Abstracts on Articles HCV-Marty

May 12, 2000

MEDLINE Abstracts

Ribavirin and Interferon for Hepatitis

C Virus Infection

What's new concerning the new combination regimen of ribavirin

and interferon alfa-2b for the treatment of chronic hepatitis C

infection? Find out in this easy-to-navigate collection of recent

MEDLINE abstracts compiled by the editors at Medscape

Infectious Diseases. [Medscape, 2000. ) 2000 Medscape, Inc.]

Clinical Trials

Is an " A la carte " Combination Interferon

alfa-2b Plus Ribavirin Regimen Possible for the

First Line Treatment in Patients With Chronic

Hepatitis C? The ALGOVIRC Project Group

Poynard T, McHutchison J, Goodman Z, Ling MH,

Albrecht J

Hepatology 2000 Jan;31(1):211-8

Randomized trials have shown the enhancement of efficacy with

interferon alfa-2b and ribavirin (IFN-R) in comparison with

interferon monotherapy (IFN) as first line treatment of chronic

hepatitis C. Further definition of response based on disease,

patient, and treatment characteristics is needed to determine the

degree of benefit for the various patient subgroups. The aim of

this study was to answer this question by analyzing the data from

1,744 naive patients included in trials that compared 24- or

48-week IFN-R treatment. Response factors were identified by

logistic regression and receiver operating characteristics curves.

Five independent characteristics were associated with a sustained

loss of hepatitis C virus (HCV) RNA (<100 copies/mL) 24

weeks after the end of treatment: genotype 2 or 3, baseline viral

load less than 3.5 million copies/mL, no or portal fibrosis, female

gender, and age younger than 40 years. There was a significant

advantage for IFN-R in comparison with IFN alone whatever the

combination of factors. The most efficient strategy is to treat all

patients for 24 weeks. If the 24-week polymerase chain reaction

(PCR) is positive, treatment can be stopped. If the 24-week

PCR is negative, patients with fewer than 4 favorable factors

should be treated for an additional 24 weeks. Conclusion: The

combination of IFN-R is better as first line treatment than IFN

monotherapy. For patients who are PCR negative after 24

weeks of treatment, genotyping and baseline viral load, fibrosis

stage, gender, and age are useful predictive factors in determining

whether to continue an additional 24 weeks of treatment.

Combination Treatment of Interferon alpha-2b

and Ribavirin in Comparison to Interferon

Monotherapy in Treatment of Chronic Hepatitis

C Genotype 4 Patients

el-Zayadi A, Selim O, Haddad S, Simmonds P, Hamdy H,

Badran HM, Shawky S

Ital J Gastroenterol Hepatol 1999 Aug-Sep;31(6):472-5

Background and Aim: Treatment of chronic hepatitis C

patients, infected with genotype 4 with interferon-alpha yielded a

limited response. Our aim was to compare the efficacy of

interferon-alpha alone and in combination with ribavirin in chronic

hepatitis C patients infected with genotype 4.

Patients: Fifty-two chronic hepatitis C patients (all males)

infected with genotype 4, who had not received interferon, were

randomized into 2 equal comparable groups.

Methods: Group I received interferon alpha-2b " Schering

Plough " 3 MU, tiw combined with ribavirin (1000 mg/day).

Group II received interferon alpha-2b alone in the same dose.

Both groups were evaluated monthly, at the end of 24 weeks of

treatment and 24 weeks later. Two patients were dropped from

group I and one patient from group II.

Results: Biochemical response: at the end of treatment, a return

to normal of ALT was obtained in 16/24 (66.7%) patients on

combination therapy vs 8/25 (32%) patients on interferon alone

(p = 0.0152). At the end of follow-up, a sustained response was

achieved in 10/24 (41.7%) patients on combination therapy vs

4/25 (16%) patients on interferon (p = 0.0468). Virologic

response: at the end of treatment, the rates of virological

response were higher in the patients on combination therapy 9/24

(37.5%) than in those on interferon 4/25 (16%) (p = 0.0380). At

the end of follow-up, loss of serum HCV RNA was reported in

5/24 (20.8%) patients on combination therapy vs 2/25 (8%)

patients on interferon (p = 0.1916). Histologic response: mild

histologic improvement was shown by a decrease in the

inflammatory score, which was highest in patients in the

combination group.

Conclusions: In chronic hepatitis C patients infected with

genotype 4, combination therapy with interferon-alpha and

ribavirin was more effective than treatment with interferon

monotherapy. At the end of the follow-up, about 50% of patients

in both groups were still viraemic though their ALT remained

normal.

Long-term Re-treatment With Interferon and

Ribavirin Combination Therapy in Patients With

Chronic Hepatitis C Who Are Non-responders to

Interferon Alone: A Preliminary Study

Vega P, Castro A, Hermida M, Calvo S, Pedreira J

Scand J Infect Dis 1999;31(4):359-61

We evaluated the efficacy and tolerance of ribavirin and

IFN-alpha combination therapy over 12 months in 28 patients

who were non- responders to IFN-alpha alone. Of 24 patients

who have finished the therapy, 6 (25%) obtained a complete

response (normal ALT and negative HCV RNA) at the end of

treatment and maintained a sustained response 27% (5/18).

Sustained Response to Interferon-alpha or to

Interferon-alpha Plus Ribavirin in Hepatitis C

Virus-Associated Symptomatic Mixed

Cryoglobulinaemia

Calleja JL, Albillos A, Moreno-Otero R, Rossi I, Cacho G,

Domper F, Yebra M, Escartin P

Aliment Pharmacol Ther 1999 Sep;13(9):1179-86

Background: Hepatitis C virus (HCV) infection has been

associated with mixed cryoglobulinaemia. AIM: To investigate

the efficacy of anti-viral therapy on the eradication of HCV and

its clinical manifestations in patients with HCV-associated

symptomatic mixed cryoglobulinaemia.

Patients and Methods: 18 out of 32 patients with symptomatic

mixed cryoglobulinaemia (MC group) received a 12-month

course of interferon (3 MU three times a week, subcutaneously).

Nonresponders or relapsers to this therapy were treated with

interferon plus ribavirin (1200 mg/day, orally) for 12-months.

226 patients with HCV infection and without cryoglobulins were

studied in comparison (Hepatitis C group). Serial quantification

of serum HCV-RNA and cryoglobulins were performed.

Results: In the MC group, 10 out of 18 patients (55%)

receiving interferon showed an end of treatment response, but at

the end of follow-up, only five (28%) patients had a sustained

response. In the hepatitis C group, 91 patients (47%) showed an

end of treatment response but only 42 (20%) a sustained

response. In the MC group alanine transaminase, cryocrit and

rheumatoid factor decreased significantly in responders, with an

improvement or disappearance of the MC-associated clinical

manifestations. Alanine transaminase, cryocrit and rheumatoid

factor increased in the relapsers and the clinical manifestations

reappeared. Nonresponders and relapsers to interferon in the

MC group were retreated with interferon plus ribavirin. Five out

of eight nonresponders showed a end of treatment response but

it was sustained in three of them. In the relapsers, treatment with

combined therapy achieved a sustained response in four out of

the five patients (80%).

Conclusions: Interferon as monotherapy or combined with

ribavirin is a safe and effective treatment in patients with

HCV-associated MC. The presence of cryoglobulins does not

affect the response to anti-viral treatment in patients with HCV

infection. The eradication of HCV is associated with an

improvement or disappearance of MC-associated clinical

manifestations.

Interferon alpha-2B and Ribavirin in

Combination for Patients With Chronic Hepatitis

C Who Failed to Respond to, or Relapsed After,

Interferon alpha Therapy: A Randomized Trial

Barbaro G, Di Lorenzo G, Belloni G, Ferrari L, Paiano A,

Del Poggio P, Bacca D, Fruttaldo L, Mongio F, Francavilla

R, o G, Grisorio B, Calleri G, Annese M, Barelli A,

Rocchetto P, Rizzo G, Gualandi G, Poltronieri I, Barbarini

G

Am J Med 1999 Aug;107(2):112-8

Purpose: To assess the efficacy of interferon alpha-2b and

ribavirin in combination in the treatment of patients with chronic

hepatitis C who had either failed to respond to therapy with

interferon alpha (nonresponders), or who had relapsed after

interferon therapy (relapsers).

Subjects and Methods: Four hundred patients with chronic

hepatitis C (200 nonresponders and 200 relapsers) were

randomly assigned in equal numbers to receive either

subcutaneous administration of recombinant interferon alpha-2b

(3 million units three times per week) and ribavirin (1,000 to

1,200 mg/daily orally) or interferon alpha-2b alone (6 million

units three times per week). Both ribavirin and interferon

alpha-2b were given for 24 weeks. The patients were then

followed for an additional 24 weeks.

Results: At the end of the treatment period, normalization of

serum alanine aminotransferase levels and absence of hepatitis C

virus RNA were seen in 21% of nonresponders and in 39% of

relapsers who were treated with interferon alpha-2b and

ribavirin, compared with 5% of nonresponders (P = 0.001) and

9% of relapsers treated with interferon alpha-2b alone (P

<0.001). At the end of follow-up, 14% of nonresponders and

30% of relapsers treated with the combination therapy had a

sustained response, compared with 1% of nonresponders (P =

0.001) and 5% of relapsers treated with interferon alpha alone (P

<0.001).

Conclusions: A 24-week course of treatment with interferon

alpha-2b and ribavirin offers a chance of sustained response,

whereas retreatment with interferon alpha-2b alone does not give

satisfactory results. The role of long-term therapy in inducing

prolonged remission remains to be explored.

Interferon Versus Ribavirin Plus Interferon in

Chronic Hepatitis C Previously Resistant to

Interferon: A Randomized Trial

Salmeron J, Ruiz-Extremera A, C,

-Ramos L, Lavin I, Quintero D, Palacios A

Liver 1999 Aug;19(4):275-80

Background: More than 70% of patients with chronic hepatitis

C are resistant to interferon therapy. Ribavirin, in association with

interferon, has been demonstrated as effective, at a dose of

800-1200 mg/day, but the efficacy of a lower dose has not been

established.

Methods: We assessed the effectiveness of the combination of

600 mg/day of ribavirin plus 3 MU of interferon over a period of

6 months, in a group of patients previously resistant to interferon.

Sixty-two patients with chronic hepatitis C with serum and

hepatic HCV RNA relapsers or non-responders to interferon,

were randomly divided into two groups: group A received 3 MU

of interferon alpha-2b, three times a week for 6 months; group B

was given the same dose plus 600 mg per day of ribavirin for 6

months. Two patients from each group dropped from therapy.

One patient from group A and two from group B withdrew from

treatment because of adverse effects.

Results: Mean alanine aminotransferase levels were similar in

both groups throughout the study. A sustained response was

observed in 7% and 7.4% of groups A and B with short-term

response in 39% and 59%, and no response in 54% and 34%

from both groups respectively (non-significant). At 12 months, 4

and 7 patients from groups A and B respectively, cleared serum

HCV RNA however, only one sustained responder from each

group cleared HCV RNA from peripheral blood mononuclear

cells. At 18 months, 3 patients remained serum HCV RNA

negative. Adverse effects were similar. Only haemoglobin values

were lower in group B in the first month of therapy (p<0.05).

Conclusion: In conclusion, the combination of 3 MU of

interferon plus 600 mg of ribavirin is not effective in chronic

hepatitis C resistant to interferon.

Effect of Retreatment With Interferon Alone or

Interferon Plus Ribavirin on Hepatitis C Virus

Quasispecies Diversification in Nonresponder

Patients With Chronic Hepatitis C

Gerotto M, Sullivan DG, Polyak SJ, Chemello L,

Cavalletto L, Pontisso P, Alberti A, Gretch DR

J Virol 1999 Sep;73(9):7241-7

Alpha interferon (IFN-alpha) treatment is effective on a

long-term basis in only 15 to 25% of patients with chronic

hepatitis C. The results of recent trials indicate that response

rates can be significantly increased when IFN-alpha is given in

combination with ribavirin. However, a large number of patients

do not respond even to combination therapy. Nonresponsiveness

to IFN is characterized by evolution of the hepatitis C virus

(HCV) quasispecies. Little is known about the changes occurring

within the HCV genomes when nonresponder patients are

retreated with IFN or with IFN plus ribavirin. In the present

study we have examined the genetic divergence of HCV

quasispecies during unsuccessful retreatment with IFN or IFN

plus ribavirin. Fifteen nonresponder patients with HCV-1 (4

patients with HCV-1a and 11 patients with HCV-1b) infection

were studied while being retreated for 2 months (phase 1) with

IFN-alpha (6 MU given three times a week), followed by IFN

plus ribavirin or IFN alone for an additional 6 months (phase 2).

HCV quasispecies diversification in the E2 hypervariable

region-1 (HVR1) and in the putative NS5A IFN sensitivity

determining region (ISDR) were analyzed for phase 1 and phase

2 by using the heteroduplex tracking assay and clonal frequency

analysis techniques. A major finding of this study was the

relatively rapid evolution of the HCV quasispecies observed in

both treatment groups during the early phase 1 compared to the

late phase 2 of treatment. The rate of quasispecies diversification

in HVR1 was significantly higher during phase 1 versus phase 2

both in patients who received IFN plus ribavirin (P = 0.017) and

in patients who received IFN alone (P = 0. 05). A trend toward

higher rates of quasispecies evolution in the ISDR was also

observed during phase 1 in both groups, although the results did

not reach statistical significance. However, the NS5A

quasispecies appeared to be rather homogeneous and stable in

most nonresponder patients, suggesting the presence of a single

well-fit major variant, resistant to antiviral treatment, in agreement

with published data which have identified an IFN sensitivity

determinant region within the NS5A. During the entire 8 months

of retreatment, there was no difference in the rate of fixation of

mutation between patients who received combination therapy

and patients who were treated with IFN alone, suggesting that

ribavirin had no major effects on the evolution of the HCV

quasispecies after the initial 2 months of IFN therapy.

A Randomized Trial of Ribavirin and

Interferon-Alpha vs. Interferon-alpha Alone in

Patients With Chronic Hepatitis C Who Were

Non- responders to a Previous Treatment.

Multicenter Study Group Under the Coordination

of the Necker Hospital, Paris, France

Pol S, Couzigou P, Bourliere M, Abergel A, Combis JM,

Larrey D, Tran A, Moussalli J, Poupon R, Berthelot P,

Brechot C

J Hepatol 1999 Jul;31(1):1-7

Background/Aim: Fifty percent of patients infected with

hepatitis C virus (HCV) show no response to alpha-interferon,

and no alternative therapy has thus far proven to be effective.

Therapeutic combination with ribavirin and alpha-interferon has

shown promising results in naive patients and in relapsers, but

based on limited series, it was reported to be inefficient in

non-responders. The aim of our study was therefore to explore

and compare, in a randomized trial, the tolerance and potential

efficacy of alpha-interferon alone with a sequential combination

of ribavirin and the same alpha-interferon regimen in those

patients.

Methods: Sixty-four non-responder patients were randomized

in the alpha2b-interferon group (a 6-month course at a dosage of

6 MU followed by a 6-month course of 3 MU three times

weekly subcutaneously) and 62 in the " combination " group

(sequential combination of the same alpha2b-interferon therapy

preceded by a 2-month course of ribavirin which was then

associated for 2 months with alpha2b-interferon at a daily dosage

of 1.0 or 1.2 g).

Results: Treatment withdrawal was necessary for six patients

from the alpha-interferon and eight patients from the combination

group. Normalization of aminotransferase activities was

significantly more frequent after the 4-month course of ribavirin

with 2 months of interferon than after 2 months of interferon

alone (52.8 vs. 26.2%, p<0.01), but this difference was not

maintained after ribavirin withdrawal. Disappearance of serum

HCV RNA (PCR) was significantly more frequent at the end of

treatment in the combination group (24.5 vs. 7.7%, p=0.02), but

did not differ 6 months after the end of therapy (9.8 and 8.3%,

respectively). The long-term response was not associated with

liver status (cirrhosis vs. absence of cirrhosis) or genotype. Mean

viremia was significantly lower in long-term responders than in

non-responders or relapsers in both groups (p<0.001 for the

interferon group and p<0.05 for the combination group), but the

large extent of viral load precluded reliable prediction. The pre-

and post-treatment hepatitis activity index did not differ between

the two groups. While a crude histopathological improvement in

the hepatitis activity index for a given patient was more frequently

observed in the combination group (69.2 vs. 35.9%, p<0.01),

improvement as defined by a decrease of at least 2 in the

hepatitis activity index was significant only for lobular necrosis

and degeneration.

Conclusions: This study demonstrates the efficacy of the

combination of ribavirin/alpha- interferon in non-responders.

Indeed, (i) it is fairly tolerated; (ii) it increases the rate of the

initial

biological response, and of the virological response by

decreasing breakthrough, though this benefit is not sustained; and

(iii) it induces a significant histological improvement in necrosis. A

simultaneous and prolonged combination of

ribavirin/alpha-interferon should be further evaluated in non-

responders.

Interferon-Ribavirin for Chronic Hepatitis C

With and Without Cirrhosis: Analysis of

Individual Patient Data of Six Controlled Trials.

Eurohep Study Group For Viral Hepatitis

Schalm SW, Weiland O, Hansen BE, Milella M, Lai MY,

Hollander A, Michielsen PP, Bellobuono A, Chemello L,

Pastore G, Chen DS, Brouwer JT

Gastroenterology 1999 Aug;117(2):408-13

Background & Amp; Aims: The aim of this study was to

compare interferon (IFN)-ribavirin combination therapy with

IFN monotherapy in chronic hepatitis C with particular focus on

its efficacy in cirrhosis.

Methods: A multivariate analysis of individual patient data of all

randomized controlled trials using an IFN-ribavirin arm, reported

between 1991 and March 1998, was performed. Centers

included 1 Asian and 5 European university-based referral

centers for liver disease. A total of 197 patients with chronic

hepatitis C received IFN-alpha (3 MU three times weekly) and

ribavirin (1-1.2 g daily) for 6 months, and 147 patients received

IFN-alpha (3 MU three times weekly) for 6 months. Patients

were characterized according to previous IFN therapy, presence

of cirrhosis, and genotype 1. Efficacy of therapy was evaluated

by assessing the sustained response rate by logistic regression

analysis.

Results: Patients without cirrhosis treated with IFN-ribavirin

had a significantly higher sustained response rate than those

treated with IFN, approximately 3-fold for previously untreated

patients (IFN- ribavirin: genotype 1, 33%; genotype 2/3, 65%;

IFN: genotype 1, 8%; genotype 2/3, 24%). In cirrhosis,

sustained response rates with IFN- ribavirin (previously

untreated: genotype 1, 7%; genotype 2/3, 24%) were also

significantly higher than those with IFN (previously untreated:

genotype 1, 1%; genotype 2/3, 5%). Clinical relevant superiority

of combination therapy over IFN monotherapy was also

observed for relapse; the same trend was observed for

nonresponders. Tolerance for IFN-ribavirin was similar for

patients with or without cirrhosis.

Conclusions: Combination with ribavirin significantly enhances

the sustained response rate of IFN therapy in major patient types

(cirrhosis, genotype 1) with chronic hepatitis C. Thus, IFN-

ribavirin combination is likely to become the antiviral therapy of

choice for cirrhosis caused by hepatitis C.

Retreatment of Non-responder or Relapser

Chronic Hepatitis C Patients With Interferon Plus

Ribavirin vs Interferon Alone

Milella M, Santantonio T, Pietromatera G, Maselli R,

Casalino C, no N, Genchi C, Pastore G

Ital J Gastroenterol Hepatol 1999 Apr;31(3):211-5

Background and Aim: Interferon-alpha treatment of chronic

hepatitis C is beneficial in only 20-30% of patients. This study

evaluates if combination therapy with Interferon-alfa plus ribavirin

is effective in inducing a response in patients who did not respond

to, or relapsed after, a standard Interferon-alfa treatment.

Patients and Methods: A total of 88 patients, 49

non-responders and 39 relapsers to previous Interferon-alfa

therapy, were randomized to receive either natural Interferon-alfa

(6 MU t.i.w.) plus ribavirin (1000 mg/daily) or natural

Interferon-alfa alone (6 MU t.i.w.) for 6 months. All were

followed for 12 months after stopping therapy. Serum

aminotransferase levels were assessed monthly and HCV RNA

was evaluated by RT-PCR (Amplicor, Roche) at end of therapy

and the end of follow-up.

Results: After treatment, a higher response rate defined as

return to normal of aminotransferases and absence of serum

HCV RNA was observed among patients treated with

Interferon-alfa-ribavirin: 4/28 (14%) vs 1/21 (5%)

non-responder patients and 9/19 (47%) vs 5/20 (25%) in the

relapsers group. At the end of follow-up, a sustained response

was found only in the combination treatment group: 4% and 32%

in non-responder and relapser patients, respectively.

Conclusions: Our results suggest that retreatment with natural

Interferon-alfa plus ribavirin is more effective than Interferon-alfa

alone in increasing the response rate in patients with chronic

hepatitis C who relapse after a previous standard IFN treatment

whereas it is less effective in non-responder patients.

Changes in Serum Hepatitis C Virus RNA in

Interferon Nonresponders Retreated With

Interferon Plus Ribavirin: A Preliminary Report

Nyberg L, Albrecht J, Glue P, Gianelli G, Zambas D, Elliot

M, Conrad A, McHutchison J

J Clin Gastroenterol 1999 Jun;28(4):313-6

Ribavirin, a nucleoside analogue, inhibits replication of RNA and

DNA viruses and may control hepatitis C virus (HCV) infection

through modulation of anti-inflammatory and antiviral actions.

Ribavirin monotherapy has no effect on serum HCV RNA levels.

In combination with interferon, this agent appears to enhance the

efficacy of interferon. The aim of this study was to monitor serum

HCV RNA levels early during therapy with interferon and

ribavirin compared with that previously seen in the same patients

during interferon monotherapy. Five patients who previously

showed no response to therapy with interferon alfa 3 MU three

times weekly for 6 months were retreated with the identical dose

of interferon alfa 2b in combination with oral ribavirin 1,000

mg/day. Serum HCV RNA levels were monitored at baseline,

week 4, week 8, and week 12 of therapy by a quantitative

multicycle polymerase chain reaction assay. In the first 8 to 12

weeks, serum HCV RNA levels showed a greater decrease in all

patients when retreated with combination therapy compared with

interferon alone. Mean (+/- SEM) serum HCV RNA levels for

interferon therapy alone were 3.3 +/- 0.95, 1.2 +/- 0.95, 1.6 +/-

1.2, and 2.3 +/- 1.2 x 10(6) copies/ml at week 0, 4, 8, and 12,

respectively. This was compared with 3.3 +/- 0.83, 0.3 +/- 0.2,

0.03 +/- 0.02, and 0.15 +/- 0.14 x 10(6), respectively, for the

interferon and ribavirin group (p < 0.07 at week 8). Two of five

patients had undetectable serum HCV RNA during combination

therapy. Combination therapy with interferon and ribavirin in

prior interferon nonresponders reduces serum HCV RNA levels

compared with interferon alone. This may suggest some

additional antiviral effect of ribavirin when given with interferon.

Interferon-alpha Plus Ribavirin in Chronic

Hepatitis C Resistant to Previous Interferon-alpha

Course: Results of a Randomized Multicenter

Trial

Andreone P, Gramenzi A, Cursaro C, Sbolli G, Fiorino S,

Di Giammarino L, Miniero R, D'Errico A, Gasbarrini G,

Bernardi M

J Hepatol 1999 May;30(5):788-93

Background/Aims: Interferon-alpha plus ribavirin seem to be

more efficacious than interferon monotherapy in chronic hepatitis

C. In a multicenter randomized trial, we evaluated the efficacy of

this association for interferon-alpha resistant chronic hepatitis C.

Methods: Fifty patients who were non-responders to

recombinant or lymphoblastoid interferon-alpha were

randomized to receive either ribavirin (800 mg/day) plus

leucocytic interferon-alpha (3 mega units thrice weekly) or the

same dose of interferon-alpha alone, for 6 months. Effects of

therapy were evaluated by serum aminotransferase and hepatitis

C virus RNA levels and control liver biopsies.

Results: At the end of treatment, aminotransferase levels

become normal in 9/26 patients receiving combination therapy

(35% [confidence interval, 16% to 53%]) and in 2/24 receiving

interferon-alpha alone (8% [confidence interval, -3% to 19%])

(p = 0.03). Aminotransferase normalization was never associated

with hepatitis C virus RNA clearance. All patients with normal

aminotransferase relapsed after discontinuation of therapy. At the

end of treatment, mean hepatitis C virus RNA levels significantly

decreased only in the group receiving combination therapy, but

returned to pretreatment values 6 months thereafter. No

histological improvement was observed in either group.

Conclusions: There is no indication for treatment with

interferon-alpha at the dose of 3 mega units thrice weekly plus

800 mg/day of ribavirin for 6 months in chronic hepatitis C

resistant to interferon-alpha.

Pilot Study of Triple Antiviral Therapy for

Chronic Hepatitis C in Interferon alpha

Non-responders

Brillanti S, Foli M, Di Tomaso M, Gramantieri L Masci C,

Bolondi L

Ital J Gastroenterol Hepatol 1999 Mar;31(2):130-4

Background: No effective therapy exists for interferon

non-responding chronic hepatitis C patients. AIMS: Pilot study

evaluating the potential efficacy and safety of triple antiviral

therapy in interferon- alpha non-responders.

Patients and Methods: Twenty consecutive adult patients with

chronic hepatitis C who had failed to respond to a 6- month

course of interferon alpha were randomly assigned to receive a

combination of interferon alpha + oral ribavirin (double therapy),

or the same combination + oral amantadine (triple therapy), for 6

months.

Results: By the end of therapy, normal alanine transaminase

(biochemical response) was obtained in 2 out of 10 patients on

double therapy but in 7 out of 10 on triple therapy (p < 0.05),

and negative serum hepatitis C virus (HCV) RNA (virological

response) occurred in 1 out of 10 patients on double therapy but

in 7 out of 10 patients on triple therapy (p < 0.01). Six months

after therapy, biochemical response was sustained in 1 (double

therapy) and 4 patients (triple therapy), respectively, and the

virological response was sustained in no patient on double

therapy but in 3 patients on triple therapy.

Conclusions: Triple antiviral therapy seems to be able to induce

biochemical and virological responses in interferon alpha non-

responders with chronic hepatitis C.

Activity of Combination Therapy With

Interferon alfa-2b Plus Ribavirin in Chronic

Hepatitis C Patients Co-infected With HIV

Dieterich DT, Purow JM, Rajapaksa R

Semin Liver Dis 1999;19 Suppl 1:87-94

The hepatitis C virus (HCV) and the human immunodeficiency

virus (HIV) often co-infect the same individuals because they

share comparable routes of transmission. Co-infection with HIV

in those patients infected with HCV influences the accuracy of

HCV diagnostic testing, levels of HCV viremia, severity of liver

histopathology, and rate of progression to cirrhosis. By contrast,

the effect of HCV co-infection on HIV disease is unclear.

Nevertheless, the combination therapy containing recombinant

interferon alfa-2b (rIFN-alpha 2b) plus ribavirin has been shown

to be efficacious in the treatment of chronic hepatitis C, whereas

alpha interferon monotherapy has been shown to be efficacious in

patients co-infected with HCV and HIV. It is therefore logical to

propose and test the hypothesis that combination rIFN-alpha

2b/ribavirin therapy will also benefit patients who are co-infected

with HCV and HIV. A double-blind, placebo-controlled study is

presently under way to investigate this hypothesis.

Outcome of Long-term Ribavirin Therapy for

Recurrent Hepatitis C After Liver Transplantation

Cattral MS, Hemming AW, Wanless IR, Al Ashgar H,

Krajden M, Lilly L, Greig PD, Levy GA

Transplantation 1999 May 15;67(9):1277-80

Ribavirin therapy was initiated at a median of 181 days after liver

transplantation in 18 patients with persistent elevation of alanine

aminotransferase values and biopsy-proven hepatitis, and

continued for 23 months (12-44 months). All patients had a

prompt biochemical response, with alanine aminotransferase

decreasing by 69%; complete normalization occurred in 5

(28%). Serum hepatitis C virus RNA levels did not change

during therapy. Liver biopsies obtained after 17 months (9-38

months) of therapy showed no improvement in

necroinflammation. However, worsening of fibrosis occurred in

12 patients; and cirrhosis developed in 5 patients (28%), with 3

patients progressing to graft failure. Biopsies from 27 untreated

patients who did not fulfill treatment criteria (median follow-up,

38 months) and 4 patients who received 3 months of ribavirin

(44 months) showed cirrhosis in 11 and 75%, respectively.

Patient and graft survival rates for treated and untreated patients

were similar. Although ribavirin improves alanine

aminotransferase, it does not prevent the development or

progression of fibrosis in patients with recurrent hepatitis C virus.

Treatment With Interferon-alpha2a Alone or

Interferon-alpha2a Plus Ribavirin in Patients With

Chronic Hepatitis C Previously Treated With

Interferon-alpha2a. CONSTRUCT Group

Bell H, Hellum K, Harthug S, Myrvang B, Ritland S,

Maeland A, von der Lippe B, Bjoro K, Skaug K, Gutigard

BG, Raknerud N, Simmonds P

Scand J Gastroenterol 1999 Feb;34(2):194-8

Background: Preliminary results from combination therapy with

interferon-alpha and ribavirin (IFN/Rib) in patients with chronic

hepatitis C have been promising, with up to 50% sustained

hepatitis C virus (HCV) RNA response. The aim of this study

was to investigate whether a sustained HCV RNA response

could be obtained with combination therapy in patients who were

non-responders or relapsers after IFN treatment.

Methods: In a multicenter study we randomized 53 HCV

RNA- positive patients into 2 treatment groups. They all had

biopsy- confirmed chronic hepatitis C, and all were recruited

from a previous IFN study: 26 were previous non-responders

and 27 responders with relapse. Group A received

interferon-alpha2a, 4.5 MIU thrice weekly for 6 months, and

group B received ribavirin, 1000-1200 mg/day, in combination

with the same dose of interferon-alpha2a for 6 months. Median

Knodell index was 5.0 in both groups. Genotype 1 was found in

24 (45%), type 2 in 3 (6%), and type 3 in 26 (49%).

Results: Sustained clearance of HCV viremia 6 months after

interferon-alpha2a treatment stop was obtained in 12 of 53

patients (23%): 6 of 27 in the IFN group (22%) and 6 of 26

(23%) in the IFN/Rib group (NS). Nine of 27 (33%) former

responders with relapse, compared with 3 of 26 (12%) non-

responders, obtained a sustained HCV RNA response (P =

0.054). In previous relapse patients sustained loss of viremia was

more frequent in genotype 3 (50%) than in genotype 1 (11%)

patients (P = 0.022).

Conclusions: In a group of previous IFN-alpha2a-treated

chronic HCV patients we obtained a similar sustained clearance

of viremia when retreated either with IFN-alpha2a alone or with

a combination of IFN- alpha2a and ribavirin for 6 months.

Previous relapse patients with HCV genotype 3 obtained

sustained loss of viremia significantly more often (50%) than

type-patients (11%). Previous IFN responders with relapse

responded better than previous non-responders.

Early Prediction of Response in Interferon

Monotherapy and in Interferon-Ribavirin

Combination Therapy for Chronic Hepatitis C:

HCV RNA at 4 Weeks Versus ALT

Brouwer JT, Hansen BE, Niesters HG, Schalm SW

J Hepatol 1999 Feb;30(2):192-8

Background/Aims: There is consensus that interferon for

hepatitis C should be stopped if alanine aminotransferase (ALT)

remains elevated after 12 weeks; however, this may lead to

unjust treatment withdrawal in around 20% of potential sustained

responders. No consensus exists for interferon-ribavirin

combination therapy. The aim of this study was to assess the

predictive value of an HCV RNA test at 4 weeks in comparison

with ALT, both in interferon monotherapy and in interferon-

ribavirin combination therapy.

Methods: Plasma HCV RNA was tested at 4 weeks in 149

naive patients undergoing 6 months and 187 undergoing up to 12

months of interferon monotherapy, and in 40 non-responders

treated for 6 months with interferon-ribavirin combination

therapy.

Results: For 6 and up to 12 months of interferon monotherapy,

the predictive value for non-response was 99% resp. 97% for a

positive HCV RNA at week 4, versus 97% resp. 91% for an

elevated ALT at week 12. Using a positive HCV RNA at week

4 as a stopping rule would lead to missing 5% resp. 12% of

potential sustained responders, versus 10% resp. 28% for an

elevated ALT at week 12. In interferon-ribavirin combination

therapy, the predictive value for non-response was 100% for

week 4 HCV RNA versus 95% for week 12 ALT, and 0%

potential sustained responders were missed by a test for week 4

HCV RNA versus 20% for week 12 ALT. The overall sensitivity

and specificity of a week 4 HCV RNA test was significantly

better (area under ROC 0.85) as compared to testing ALT at

week 4 (0.78, p<0.001), week 8 (0.76, p<0.001) or week 12

(0.78, p<0.001).

Conclusion: A positive HCV RNA test (> or =10(3) copies/

ml) at 4 weeks is highly predictive for non-response and leads to

significantly less misidentification of potential sustained

responders than ALT at week 4, 8 or 12, both in 6 or up to 12

months interferon monotherapy and in 6 months

interferon-ribavirin combination therapy of chronic hepatitis C.

Photoallergic Skin Reaction to Ribavirin

Stryjek-Kaminska D, Ochsendorf F, Roder C, Wolter M,

Zeuzem S

Am J Gastroenterol 1999 Jun;94(6):1686-8

A 65-yr-old woman with chronic hepatitis C was treated with

three million units interferon-alpha t.i.w. and 1000 mg ribavirin

daily. At wk 16 of combination therapy the patient developed an

itchy eczematous erythema, partly of urticarial character, which

was almost confined to ultraviolet (UV)-exposed sites.

Histopathological examination of the skin lesions was consistent

with a photoallergic reaction. The minimal erythematous dose for

UVA and UVB was assessed on healthy skin. After 24 h, a

distinct erythema at the UVB irradiated site was found, whereas

no reaction was seen with UVA provocation up to a dose of 10

J/cm2. Correspondingly, determination of the absorption

spectrum of ribavirin revealed maximum absorption within UVB

at 282.5 nm. Ribavirin was stopped, and the cutaneous lesions

and pruritus completely disappeared without subsequent

hyperpigmentation. This case indicates that ribavirin is a potential

photosensitizer for UVB, which may become increasingly

relevant in patients with chronic hepatitis C undergoing

combination therapy for 6-12 months with interferon-alpha and

ribavirin.

Pharmacoeconomics

Cost Effectiveness of Interferon alpha2b

Combined With Ribavirin for the Treatment of

Chronic Hepatitis C

Younossi ZM, Singer ME, McHutchison JG, Shermock

KM

Hepatology 1999 Nov;30(5):1318-24

Treatment of chronic hepatitis C with Interferon (IFN) alpha2b

monotherapy results in 10% to 15% sustained virological

response (SVR). Combining IFN with ribavirin increases this

response. In this analysis, using the Markov model, 6 treatment

strategies for chronic hepatitis C (previously untreated) were

compared on the basis of incremental cost per additional

quality-adjusted life years ($/QALY). Our results showed that

the no treatment strategy was associated with a cost of $38,747

and 13.10 QALYs. The strategy using IFN alone for 48 weeks

was associated with a cost of $35,642 and 14.05 QALYs. The

strategy using IFN monotherapy followed by combination

therapy for nonresponders and relapsers was associated with a

cost of $34, 561 and 15.53 QALYs. A similar strategy, but

limiting combination to relapsers only, was associated with a cost

of $34,758 and 14.40 QALYs. The strategy using IFN with

ribavirin as the initial therapy for all patients was associated with

a cost of $34,792 and 15.31 QALYs. Finally, the strategy using

viral genotyping first and then adjusting the duration of

combination therapy based on genotype was associated with a

cost of $37,263 and 15.89 QALYs. The strategy using

genotyping to guide duration of combination therapy was the

most cost-effective approach with an incremental

cost-effectiveness ratio of $7,500 per QALY. Sensitivity

analyses confirmed the robustness of these results. We conclude

that combination of IFN and ribavirin with duration of therapy

based on the viral genotype, is a cost-effective approach in

treating patients with chronic hepatitis C.

Factors Determining Response to Treatment

Interferon-Antibodies and the Breakthrough

Phenomenon During Ribavirin/Interferon-alpha

Combination Therapy and Interferon-alpha

Monotherapy of Patients With Chronic Hepatitis

C

Hoffmann RM, Berg T, Teuber G, Prummer O, Leifeld L

Jung MC, Spengler U, Zeuzem S, Hopf U, Pape GR

Gastroenterol 1999 Aug;37(8):715-23

Background/Aims: The significance of interferon antibodies

with respect to response to treatment in patients with chronic

hepatitis C treated with interferon-alpha (INF-alpha) remains a

matter of debate. The influence of ribavirin on IFN-antibody

formation in combination therapy with IFN-alpha has not yet

been studied. Therefore we evaluated the relationship between

IFN-antibodies and response to ribavirin/IFN-alpha combination

therapy and IFN-alpha monotherapy.

Methods: We studied 169 patients with chronic hepatitis C who

were treated either with IFN alpha 2a (6 MU, thrice weekly)

alone or in combination with ribavirin (14 mg/kg per day) for

twelve weeks. Thereafter, patients who achieved a virological

response (HCV-RNA-negative) were treated with 3 MU IFN-

alpha thrice weekly for another 40 weeks. IFN antibodies were

analyzed and quantified by a double-antigen sandwich enzyme

immunoassay (EIA). In 86 patients two neutralization assays--an

antiviral neutralization assay as well as an antiproliferative

neutralization assay--were performed in addition. The

relationship of the development of IFN- antibodies with the

virologically defined response to treatment was analyzed.

Results: Ribavirin did neither influence the prevalence nor the

level of IFN-antibodies. The frequencies of IFN-antibody

formation did not differ in the response groups. However,

patients with breakthrough showed significantly higher

IFN-antibody titers as compared to responder at end of

treatment (median 1,336 BU/ml vs. 148 BU/ml; p = 0.018).

Among the breakthrough patients those with IFN- antibodies

showed the reappearance of HCV-RNA during therapy

significantly earlier (median week 24) than those without IFN-

antibodies (median week 32; p = 0.03).

Conclusion: The addition of ribavirin to IFN-alpha does not

influence the formation of IFN- antibodies. The development of

high-titer IFN-antibodies during IFN- alpha or

ribavirin/IFN-alpha therapy of patients with chronic hepatitis C

may account for the early occurrence of breakthrough in some

patients, while other mechanisms seem to be responsible for this

phenomenon in the majority of the afflicted patients.

Response to Retreatment With

Interferon-alpha Plus Ribavirin in Chronic

Hepatitis C Patients Is Independent of the NS5A

Gene Nucleotide Sequence

Ibarrola N, Moreno-Monteagudo JA, Saiz M,

-Monzon C, Sobrino F, -Buey L, Lo Iacono

O, Moreno-Otero R, ez-Salas E

Am J Gastroenterol 1999 Sep;94(9):2487-95

Objective: Interferon-alpha plus ribavirin is an effective

treatment for chronic hepatitis C patients. We evaluated whether

the response to this combined therapy correlated with the

presence of mutations in a region of 372 nucleotides within the

NS5A gene.

Methods: Sixty-two patients, 42 nonresponders and 20

relapsers to a previous course of interferon-alpha, received 3

million units thrice weekly of interferon- alpha-2b and 1-1.2 g

daily of ribavirin for 12 months. Basal biochemical and virological

(HCV RNA and genotype) parameters were determined.

Clinical examinations were carried out at 1, 2, 3, 6, and 12

months. In addition, nucleotide sequencing of the NS5A gene

was determined for viral samples obtained from 38 of these

patients at the baseline of the combined therapy, as well as in 15

of them before initiating the previous course of interferon as

monotherapy.

Results: On finishing the 12 months, 36 patients (58.1%) had

normal aminotransferases and 25 (40.3%) cleared viremia.

Nucleotide sequencing indicated the same level of genetic

variability within the group of responder and nonresponder

patients all along the 124 amino acid residues of the NS5A gene

studied. Neither the type of amino acid substitution nor the

number of them was significantly different in one group relative to

the other.

Conclusions: Therapy with interferon-alpha- 2b plus ribavirin

was well tolerated, achieving an end-of-treatment response in 25

(40.3%) patients. Response did not correlate with the presence

of mutations in the NS5A gene analyzed, including the interferon

sensitivity determining region (ISDR) and its flanking sequences.

Improved Correlation Between Multiple

Mutations Within the NS5A Region and

Virological Response in European Patients

Chronically Infected With Hepatitis C Virus Type

1b Undergoing Combination Therapy

Sarrazin C, Berg T, Lee JH, Teuber G, Dietrich CF, Roth

WK, Zeuzem S

J Hepatol 1999 Jun;30(6):1004-13

Background/Aims: Studies from Japan showed that HCV-1b

isolates with at least four amino acid changes within

NS5A2209-2248 compared with the prototype sequence

HCV-J are more sensitive to interferon than isolates with a

prototype sequence. However, the data were not unequivocally

confirmed in studies from other geographical areas. These

discrepancies may be explained by differences in the prevalence

of multiple mutations within the NS5A2209-2248 and/or the

treatment efficacy.

Methods: In the present study, we therefore investigated the

correlation between NS5A2209-2248 sequences of HCV-1b

isolates and sustained virological response in 72 European

patients treated with 3x6 MU interferon-a per week with (n =

26) and without (n = 46) ribavirin (1000-1200 mg/day). Serum

HCV RNA was amplified by reverse transcription-polymerase

chain reaction (RT-PCR) and the NS5A2209-2248 region was

analyzed by sequencing of PCR products or individual clones.

Results: Compared with HCV-1b prototype sequences, 19

patients (26%) had no amino acid changes (prototype), 47

patients (65%) had 1-3 mutations (intermediate type) and six

patients (8%) had at least 4 mutations in the NS5A2209-2248

region (mutant type). Nine of the 12 patients with sustained

virological response were infected with an intermediate type

HCV-1b, the remaining three patients revealed a mutant type

HCV-1b. A sustained virological response was achieved in three

of four patients with a mutant type HCV-1b treated with

interferon-alpha and ribavirin, but in none of the mutant type

HCV-1b infected patients treated with interferon-a alone.

Quasispecies analysis of HCV in the NS5A2209-2248 region

showed only minor heterogeneity of the amino acid sequence.

Conclusions: The prevalence of mutant type HCV-1b isolates in

European patients is low. In patients treated with combination

therapy interferon-a and ribavirin, a correlation between mutant

type HCV-1b isolates and sustained virological response was

observed. The discrepancies between previous studies appear to

be related to the efficacy of antiviral treatment and to the low

prevalence of mutant type HCV-1b isolates in Western

countries.

Reviews

Long-term Efficacy of Treatment of Chronic

Hepatitis C With alpha Interferon or alpha

Interferon and Ribavirin

E, Webster G, s R, Dusheiko G

J Hepatol 1999;31 Suppl 1:244-9

The major objective of treatment of chronic hepatitis C virus

(HCV) infection is to prevent progression to cirrhosis, and

thereby prevent complications of end-stage liver disease. The

established treatment of chronic HCV is with alpha interferon.

Recent results with ribavirin and alpha interferon together suggest

that combination antiviral therapy will become the benchmark

treatment. For both naive and relapsed patients, however, it has

become important to assess the long-term outcome of treatment,

in order to gauge whether treatment has indeed modified the

natural history of chronic hepatitis C virus infection. It seems

likely that most sustained responders (85-90%) treated with

combination ribavirin and alpha interferon will continue to have a

long- term biochemical and virological response, as has been

demonstrated with alpha interferon alone, but further long-term

follow-up of patients treated with combination therapy is

required.

Safety of Combination Interferon

alfa-2b/Ribavirin Therapy in Chronic Hepatitis

C-Relapsed and Treatment-Naive Patients

Maddrey WC

Semin Liver Dis 1999;19 Suppl 1:67-75

The coadministration of ribavirin with recombinant interferon

alfa-2b (rIFN-alpha 2b) compared with rIFN-alpha 2b alone

markedly enhanced sustained virologic response rates in relapsed

and treatment-naive chronic hepatitis C patients. The potential for

ribavirin to likewise exacerbate the adverse events associated

with the alpha interferons is reviewed. The overall safety and

tolerability of combination rIFN-alpha 2b/ribavirin therapy was

evaluated in 2,089 patients treated in phase III clinical studies

conducted in the United States and internationally. Serious

adverse events were also evaluated on an interim basis in >

25,000 patients--a majority of whom were treated with

combination therapy (open label)--treated worldwide in

investigator-initiated studies. Patients in the phase III studies

received 3 million International Units rIFN-alpha 2b three times

per week by subcutaneous injection plus either ribavirin or

placebo orally in divided daily doses of 1,000 or 1,200 mg for

patients weighing < or = 75 or > 75 kg, respectively. Adverse

event frequency and severity and dose modifications were

recorded throughout the 24-week (relapse) or 48- week (naive)

treatment period and 24-week follow-up period. Clinically

significant adverse events included anemia and depression. There

was no evidence that the adverse effects of alpha interferon (e.g.,

fatigue, depression, neutropenia) were exacerbated by ribavirin.

Severe adverse events were limited due to strict adherence to

dose-modification criteria; approximately 6% to 9% of patients

discontinued combination therapy because of an adverse event.

Clinically serious adverse events, dose reductions and

discontinuations, and potential mechanisms of toxicity associated

with rIFN-alpha 2b and ribavirin are examined.

Combination Therapy With Interferon Plus

Ribavirin for the Initial Treatment of Chronic

Hepatitis C

McHutchison JG, Poynard T

Semin Liver Dis 1999;19 Suppl 1:57-65 [published erratum

appears in Semin Liver Dis 1999;19(3):353]

The limited efficacy of alpha interferon (IFN) monotherapy for

hepatitis C virus (HCV) infection has led to the investigation of

alternative treatment approaches, including combining interferons

with other antiviral agents. In several small, pilot studies, the

combination of IFN plus ribavirin was significantly more effective

than IFN monotherapy for the initial treatment of HCV. The

encouraging results from these studies provided the rationale for

conducting two (one US, one International) large, multicenter,

randomized, placebo- controlled clinical trials of IFN plus

ribavirin therapy for the initial treatment of HCV patients. Of

patients receiving therapy [corrected] for 24 weeks, 31% (US)

and 35% (International) achieved sustained virologic remission

with interferon plus ribavirin [corrected], compared with only 6%

(US) receiving interferon [corrected] plus placebo. Sustained

virologic response rates were improved in patients treated for 48

weeks (interferon plus ribavirin, 38% [uS]; 43% [international]

compared to interferon plus placebo, 13% [uS]; 19%

[international]) [corrected]. Improvement was also observed in

terms of biochemical and histologic end points in those receiving

combination therapy. Pretreatment variables (HCV genotype,

viral burden, stage of fibrosis) were less important as predictors

of treatment outcome in patients receiving combination therapy.

The safety profile of combination therapy reflected the individual

safety profiles of IFN and ribavirin, without synergism.

Combination therapy with IFN plus ribavirin was more effective

than IFN monotherapy for the initial treatment of HCV in terms

of virologic, biochemical, and histologic end points. The

combination appears to be well tolerated with a predictable

safety profile.

Combination Therapy With Interferon alfa and

Ribavirin as Retreatment of Interferon Relapse in

Chronic Hepatitis C

GL

Semin Liver Dis 1999;19 Suppl 1:49-55

Interferon (IFN) results in normalization of the serum alanine

aminotransferase (ALT), loss of detectable serum hepatitis C

virus (HCV) RNA, and histologic improvement in approximately

40% of patients. However, regardless of the duration of initial

therapy, most patients relapse within the first few months after the

drug is stopped and only a small proportion have a sustained

response. Retreatment of IFN relapsers with the combination of

IFN and oral ribavirin for 6 months results in end-of-treatment

loss of detectable HCV RNA and normalization of the ALT level

in over 80% of patients. Nearly half achieve a sustained

viral-negative response. Histologic improvement occurs in nearly

two thirds of patients retreated with combination therapy and is

most pronounced in those who lose serum HCV-RNA.

CONTENTS

Clinical Trials

Is an " A la carte "

Combination

Interferon

alfa-2b Plus

Ribavirin

Regimen Possible for

the First

Line Treatment in

Patients

With Chronic

Hepatitis C?

The ALGOVIRC Project

Group

Combination Treatment

of

Interferon alpha-2b

and

Ribavirin in

Comparison to

Interferon

Monotherapy in

Treatment of Chronic

Hepatitis C Genotype

4

Patients

Long-term

Re-treatment With

Interferon and

Ribavirin

Combination Therapy

in

Patients With Chronic

Hepatitis C Who Are

Non-responders to

Interferon

Alone: A Preliminary

Study

Sustained Response to

Interferon-alpha or

to

Interferon-alpha Plus

Ribavirin in

Hepatitis C

Virus-Associated

Symptomatic Mixed

Cryoglobulinaemia

Interferon alpha-2B

and

Ribavirin in

Combination for

Patients With Chronic

Hepatitis C Who

Failed to

Respond to, or

Relapsed

After, Interferon

alpha

Therapy: A Randomized

Trial

Interferon Versus

Ribavirin

Plus Interferon in

Chronic

Hepatitis C

Previously

Resistant to

Interferon: A

Randomized Trial

Effect of Retreatment

With

Interferon Alone or

Interferon

Plus Ribavirin on

Hepatitis C

Virus Quasispecies

Diversification in

Nonresponder Patients

With

Chronic Hepatitis C

A Randomized Trial of

Ribavirin and

Interferon-Alpha vs.

Interferon-alpha

Alone in

Patients With Chronic

Hepatitis C Who Were

Non-

responders to a

Multicenter Study

Group Under the

Coordination of the

Necker

Hospital, Paris,

France

Interferon-Ribavirin

for

Chronic Hepatitis C

With and

Without Cirrhosis:

Analysis of

Individual Patient

Data of Six

Controlled Trials.

Eurohep

Study Group For Viral

Hepatitis

Retreatment of

Non-responder or

Relapser

Chronic Hepatitis C

Patients

With Interferon Plus

Ribavirin

vs Interferon Alone

Changes in Serum

Hepatitis

C Virus RNA in

Interferon

Nonresponders

Retreated

With Interferon Plus

Ribavirin: A

Preliminary

Report

Interferon-alpha Plus

Ribavirin in Chronic

Hepatitis

C Resistant to

Course:

Results of a

Randomized

Multicenter Trial

Pilot Study of Triple

Antiviral

Therapy for Chronic

Hepatitis

C in Interferon alpha

Non-responders

Activity of

Combination

Therapy With

Interferon

alfa-2b Plus

Ribavirin in

Chronic Hepatitis C

Patients

Co-infected With HIV

Outcome of Long-term

Ribavirin Therapy for

Recurrent Hepatitis C

After

Liver Transplantation

Treatment With

Interferon-alpha2a

Alone or

Interferon-alpha2a

Plus

Ribavirin in Patients

With

Chronic Hepatitis C

Previously Treated

With

Interferon-alpha2a.

CONSTRUCT Group

Early Prediction of

Response

in Interferon

Monotherapy

and in

Interferon-Ribavirin

Combination Therapy

for

Chronic Hepatitis C:

HCV

RNA at 4 Weeks Versus

ALT

Photoallergic Skin

Reaction

to Ribavirin

Pharmacoeconomics

Cost Effectiveness of

Interferon alpha2b

Combined

With Ribavirin for

the

Treatment of Chronic

Hepatitis C

Factors Determining

Response to Treatment

Interferon-Antibodies

and the

Breakthrough

Phenomenon

During

Ribavirin/Interferon-alpha

Combination Therapy

and

Interferon-alpha

Monotherapy of

Patients

With Chronic

Hepatitis C

Response to

Retreatment

With Interferon-alpha

Plus

Ribavirin in Chronic

Hepatitis

C Patients Is

Independent of

the NS5A Gene

Nucleotide

Sequence

Improved Correlation

Between Multiple

Mutations

Within the NS5A

Region and

Virological Response

in

European Patients

Chronically Infected

With

Hepatitis C Virus

Type 1b

Undergoing

Combination

Therapy

Reviews

Long-term Efficacy of

Treatment of Chronic

Hepatitis C With

alpha

Interferon or alpha

Interferon

and Ribavirin

Safety of Combination

Interferon

alfa-2b/Ribavirin

Therapy in Chronic

Hepatitis

C-Relapsed and

Treatment-Naive

Patients

Combination Therapy

With

Interferon Plus

Ribavirin for

the Initial Treatment

of

Chronic Hepatitis C

Combination Therapy

With

Interferon alfa and

Ribavirin

as Retreatment of

Interferon

Relapse in Chronic

Hepatitis

C

INTERACT

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