Outcomes and Costs of Care in Hepatitis C: Combination Therapy Scores Again

[Guest guest]

American Journal of Gastroenterology

Editorial

June 2000

Volume 95, Number 6

Pages 1392-1393

Outcomes and Costs of Care in Hepatitis C: Combination Therapy Scores Again

S. Koff, M.D.a

Prospective, multicenter, pharmaceutical company-sponsored, randomized

clinical trials in the treatment of chronic hepatitis C have shown that

clearance of hepatitis C virus (HCV) is more likely in those treated with

-interferons than in untreated patients. Sustained treatment-induced

virological clearance is highly correlated with biochemical improvement,

continued absence of circulating virus, improved histology, improvements in

health-related quality of life, and most probably, a reduced risk of

premature death from end-stage liver disease or cirrhosis-related

hepatocellular carcinoma. The combination of interferon -2b plus ribavirin

is even more likely to result in sustained virological clearance than is

treatment with interferon -2b alone and has become the treatment of choice

in previously untreated patients. Despite these observations, many

questions remain unanswered about the natural history of the disease, and

our ability to identify those patients most likely to develop advanced

disease remains limited. Why so many patients do not have a virological

response continues to be uncertain, and the impact of treatment on the

course of the disease in virological nonresponders is still enigmatic. It

should be recalled that hepatitis C is not invariably progressive, that the

costs of treatment are high, and that long-term prospective studies of

treated patients have been few in number. As a consequence, management

strategies that are most favorable in the long term for the patient, the

healthcare payer, and society require identification. Treatment strategies

have become the subject of a large and growing number of " armchair " studies

attempting to define better the value of treatment of chronic hepatitis C

by developing decision analysis models of outcomes, identifying the costs

of treatment (as well as the costs of nontreatment) and using these in

Markov computer simulations of hypothetical cohorts of hepatitis C patients

to assess cost-effectiveness. These have been undertaken, in large part,

because the disease is now recognized as common, the potential clinical

outcomes are serious for some patients, and both treatment and failure to

treat are potentially expensive. In the 10 years since the first economic

evaluation was published (1), the models have become more sophisticated,

and more data from clinical trials and follow-up of treated patients have

been incorporated into the decision analyses. With few exceptions,

published analyses undertaken in the United States, specifically designed

to relate the effectiveness of treatment of chronic hepatitis C to the

costs of care, have suggested that treatment is indeed cost-effective but

not cost-saving when compared to no treatment. In addition, despite the

fact that combination therapy is more costly than interferon monotherapy,

Wong et al. (2) now report in this issue that combination therapy is more

cost-effective than interferon monotherapy. This study, as well as one

published recently by Younossi et al. (3) used published data about

virological response rates from the large registration trials reported in

late 1998. Despite differences in the models employed, both studies

indicate that the most cost-effective strategy for previously untreated

patients is the use of combination therapy. Adjustment of treatment

duration based on genotype and possibly other favorable response features

seems to improve cost-effectiveness. These observations support the not

unanticipated premise that 48 wk of combination therapy is more

cost-effective than 24 wk in patients with genotype 1, the predominant

genotype in the US. However, in patients with non-genotype 1, in those with

low viral loads, in younger patients, and in women, as well as in those

with mild histology, shorter duration combination therapy makes economic

and clinical sense. For patients who have genotypes 2 or 3 but in whom

several less favorable response factors are present, 48 wk of therapy may

be appropriate. A number of other economic analyses of management with

combination therapy of chronic hepatitis C deserve mentioning, although

most have been published as abstracts rather than full-length journal

articles (4). These studies suggest that retreatment with combination

therapy of the relapsed patient may be a cost-effective strategy, and that

even retreatment of the nonresponding patient with interferon monotherapy,

despite its relatively low success rate, may fall within an acceptable

cost-effectiveness range. Early combination treatment for the previously

untreated patient with histologically mild disease may be more

cost-effective than so-called " watchful waiting " with repeated biopsy and

the treatment decision based on the finding of histological progression

(5). Elsewhere it has been reported that empiric interferon monotherapy,

without expensive virological studies and liver biopsy, is a reasonable

strategy in the previously untreated patient (6). Based on the current

evidence of the cost-effectiveness and improved response rate of the

combination regimen, it seems very likely that combination therapy, with

duration of therapy determined by genotyping alone and without pretreatment

liver biopsy or HCV RNA quantitation, is also likely to be a cost-effective

approach. Some of us, persuaded by this argument, are now reserving liver

biopsy for those patients who fail to respond to treatment. Of course, for

many hepatologists, the concept of treating without a liver biopsy is an

anathema; some traditions die hard. A number of questions are unresolved.

These include determining the cost-effectiveness of combination treatment

for the patient with chronic hepatitis C in whom persistently normal serum

ALT levels are found pretreatment. Even more importantly, the clinical and

economic benefits of monotherapy with the pegylated interferons, which are

likely to induce sustained response rates comparable to or slightly better

than that associated with today's combination therapy, even in patients

with bridging fibrosis or cirrhosis, will be the next important topic for

economic evaluation. Pegylated interferons are likely to be approved for

the treatment of chronic hepatitis C quite soon, and it seems likely that

ongoing trials will demonstrate an enhanced sustained virological response

induced by the combination of pegylated interferon with ribavirin or with

other adjunctive antiviral therapy. Assuming an even higher response rate

and reasonable drug costs, these regimens will supplant today's combination

therapy and should prove to be of even greater economic benefit. aDivision

of Digestive Diseases and Nutrition, Department of Medicine, University of

Massachusetts Medical School, Worcester, Massachusetts

References

1. de Ancos JL, JA, Dusheiko GM. An economic evaluation of

the costs of alpha-interferon treatment of chronic active hepatitis due to

hepatitis B or C virus. J Hepatol 1990;11:511-8. 2. Wong JB, Poynard T,

Ling M-H, et al. Cost-effectiveness of 24 or 48 weeks of interferon -2b

alone or with ribavirin as initial treatment of chronic hepatitis C. Am J

Gastroenterol 2000;95:1524-30. 3. Younossi ZM, Singer ME, McHutchison JG,

et al. Cost effectiveness of interferon alfa-2b combined with ribavirin for

the treatment of chronic hepatitis C. Hepatology 1999;30:1318-24. 4. Koff

RS. Cost-effectiveness of combined interferon and ribavirin versus

interferon alone. Clin Liver Dis 1999;3:827-41. 5. Wong JB, Koff RS. The

risks and benefits of biopsy managed care of histologically mild chronic

hepatitis C versus initial combination therapy. Hepatology 1999;30:480A. 6.

Wong JB, WG, Koff RS, et al. Pretreatment evaluation of chronic

hepatitis C. Risks, benefits, and costs. JAMA 1998;280:2088-93.

Reprint requests and correspondence: S. Koff, M.D., Division of

Digestive Diseases and Nutrition, UMass Memorial Medical Center, Shaw

Building, SH-143, 55 Lake Avenue, North, Worcester, MA 01655. Received Feb.

19, 2000; accepted Feb. 23, 2000.

Copyright ©2000 the American College of Gastroenterology

------------------------------

[Guest guest]

American Journal of Gastroenterology

Editorial

June 2000

Volume 95, Number 6

Pages 1392-1393

Outcomes and Costs of Care in Hepatitis C: Combination Therapy Scores Again

S. Koff, M.D.a

Prospective, multicenter, pharmaceutical company-sponsored, randomized

clinical trials in the treatment of chronic hepatitis C have shown that

clearance of hepatitis C virus (HCV) is more likely in those treated with

-interferons than in untreated patients. Sustained treatment-induced

virological clearance is highly correlated with biochemical improvement,

continued absence of circulating virus, improved histology, improvements in

health-related quality of life, and most probably, a reduced risk of

premature death from end-stage liver disease or cirrhosis-related

hepatocellular carcinoma. The combination of interferon -2b plus ribavirin

is even more likely to result in sustained virological clearance than is

treatment with interferon -2b alone and has become the treatment of choice

in previously untreated patients. Despite these observations, many

questions remain unanswered about the natural history of the disease, and

our ability to identify those patients most likely to develop advanced

disease remains limited. Why so many patients do not have a virological

response continues to be uncertain, and the impact of treatment on the

course of the disease in virological nonresponders is still enigmatic. It

should be recalled that hepatitis C is not invariably progressive, that the

costs of treatment are high, and that long-term prospective studies of

treated patients have been few in number. As a consequence, management

strategies that are most favorable in the long term for the patient, the

healthcare payer, and society require identification. Treatment strategies

have become the subject of a large and growing number of " armchair " studies

attempting to define better the value of treatment of chronic hepatitis C

by developing decision analysis models of outcomes, identifying the costs

of treatment (as well as the costs of nontreatment) and using these in

Markov computer simulations of hypothetical cohorts of hepatitis C patients

to assess cost-effectiveness. These have been undertaken, in large part,

because the disease is now recognized as common, the potential clinical

outcomes are serious for some patients, and both treatment and failure to

treat are potentially expensive. In the 10 years since the first economic

evaluation was published (1), the models have become more sophisticated,

and more data from clinical trials and follow-up of treated patients have

been incorporated into the decision analyses. With few exceptions,

published analyses undertaken in the United States, specifically designed

to relate the effectiveness of treatment of chronic hepatitis C to the

costs of care, have suggested that treatment is indeed cost-effective but

not cost-saving when compared to no treatment. In addition, despite the

fact that combination therapy is more costly than interferon monotherapy,

Wong et al. (2) now report in this issue that combination therapy is more

cost-effective than interferon monotherapy. This study, as well as one

published recently by Younossi et al. (3) used published data about

virological response rates from the large registration trials reported in

late 1998. Despite differences in the models employed, both studies

indicate that the most cost-effective strategy for previously untreated

patients is the use of combination therapy. Adjustment of treatment

duration based on genotype and possibly other favorable response features

seems to improve cost-effectiveness. These observations support the not

unanticipated premise that 48 wk of combination therapy is more

cost-effective than 24 wk in patients with genotype 1, the predominant

genotype in the US. However, in patients with non-genotype 1, in those with

low viral loads, in younger patients, and in women, as well as in those

with mild histology, shorter duration combination therapy makes economic

and clinical sense. For patients who have genotypes 2 or 3 but in whom

several less favorable response factors are present, 48 wk of therapy may

be appropriate. A number of other economic analyses of management with

combination therapy of chronic hepatitis C deserve mentioning, although

most have been published as abstracts rather than full-length journal

articles (4). These studies suggest that retreatment with combination

therapy of the relapsed patient may be a cost-effective strategy, and that

even retreatment of the nonresponding patient with interferon monotherapy,

despite its relatively low success rate, may fall within an acceptable

cost-effectiveness range. Early combination treatment for the previously

untreated patient with histologically mild disease may be more

cost-effective than so-called " watchful waiting " with repeated biopsy and

the treatment decision based on the finding of histological progression

(5). Elsewhere it has been reported that empiric interferon monotherapy,

without expensive virological studies and liver biopsy, is a reasonable

strategy in the previously untreated patient (6). Based on the current

evidence of the cost-effectiveness and improved response rate of the

combination regimen, it seems very likely that combination therapy, with

duration of therapy determined by genotyping alone and without pretreatment

liver biopsy or HCV RNA quantitation, is also likely to be a cost-effective

approach. Some of us, persuaded by this argument, are now reserving liver

biopsy for those patients who fail to respond to treatment. Of course, for

many hepatologists, the concept of treating without a liver biopsy is an

anathema; some traditions die hard. A number of questions are unresolved.

These include determining the cost-effectiveness of combination treatment

for the patient with chronic hepatitis C in whom persistently normal serum

ALT levels are found pretreatment. Even more importantly, the clinical and

economic benefits of monotherapy with the pegylated interferons, which are

likely to induce sustained response rates comparable to or slightly better

than that associated with today's combination therapy, even in patients

with bridging fibrosis or cirrhosis, will be the next important topic for

economic evaluation. Pegylated interferons are likely to be approved for

the treatment of chronic hepatitis C quite soon, and it seems likely that

ongoing trials will demonstrate an enhanced sustained virological response

induced by the combination of pegylated interferon with ribavirin or with

other adjunctive antiviral therapy. Assuming an even higher response rate

and reasonable drug costs, these regimens will supplant today's combination

therapy and should prove to be of even greater economic benefit. aDivision

of Digestive Diseases and Nutrition, Department of Medicine, University of

Massachusetts Medical School, Worcester, Massachusetts

References

1. de Ancos JL, JA, Dusheiko GM. An economic evaluation of

the costs of alpha-interferon treatment of chronic active hepatitis due to

hepatitis B or C virus. J Hepatol 1990;11:511-8. 2. Wong JB, Poynard T,

Ling M-H, et al. Cost-effectiveness of 24 or 48 weeks of interferon -2b

alone or with ribavirin as initial treatment of chronic hepatitis C. Am J

Gastroenterol 2000;95:1524-30. 3. Younossi ZM, Singer ME, McHutchison JG,

et al. Cost effectiveness of interferon alfa-2b combined with ribavirin for

the treatment of chronic hepatitis C. Hepatology 1999;30:1318-24. 4. Koff

RS. Cost-effectiveness of combined interferon and ribavirin versus

interferon alone. Clin Liver Dis 1999;3:827-41. 5. Wong JB, Koff RS. The

risks and benefits of biopsy managed care of histologically mild chronic

hepatitis C versus initial combination therapy. Hepatology 1999;30:480A. 6.

Wong JB, WG, Koff RS, et al. Pretreatment evaluation of chronic

hepatitis C. Risks, benefits, and costs. JAMA 1998;280:2088-93.

Reprint requests and correspondence: S. Koff, M.D., Division of

Digestive Diseases and Nutrition, UMass Memorial Medical Center, Shaw

Building, SH-143, 55 Lake Avenue, North, Worcester, MA 01655. Received Feb.

19, 2000; accepted Feb. 23, 2000.

Copyright ©2000 the American College of Gastroenterology

------------------------------