown, making accurate counseling of patients and rational decision-making about treatment less than optimal. The decision to treat or not to treat with combination therapy (i.e., interferon or pegylated interferon with ribavirin), an often-punishing regimen, must be made on a patient-by-patient basis. After a year of treatment, sustained viral clearance from the blood occurs in only 30% to 50% of patients with the most common genotype, HCV type 1.

Because there is poor correlation between extent of disease and clinical symptoms or levels of serum alanine aminotransferase,(2) the most reliable prognosticators are the liver histology and duration of infection, if known. Most patients with minimal or mild necroinflammation and no significant fibrosis have a good long-term outlook. If the liver biopsy shows only 0 to 1 fibrosis on Knodell scoring, which indicates that there is either no portal triad fibrosis or none extending into the adjacent liver lobule, and the patient has a known onset of hepatitis C of more than 20 years previous, one can be relatively confident that there will not be disease progression. A decision to defer treatment is recommended in these patients, unless there are special reasons to eliminate the virus, regardless of the histologic findings, such as to meet the desire of an active surgeon or a mother-to-be.1 On the other hand, if the patient has moderate to advanced disease, treatment is usually!

offered.

Progression of fibrosis, the major determinant of serious sequelae in chronic hepatitis C, does not advance in a linear fashion to cirrhosis,(3) and is, therefore, less ominous over the long term than is generally realized. Analyses of retrospective and prospective studies by Seeff and associates (4) in United States veterans, Kenny-Walsh and associates (5) in young Irish women, and Vogt and associates (6) in German children show that only 2% to 5% of such populations progress to cirrhosis in 20 to 25 years of follow-up. I have repeated liver biopsies in Irish women previously exposed to contaminated anti-immunoglobulin D in 1997, (5) and I confirm that in the presence of persistent viremia, 17% of these patients demonstrated spontaneous improvement in their liver inflammatory scores.(7)

Arguments for treating all patients based on cost-effectiveness8 are, in my opinion, unconvincing. Such computer models simulate what would happen to a “virtual†group of patients with mild and moderate hepatitis C during the next 20 years. However, the data I have cited (4-7) suggest that outcomes are excellent for those who do not have significant fibrosis. Most hepatopathologists consider that inflammation per se, which is used in the published modeling studies8 as the sole marker of subsequent progression to cirrhosis, may have little to do with such progression—in contrast to fibrosis. It should also be pointed out that nearly all of these studies8 were sponsored by the manufacturers of the product.

For most of my patients showing no significant fibrosis on liver biopsy and only minimal or mild necroinflammatory activity, I favor waiting for better therapy in the future.(2) I do not believe that the prognosis of these patients is as daunting as often stated, but I do believe that the outlook for more effective therapies is promising.

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Rebuttal

by D. Mullen, MD

Dr. Levine presents a reasonable argument for watchful waiting of patients with chronic hepatitis C that has been deemed mild when liver biopsy reveals no significant fibrosis. Viewed from the broad public health perspective, his opinion has merit. But while Dr. Levine may “favor waiting for better therapy in the future,†in my practice patients make their own decision regarding initiating therapy when mild hepatitis and no fibrosis are found on biopsy. If more severe disease—especially fibrosis—is seen, I gently push for therapy, whereas in mild cases I truly leave the decision in the hands of the patient. I spend a great deal of time educating the patient on the generally benign short-term outcome if no treatment is initiated as well as the potential side effects of the treatment. Nonetheless, the uncertainty about long-term outcome, concerns about being able to tolerate treatment when they are older, symptoms such as fatigue, and the tantalizing possibility of sustained v!

iral

response bring many (but certainly not all) of my patients to decide to commence initial therapy.

I share Dr. Levine’s healthy skepticism for cost-effectiveness analyses based on data generated from computer models and virtual patients. We are also in agreement that fibrosis rather than inflammatory activity is the histological hallmark of most concern in gauging long-term outcome for patients. Indeed, the improvement in inflammation he mentions in his female Irish patients probably represents the spontaneous fluctuation of disease activity we see in many of our chronic hepatitis C patients. If liver biopsies are conducted when transaminases are higher, higher inflammatory activity is often seen. The opposite is also true, although a strong correlation between transaminase levels and inflammatory activity in liver biopsies is not always evident.

There are good data that children in Germany (6) and young women in Ireland (5) and Germany (9) have good outcomes for the first 20 years after infection. Whether this mild progression of disease will continue for the next two to three decades is not known. The study of Seeff and colleagues in males from the United States is of significant interest because of the great length of follow-up; however, only 17 patients in this cohort were at risk for progression to severe liver disease from chronic hepatitis C..(4) Therefore, the issue of long-term prognosis is far from answered. To a significant extent, I believe many of our patients choose to initiate therapy even with very mild findings on biopsy because of this uncertainty about their long-term outcome.

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The Argument for Immediate Antiviral Therapy

by D. Mullen, MD

The argument in favor of immediate antiviral therapy in patients with chronic hepatitis C who demonstrate mild hepatitis on biopsy of the liver is straightforward. We cannot tell patients that their liver disease will not progress over the coming decades because our understanding of the natural history of chronic hepatitis C is incomplete.(3,4,10) Moreover, we cannot predict that patients with marked symptoms like fatigue will spontaneously improve nor that asymptomatic patients will remain so. What we can tell patients, however, is that we now have treatment that is effective in a considerable proportion of affected individuals.

A realistic prediction is that 20% to 40% of patients treated with combination interferon (interferon plus ribavirin)(11,12) or long-acting (pegylated) interferon (13,14) will attain sustained viral response (SVR) after six to 12 months of therapy. Patients achieving SVR—which, by convention, is considered absence of detectable hepatitis C viral RNA by a sensitive assay six months after the completion of therapy—can expect sustained, possibly lifelong cessation of ongoing symptoms and no progression of disease.(15) The benefit of immediate therapy is even more compelling in patients infected with genotype 2 or 3 hepatitis C, in whom SVR rates greater than 50% can be achieved.(13) Given these figures for treatment outcome, many patients opt for immediate therapy despite the considerable side effects of interferon-based treatment.

The alternative to immediate treatment is intermittent monitoring of liver tests, possibly supplemented by a repeat liver biopsy in a number of years to ensure that disease progression does not occur.(8,16) There are some practical problems with this approach. The first is that, for a variety of reasons, patients can be lost to follow-up. (One cause for this treatment dropout, which is somewhat peculiar to the United States, is patients’ subsequent loss of medical insurance.) Whatever the reason, patients may not have follow-up liver biopsies or monitoring of liver tests for years or even decades. If, in the intervening time, marked fibrosis or cirrhosis develops, response to treatment will be diminished.(17)

Concern that viral levels may increase, which also reduces the effectiveness of treatment, has not yet been laid to rest.(18) Certainly the ability of patients to tolerate the side effects of interferon-based treatment is lessened with advancing age and the advent of concurrent diseases, making treatment more hazardous. Taken as a whole, these factors tend to strongly support early commencement of antiviral treatment in patients with chronic hepatitis C, even those with mild disease on liver biopsy. Although I am arguing the point on an all-or-nothing basis, the realities of treatment commencement are far more complex. Viewed from the patient’s perspective, a relatively optimistic prediction for attaining SVR (e.g., genotype 2 or 3 infection, low viral levels) will often lead to a decision to commence treatment. In contrast, patients given lower predictions for SVR will often opt to postpone treatment until better outcomes or less-toxic therapy are available. It is perhaps s!

urprising

that in the county hospital in which I work, with its underinsured population, economic issues rarely affect the decision to commence antiviral treatment. Effective indigent-care support programs have been in place for some time.

The very detailed analysis reported by Wong and Koff supports the decision to immediately commence antiviral therapy in hepatitis C patients with mild hepatitis on liver biopsy.(8) These authors conclude that immediate combination therapy, in comparison with watchful waiting, will reduce future risk for cirrhosis, prolong life, and—most importantly, from the public health perspective—be cost effective.

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Rebuttal

by A. Levine, MD

The “marked symptoms like fatigue†to which Dr. Mullen refers are rarely (in fewer than 5% of cases) associated with mild hepatitis, but they may be present in more advanced liver disease. Rather, fatigue occurs in most patients when they are told by their physicians that the disease they have is often fatal. I have found that fear, fatigue, and subsequent depression are iatrogenic symptoms that invariably abate when I can identify a good prognosis with the known onset of disease two or more decades earlier and describe the biopsy report showing no significant fibrosis.

I would also disagree with Dr. Mullen’s statement that “understanding of the natural history of chronic hepatitis C is incomplete.†We know a considerable amount about the natural history of mild chronic hepatitis C.(3,19,20) Furthermore, I do not believe, as Dr. Mullen does, “that viral levels may increase†over time. Rather, host immunity alone influences the disease process.(21)

I concur with my colleague that patients with genotypes 2 and 3 should receive immediate treatment because fewer than 85% achieve sustained viral clearance after six months of therapy. Unfortunately, we do not have such “effective†therapy for genotype 1 patients. I also agree that some patients may be lost to follow-up. However, those without significant fibrosis do not need frequent tests of liver enzymes and biopsies, as presumed by the cost-effectiveness analysis of Wong and Koff.(8) If the follow-up biopsies for mild hepatitis were performed every 10 years instead of every three to five years, which is reasonable in this cohort, the cost-effectiveness argument is negated. Exceptions to this plan might be those patients who have concomitant heavy alcohol intake.

As we gain more experience, we should keep an open mind about the value of present and future therapy. Surprisingly, my colleagues and I (22-24) find that necroinflammation and fibrosis are reduced in nonresponders after interferon therapy, despite persistent viremia.

References

1.  Levine RA. Treating histologically mild chronic hepatitis C: Mono-therapy, combination therapy, or tincture of time? Ann Intern Med. 1998;129:323-326.

2.  Stanley AJ, Haydon GH, Piris J, et al. Assessment of liver histology in patients with hepatitis C and normal transaminase levels. Eur J Gastroenterol Hepatol. 1996;8:869-872.

3.  Poynard T, Bedossa P, Opolon P, for the OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:825-832.

4.  Seeff LB, RN, Rabkin CS, et al. Forty-five year follow-up of hepatitis C virus infection among healthy young adults—a retrospective cohort study. Ann Intern Med. 2000;132:105-111.

5.  Kenny-Walsh E, for the Irish Hepatology Research Group. Clinical outcomes after hepatitis infection from contaminated antiglobulin. N Engl J Med. 1999;340:1228-1233

6.  Vogt M, Lang T, Frosner G, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med. 1999;341:866-870.

7.  Levine RA, Goulding C, O’Keane JC, et al. Spontaneous reduction in histological activity index in untreated, noncirrhotic, and persistently viremic Irish women with chronic hepatitis C. Gastroenterology. 2000;118:A944.

8.  Wong JD, Koff RF. Watching and waiting with periodic liver biopsy versus immediate empirical therapy for histologically mild chronic hepatitis C: a cost-effectiveness analysis. Ann Intern Med. 2000;133:665-675.

9.  Wiese M, Berr F, Lafrenz M, et al. Low frequency of cirrhosis in a hepatitis C (genotype 1b) single-source outbreak in Germany. A 10-year multicenter study. Hepatology. 2000;32:91-96.

10. Tong MJ, El-Farra NS, Reikers AR, Co RL. Clinical outcomes after trans-fusion-associated hepatitis C. N Engl J Med. 1995;332:1463-1466.

11. McHutchison JG, Gordon SC, Schiff ER et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med. 1998;339:1485-1492.

12. Poynard T, Marcellin P, Lee ,S et al. Randomized trial of interferon alfa-2b plus ribavirin for 48 weeks or 24 weeks versus interferon alfa-2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet. 1998;352:1426-1432.

13. Zeuzem S, Victor-Feinman S, Rasenaur J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med. 2000;343:1666-1672.

14.  Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med. 2000;343:1673-1680.

15.  Reichard O, Glaumann H, Fryden A, et al. Long-term follow-up of chronic hepatitis C patients with sustained virological response to alfa interferon. J Hepatol. 1999;30:783-787.

16.   GR, Goldin RD, Main J, et al. Management of chronic hepatitis C: clinical audit of biopsy-based management. BMJ. 1997;315:453-458.

17.   Everson GT, Jensen DM, Craig JR, et al. Efficacy of interferon treatment for patients with chronic hepatitis C: comparison of response in cirrhotics, fibrotics, and non-fibrotics. Hepatology. 1999;30:271-276.

18.   Yuki N, Hayashi N, Kasahara, A et al. Pretreatment viral load and response to prolonged interferon-alfa course for chronic hepatitis C. J Hepatol. 1995;22:457-463.

19.  Seeff LB, Hollinger FB, Alter HJ et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart and Lung and Blood Institute collaborative study. Hepatology. 2000;33:455-463.

20.   Levine RA, on SO, Murry F, et al. Fibrosis (F) and histological activity index (HAI) improve spontaneously in untreated, noncirrhotic, persistently viremic Irish women with chronic hepatitis C. Hepatology. In press, 2001.

21.  Rehermann B. Interaction between the hepatitis C virus and the immune system. Semin Liver Dis. 2000;20:127-142.

22.  Arif A, Levine RA, on SO, et al. Effect of interferon alpha-2b and ribavirin therapy on virological and histological outcomes in non-cirrhotic patients with chronic hepatitis C. Gastroenterology. 2001;120:A382.

23.  Shiffman ML, Hofmann CM, EB, et al. Relationship between biochemical, virological, and histological response during interferon treatment of chronic hepatitis C. Hepatology. 1997;26:780-785.

24.   Sobesky R, Mathurin P, Charlotte F, et al. Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C; results of a US multicenter study. Gastroenterology. 1999;116:378-386.

 

Later,

Liz

[Guest guest]

and 20% of these patients develop

cirrhosis within 20 to 50 years.(1)

Liz, very good article.

This is the first time I have read where HCV was documented that the progression to cirrhosis can occur in 20 to 50 years.

How do they know in 50 years !!!!!!!!

How long has the medical profession know about HCV and tracked it's progression in patients ???

Probably a lot longer than they or the government wants to admit !!!!!!

To me the most significant issue of HCV is:

The long-term natural history of this disease is unknown, making accurate counseling of patients and rational decision-making about treatment less than optimal.

It's a wait and see or trial and error approach to our HCV and medical care because not enough scientific evidence is known or officially acknowledged about this chronic worldwide epidemic.

Physician's have a "less than optimal" knowledge of HCV and we have even less to make sound educated choices along with our treating Physician's.

This worries me a great deal because I want proven scientific evidence to base my health care decisions on.

I feel medical professionals are now using me as their long term study case and I'm tired of being the guinea pig.

This must be frustrating for all involved.

I Pray daily for a scientific breakthrough and better medical care options for us ALL.

Take Care and God Bless.

Deb