24 vs 48 weeks Pegasys/RBV in HCV Genotype 2/3 Coinfection: does this study answer the question         Reported by Jules Levin   An Italian research group (Puoti, Zanini et al, Master coinfection study group, IAS/Rio, poster MoPpLB0103) studied whether 24 or 48 weeks therapy (Pegays+ribavirin) showed better viral outcomes for HCV/HIV patients with genotype 2/3. As it turned out 92-100% of study patients had genotype 3. The incidence of relapses in patients who were HCV RNA negative at end of treatment was the main outcome compared between the two groups.   The authors concluded that these study results "suggest that the optimal duration of therapy in coinfected patients with genotypes 2/3 is at least 48 weeks", because the study observed a higher relapse rate among patients who were HCV negative after 24 weeks therapy compared to those who were HCV negative after 48 weeks therapy.   Does this study answer the question? I don't think this study was conducted in a manner to provide a conclusive answer to the question. To better address the question therapy and patients should be stratified by baseline viral load, the presence of cirrhosis, and perhaps other characteristics. That is, if you select patients with all the characteristics that would lend themselves to achieving an SVR with only 24 weeks therapy, that would be a better patient population in which to study this question. Such characteristics would include: patients with >500 CD4s and <50 copies/ml, with reconstituted immune systems; no fatty liver; no cirrhosis, early stage HCV disease; low HCV viral load; full adherence; use of EPO; undetectable HCV RNA by week 4 or 8. Perhaps these patients could achieve better outcomes with shorter than 48 weeks therapy. Even with these considerations it is reasonable to think that in HIV at least 48 weeks therapy is necessary to optimize response rates.   BACKGROUND: In HCV monoinfection, study results show the 24 weeks therapy with peginterferon plus ribavirin may be adequate duration of therapy for patients with genotype 2/3. The Hadziyannis study of Pegasys plus 800mg daily ribavirin found 73-78% SVR rates for genotype 2/3 for 24 or 48 weeks therapy regardless of viral load levels at baseline of weight. This study set a standard for 24 weeks therapy with peginterferon plus RBV in genotypes 2/3 who are HCV monoinfected. However, this study did not examine the effects of adherence on outcomes of 24 vs 48 weeks therapy. It is possible that high adherence levels (80-100%) would have resulted in a better SVR rate with 48 weeks therapy. Dose reductions of peginterferon or ribavirin were likely to have occurred more often for patients receiving 48 weeks therapy. So, you could make a case that a patients with 100% adherence and no dose reductions would achieve better SVR rates with 48 weeks therapy. But, perhaps 24 weeks might be adequate for most patients.   A study published in the NEJM (June 2005) found that for HCV monoinfected genotype 2/3 patients with undetectable HCV RNA after 4 weeks of peginterferon alfa-2b plus ribavirin, 12 weeks of therapy was as effective as 24 weeks of therapy in terms of SVR rates. But there was a slight suggestion that the risk for relapse could be a bit higher in the 12-week group. Here is link to study article:   Peginterferon Alfa-2b and Ribavirin for 12 vs. 24 Weeks in HCV ... www.natap.org/2005/HCV/062305_01.htm   Another consideration is long-term outcomes over the course of many years. Although SVR rates appear the same with 24 or 48 weeks duration of therapy for patients in certain categories, will this hold up 10-20 years in the future?   BACK TO ITALIAN COINFECTION STUDY 36 patients received 48 weeks of Pegasys + ribavirin therapy (800-1200 mg/daily dosed by weight). Only 2 (11%) of the 19 patients concluding the 48-week treatment period relapsed. Per-protocol analysis showed a significantly lower relapse rate in the patient group receiving 48 weeks therapy compared to those receiving only 24 weeks therapy (11% vs 40%, p=0.04), "that was not observed in the ITT analysis 53% vs 40%" (stated in the program book).   STUDY AIM: to optimize duration of treatment for chronic hepatitis C in persons infected by HIV and HCV genotype 2 or 3. STUDY DESIGN: Randomized prospective, open, controlled trial, METHODS: The study enrolled patients on stable ART >6 weeks, CD4 count >200 & HIV RNA <10,000 c/ml, or ART naïve with CD4 count >300. All patients received Pegasys at 180 mcg once a week by subcutaneous injection in combination with ribavirin 10.6-13 mg/kg/day for 28 weeks. Ribavirin dose was based on weight: <65 kg, 800 mg daily; 66-85 kg, 1000 mg daily; >85 kg, 1200 mg daily.   All patients showing negative HCV RNA at 24 weeks were randomized at the 28th week to: stop treatment or continue treatment for an additional 20 weeks for a total of 48 weeks therapy. Of the128 coinfected patients who were enrolled in the study 74 were HCV PCR negative after 24 weeks of therapy.   The incidence of relapses in patients who were HCV RNA negative at end of treatment was the main outcome compared between the two groups. 128 patients were enrolled. 46 patients (36%) stopped treatment before 24 weeks: 20 (16%) because of adverse events and 26 (20%) for intolerance. 30 of these 46 (65%) showed HCV RNA negativity during treatment, but 14 out of 30 (47%) relapsed after stopping treatment. 8 out of 82 patients (10%) did not show negative HCV RNA at the end of the first 24 weeks of treatment. THEN, 74 patients were randomized: 38 to stop treatment and 36 to continue treatment for a total of 48 weeks. 15 (40%) of the patients who stopped at 24 weeks relapsed after treatment withdrawal.   17 patients from the group that continued treatment prematurely stopped therapy: 4 for serious adverse event (2 relapsed) and 13 for intolerance (11 relapsed). Only 2 (11%) of the 19 patients concluding the 48-week treatment period relapsed.     ADVERSE EVENTS   Serious adverse events were reported in 40 (31%) of the 128 patients in weeks 0-24, and 8 (22%) of patients in weeks 28-48 of treatment. The overall SAE-related treatment withdrawal rate was 18%: 12% (n=16) of the 128 patients during weeks 0-24, and 8% (n=3) in the 36 patients during weeks 28-48. This shows patients probably got used to the side effects or were better able to tolerate them after a while. Or the patients continuing therapy had more incentive to continue.   During weeks 0-24 (n=128) there were 8 grade 3 neuropsyciatric events (7/8) cases resolved with peginterferon and/or RBV dose reduction, and 5 grade 4 cases. During weeks 28-48 there was 1 grade 3 and 1 grade 4 neuropsychiatric event. The grade 3 event resolved with peginterferon and/or RBV dose reduction.   ANEMIA: There were 6 cases of grade 3 anemia (all resolved with peginterferon and/orRBV dose reduction) and 1 case of grade 4 anemia during weeks 0-24. During weeks 28-48 there were 2 cases of grade 2 anemia (resolves with peginterferon and/or RBV dose reduction) and 1 case of grade 4 anemia.   NEUTROPENIA: there were 10 cases of grade 3 neutropenia (all resoleved with peginterferon and/or RBV dose reduction) and 1 case of grade 4 during weeks 0-24. During weeks 28-48 there were 2 cases of grade 3 neuropenia (all resolved with peg and/or RBV dose reduction) and no grade 4 cases.   THROMBOCYTOPENIA: there was 1 case of grade 3 (resolved with peg and/or RBV dose reduction) and 2 cases of grade 4. There were no cases during weeks 28-48.   There was 1 case of neuropathy reported, grade 4 during weeks 28-48.   The study apparently did not use adjunctive therapy such as EPO for anemia or neutropenia.       * Treatment of Genotype 4 HCV Studies continue to yield conflicting data on the treatment of genotype 4 HCV, which is the most prevalent type in the Middle East and parts of Africa. While some have shown that genotype 4 is resistant to treatment (like genotype 1), others suggest it may be easier to treat (like genotypes 2 and 3). In the July Journal of Viral Hepatitis, M. Derbala and colleagues reported on a study of 61 patients with chronic genotype 4 HCV in Egypt. Subjects received either conventional interferon plus ribavirin or Peg-Intron plus ribavirin. End-of-treatment response rates were 35% in the conventional interferon group and 43% in the Peg-Intron group. SVR rates were 26% and 33%, respectively – closer to those seen for genotype 1 than for genotypes 2/3 in other studies. In contrast to past research, however, end-of-treatment and sustained response rates did not differ significantly between conventional and pegylated interferon. The authors concluded that, “the poor response of genotype 4 in Egypt (genotype 4a) to different forms of interferons may be related to an intrinsic resistance to the direct antiviral effect of interferon.” In related news, S. Kamal and colleagues reported on a study of treatment duration and viral kinetics in patients with genotype 4 HCV in the June issue of Gut. In this trial, 287 subjects were randomly assigned to received Peg-Intron plus ribavirin for 24, 36, or 48 weeks. Using an intent-to-treat analysis (all randomized patients were included in the analysis), SVR rates were 29%, 66%, and 69%, respectively. Subjects who went on to achieve SVR showed greater antiviral efficacy and rapid viral load decline from baseline to week 4. There was no significant difference in efficacy when comparing 36 and 48 weeks of therapy, but the incidence of adverse side effects was higher in the group treated longer. It is unclear why SVR rates in Kamal’s study were about twice as high as those obtained by Derbala, especially since both trials were conducted in Egypt, and thus patients could be expected to have similar demographic factors with respect to HCV variants. http://www.hcvadvocate.org/news/newsRev/2005/HJR-2.12.html#3     European Union's CHMP Adopts Positive Opinion for Shorter Course of PEGINTRON(R) and REBETOL(R) Combination Therapy for Certain Hepatitis C Patients with Genotype 1 and Low Viral Load         This press release was issued by Schering-Plough.   KENILWORTH, N.J., July 29 /PRNewswire-FirstCall/ -- Schering-Plough Corporation (NYSE: SGP - News) today reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) has issued a positive opinion recommending approval of revised dosing instructions which allow a shorter, 24-week course of weight-based PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800 - 1,200 mg) daily combination therapy among a subgroup of patients with hepatitis C virus (HCV) genotype 1 infection and low viral load (< 600,000 IU/ml). A shorter 24-week course of therapy can be considered for these patients who have achieved rapid virologic response, defined as undetectable virus (HCV-RNA negative) at week 4 of treatment that is maintained through week 24. A 92 percent sustained virologic response was achieved with 24 weeks of treatment among the 41 percent of patients who met the criteria for early response.   PEGINTRON and REBETOL combination therapy was previously approved in the EU for a 48-week course of therapy for all patients with genotype 1 who exhibit virological response at week 12. Approval of this shorter PEGINTRON and REBETOL combination treatment regimen cuts by half the duration of therapy for a subset of hepatitis C patients with genotype 1 and low viral load. This is the only treatment regimen approved in the European Union (EU) for a 24-week course of therapy in certain genotype 1 patients.   The CHMP recommendation serves as the basis for a European Commission approval of this labeling change. A Commission Decision will result in Marketing Authorization with unified labeling that will be valid in the current EU 25 member states as well as in Iceland and Norway.   "The important results of this clinical study with PEGINTRON and REBETOL reflect the ongoing efforts of Schering-Plough to define optimal dose and treatment schedules for specific HCV patient groups," said Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute.   Study Results   The recommended labeling change for PEGINTRON and REBETOL is based on results of a clinical study involving 235 patients with HCV genotype 1 and low viral load who received 24 weeks of combination therapy with weight-based PEGINTRON (1.5 mcg/kg once weekly) and REBETOL (800 - 1,400 mg daily); only two patients weighing >105 kg received the 1,400 mg dose). In the study, 41 percent of patients (97/235) had undetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. Patients in this subgroup achieved a 92 percent (89/97) rate of sustained virological response (SVR). The high sustained response rate in this group of patients was identified in an interim analysis and prospectively confirmed.   Genotype 1 virus is the most common worldwide, the most difficult to treat successfully and accounts for about 70 percent of HCV infections among European patients overall, varying by geography. For patients with HCV genotypes 2 or 3, the EU labeling for PEGINTRON recommends that all patients be treated for 24 weeks. Patients infected with HCV genotype 4 are considered harder to treat and generally 48 weeks of therapy is recommended.   About PEGINTRON and REBETOL Combination Therapy   PEGINTRON and REBETOL combination therapy for chronic hepatitis C was approved in the European Union (EU) in March 2001. The recommended dose in the EU for combination therapy is PEGINTRON 1.5 mcg/kg/once weekly plus REBETOL 800-1,200 mg daily, adjusted to body weight. PEGINTRON had previously received centralized marketing authorization in the EU and is marketed as a monotherapy in cases of intolerance or contraindication to ribavirin for the treatment of adult patients with chronic hepatitis C.   PEGINTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy dosed according to patient body weight that is designed to achieve an effective balance between antiviral activity and elimination half-life. REBETOL is an oral formulation of ribavirin, a synthetic nucleoside analog with broad-spectrum antiviral activity.   Chronic hepatitis C is estimated to affect more than 10 million people in major world markets, including 5 million in Europe. It is a leading cause of chronic liver disease and one of the most common reasons for liver transplant in Europe.   Important Information Regarding U.S. Labeling for PEG-INTRON and REBETOL   WARNING   Alpha interferons, including PEG-INTRON, cause or aggravate fatal or life- threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many but not all cases these disorders resolve after stopping PEG-INTRON therapy.   Ribavirin causes hemolytic anemia. Anemia associated with REBETOL therapy may exacerbate cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL. It is advised that complete blood counts (CBC) be obtained at baseline and at weeks 2 and 4 of therapy or more frequently if clinically indicated.   REBETOL and combination REBETOL/PEG-INTRON therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and during the 6 months after stopping therapy. REBETOL and combination REBETOL/PEG-INTRON therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (at least two reliable forms) during treatment and during the 6- month post-treatment follow-up period. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of REBETOL. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling (800) 727-7064.   PEG-INTRON There are no new adverse events specific to PEG-INTRON as compared to INTRONÂ A (interferon alfa-2b, recombinant) for Injection, however, the incidence of some (e.g., injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEG-INTRON were "flu-like" symptoms, occurring in approximately 50% of patients, which may decrease in severity as treatment continues. Application site disorders were common (47%), but all were mild (44%) or moderate (4%) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation). Injection site pain was reported in 2% of patients receiving PEG-INTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEG-INTRON.   Psychiatric adverse events, which include insomnia, were common (57%) with PEG-INTRON, but similar to INTRON A (58%). Depression was most common at 29%. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1% of patients during or shortly after completing treatment with PEG-INTRON.   PEG-INTRON/REBETOL is contraindicated in patients with autoimmune hepatitis, decompensated liver disease, and in patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia).   The following serious or clinically significant adverse events have been reported at a frequency less than 1% with PEG-INTRON or interferon alpha: severe decreases in neutrophil or platelet counts, hypothyroidism, hyperglycemia, hypotension, arrhythmia, ulcerative and hemorrhagic colitis, development or exacerbation of autoimmune disorders including thyroiditis, RA, systemic lupus erythematosus, psoriasis, pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, some resulting in patient deaths), urticaria, angioedema, bronchoconstriction, anaphylaxis, retinal hemorrhages, and cotton wool spots.   In the PEG-INTRON/REBETOL combination trial the incidence of serious adverse events was 17% in the PEG-INTRON/REBETOL groups compared to 14% in the INTRON A/REBETOL group. The incidence of severe adverse events in the PEG-INTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEG-INTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-INTRON (1.5 mcg/kg)/ REBETOL and in 34% of those receiving INTRON A/REBETOL.   REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.   Schering-Plough Corporation is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough's vision is to earn the trust of the physicians, patients and customers served by its more than 30,000 people around the world. The company's Web site is www.schering-plough.com.

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Peginterferon-α-2a (40KD) and Ribavirin for 16 or 24 Weeks in Patients With Genotype 2 or 3 Chronic Hepatitis C

“…patients chronically infected with HCV-2 (independent from pretreatment viremia) and those infected with HCV-3 and a pretreatment HCV RNA level equal or below 800,000 IU/mL, who can achieve a rapid virologic response defined as HCV RNA below 600 IU/mL at week 4, can be treated for only 16 weeks with peginterferon-α-2a and ribavirin without compromising the chances for a sustained virologic response. The data of the present study are less conclusive for HCV-3-infected patients with a pretreatment viremia above 800,000 IU/mL, who achieve a rapid virologic response as well as for those patients who cannot achieve a rapid virologic response…”

Gastroenterology
Volume 129, Issue 2, Pages 522-527 (August 2005)
    
Data of the present study were presented in part at the 55th Annual Meeting of the American Association for the Study of Liver Diseases, October 29-November 2, 2004, Boston, Massachusetts.

Michael von Wagner⁎, Miriam Huber‡, Thomas Berg§, Holger Hinrichsen‖, Jens Rasenack¶, Tobias Heintges#, Alexandra Bergk§, Christine Bernsmeier‖, Dieter Häussinger#, Eva Herrmann⁎, Stefan Zeuzem*

ABSTRACT
Background & Aims: Standard therapy of patients with chronic hepatitis C virus (HCV) infected with HCV genotype-2 or -3 is the combination of pegylated interferon-α and ribavirin for 24 weeks. Whether shorter treatment durations are possible for these patients without compromising sustained virologic response rates is unknown.

Methods: Patients chronically infected with HCV-2 (n = 39), HCV-2/3 (n = 1), or HCV-3 (n = 113) were treated with peginterferon-α-2a (180 μg/wk) plus ribavirin 800-1200 mg/day. HCV RNA was quantitatively assessed after 4 weeks. Patients with a rapid virologic response (HCV RNA below 600 IU/mL) were randomized for a total treatment duration of 16 (group A) or 24 weeks (group B). All patients with HCV RNA ≥600 IU/mL at week 4 (group C) were treated for 24 weeks. End-of-treatment and sustained virologic response were assessed by qualitative RT-PCR (sensitivity 50 IU/mL).

Results:

Only 11 of 153 patients (7%) were allocated to group C. End-of-treatment and sustained virologic response rates were 94% and 82%, (group A), 85% and 80% (group B), and 73% and 36% (group C), respectively.

In patients infected with genotype HCV-3 and high viral load (>800,000 IU/mL), a significant lower sustained virologic response rate was found than in patients infected with HCV-3 and a viral load lower or equal to 800,000 IU/mL (59% vs 85%, respectively; P = .003).

Conclusions: In HCV-2 and -3 (low viral load)-infected patients who have a rapid virologic response, treatment for 16 weeks with peginterferon-α-2a and ribavirin is sufficient. In patients infected by HCV-3 (high viral load), longer treatment may be necessary.

MORE RESULTS
Virologic Response According to HCV Genotype and Pretreatment Viremia

Sustained virologic response rates in genotype HCV-2-infected patients were higher than in genotype HCV-3-infected patients (92% vs 73%, respectively) and were not affected by pretreatment viremia. Genotype HCV-3-infected patients with a baseline viremia above 800,000 IU/mL, however, achieved a lower sustained virologic response rate compared with patients with a baseline viremia equal or below 800,000 IU/mL (59% vs 85%, respectively, P = .003).

No differences in sustained virologic response rates were observed between treatment groups A and B for patients infected with genotype HCV-2. The sustained virologic response rate of HCV-3-infected patients with a pretreatment viremia equal or below 800,000 IU/mL was not compromised by a 16-week treatment duration (group A) compared with 24 weeks (group B) (Figure 2). The sustained virologic response rate in HCV-3-infected patients with a baseline viremia above 800,000 IU/mL was higher with 24 weeks of combination therapy in group B than with 16 weeks treatment in group A (67% vs 55%, respectively, P > .2) but did not reach statistical significance.

Characteristics of the Patients
This study was performed between January 2002 and March 2004 in 6 German tertiary referral centers. According to the inclusion and exclusion criteria, 153 patients were enrolled: 39 (26%) and 113 patients (74%) were infected with genotypes HCV-2 and -3, respectively, whereas in 1 patient (<1%), genotypes HCV-2 and -3 could not be differentiated.

Virologic and Biochemical Response
After 4 weeks treatment with peginterferon-α-2a plus ribavirin, HCV RNA was below 600 IU/mL in 142 of 152 patients (93%). This rapid virologic response was achieved by 37 of 38 patients (97%) infected with genotype HCV-2 and by 103 of 112 patients (92%) infected with genotype HCV-3 (P > 0.2). These patients and 1 patient who was negative at week 2 with a missing HCV RNA result at week 4 were randomized to groups A (n = 71) and B (n = 71). Patients with HCV RNA ≥600 IU/mL at week 4, including 1 patient with missing HCV RNA results at weeks 2 and 4, were allocated to group C (n = 11).

An overall intent-to-treat virologic response at the end of therapy was achieved in 135 of 153 patients (88%) and a sustained virologic response in 119 of 153 patients (78%). Virologic response rates were similar in patients randomized to either 16 weeks (group A) or 24 weeks of combination therapy (group B). In groups A and B, 67 of 71 patients (94%) and 60 of 71 patients (85%) achieved an end of treatment response and 58 of 71 patients (82%) and 57 of 71 patients (80%) sustained a virologic response, respectively. This corresponds to a difference in sustained virologic response between groups A and B of at most 11.5% (97.5% 1-sided confidence interval). The sustained virologic response rate in patients without a rapid virologic response who were treated for 24 weeks (group C), however, was lower than in group B (36% vs 81%, respectively, P = .005), whereas the end-of-treatment response rate was only slightly lower in group C (72% vs 84%, respectively, P = ns).

Sustained biochemical response rates in groups A, B, and C were 89%, 87%, and 67%, respectively. Sustained biochemical response was observed in 110 of 115 sustained virologic responders (96%), whereas 5 sustained virologic responders did not show a biochemical response with ALT levels ranging up to 2.95 times the upper limit of normal. Each of the 5 subjects was infected with HCV-2.

Other Predictors of Response
From multivariate logistic regression analysis of all patients, genotype HCV-2, low viral load, and low γ-glutamyltransferase (GGT) value were independent factors of sustained virologic response. When the analysis was based on patients infected with genotype HCV-3 only, baseline viral load (P = .01) and GGT value (P = .02) remained as independent negative predictors for sustained virologic response. Fibrosis score and GGT were slightly higher in patients without rapid virologic response (group C) compared with patients with rapid virologic response (groups A and B); however, differences did not reach statistical significance.
Adverse Events and Dose Modifications

Seven serious adverse events were reported by the 153 patients enrolled into this study (bacterial infection, carcinoma, diverticulitis, paranoid reaction, pneumonia, pregnancy of partner, tuberculosis). Only 1 patient (group B) discontinued therapy because of an adverse event (intravenous drug abuse). In addition, 8 patients (1 in group A, 5 in group B, and 2 in group C) prematurely withdrew from therapy for nonsafety reasons. Adverse events were typical of those previously reported with combination therapy with (pegylated) interferon and ribavirin. In general, the frequency of adverse events was lower in the 16-week treatment group (group A) compared with the 24-week treatment groups (groups B and C).

Twenty-two of 153 patients (14%) and 17 of 153 patients (11%) required dose reduction or treatment interruption because of adverse events of peginterferon-α and ribavirin, respectively. Neutropenia (3%) and anemia (6%) were the most common adverse events leading to dose modification.

AUTHOR DISCUSSION
Discussion
return to Article Outline

Previous studies have convincingly shown that combination therapy with pegylated interferon-α plus ribavirin for 24 weeks achieves similar sustained virologic response rates in patients infected with genotype HCV-2 or -3 as combination therapy for 48 weeks.9,10 Subsequent approaches are currently investigating whether either the dose for peginterferons and/or the duration of therapy can be reduced without compromising sustained virologic response rates. In the present study, patients infected with genotype HCV-2 or -3 who achieved a rapid virologic response were randomized to either the standard treatment duration of 24 weeks or a shorter duration of 16 weeks. Patients received a standard dose of peginterferon-α-2a (180 μg once per week) and weight-based ribavirin doses (800-1200 mg/day).

The mechanism of action of ribavirin in the treatment of patients with chronic hepatitis C remains unknown. Ribavirin in addition to (pegylated) interferon enhances the virologic response and more importantly reduces relapse rates in patients who achieve an end-of-treatment virologic response. Therefore, it was decided to use a high dose of ribavirin (800-1200 mg/day according to body weight) in the present study to avoid virologic relapse, particularly in patients randomized to 16 weeks of combination therapy. During the course of the present study, Hadziyannis et al reported that 24 weeks of combination therapy with a flat ribavirin dose of 800 mg/day is sufficient in patients infected with genotype HCV-2 or -3.9 Whether 800 mg of ribavirin per day is sufficient for treatment durations shorter than 24 weeks will be answered by an international multicenter trial (ACCELERATE).

The present study demonstrates that 16 weeks of therapy with peginterferon-α-2a plus weight-based ribavirin is sufficient for patients chronically infected with genotype HCV-2 or -3 who achieve a rapid virologic response at week 4. Patients treated for 16 weeks also tended to report adverse events less frequently than patients treated for 24 weeks. The rapid virologic response was independent from baseline HCV RNA levels. Seven percent of mainly HCV-3-infected patients could not achieve a rapid virologic response at week 4 and were treated according to current guidelines for 24 weeks. The sustained virologic response rate, however, was significantly impaired in these patients.

Several studies have shown that an early virologic response predicts sustained virologic response.12-14 A less than 2 log10 decline of HCV RNA within the initial 12 weeks of therapy has been generally accepted as an early stopping algorithm with a negative predictive value of 98%-100%.12,15 However, this algorithm is only useful in genotype HCV-1-infected patients, and less than 2% of patients infected with genotype HCV-2 or -3 are unable to meet this criterion.

In the present study, the sustained virologic response rate was higher in patients infected with HCV-2 than in those infected with HCV-3, supporting the concept that virologic response rates should be presented according to single genotypes rather than to a combination of genotypes. The rapid and the sustained virologic response rates in HCV-2-infected patients were above 90%, suggesting that neither quantification of HCV RNA before starting nor during therapy is required to define the duration of treatment in these patients.

In HCV-3-infected patients, however, a different algorithm may be required. Within the group of chronically HCV-3-infected patients treated for 16 weeks, a higher virologic relapse rate was observed in patients with a baseline HCV RNA concentration of more than 800,000 IU/mL, and, in this subgroup, the sustained virologic response rate was lower for the 16-week compared with the 24-week treatment group. Quantification of HCV RNA at baseline and at early time points during therapy (eg, at 4 weeks as in the present study) may allow to individualize treatment duration in these patients. However, further detailed analyses of baseline parameters, initial viral decline, and sustained virologic outcome are required to define the optimal duration of therapy in these patients. It is also conceivable that a small subgroup of HCV-3-infected patients can be identified according to baseline parameters and/or slower early decline of HCV RNA, who may benefit from longer than 24 weeks of therapy.

The concept of shorter combination therapy with pegylated interferon and ribavirin in patients chronically infected with genotype HCV-2 or -3 is supported by 2 other trials. In an uncontrolled study, Dalgard et al determined the efficacy of 14 weeks combination treatment with peginterferon-α-2b (1.5 μg/kg once per week) plus ribavirin (800-1400 mg according to body weight) in HCV-2- or HCV-3-infected patients who achieved an early virologic response, defined as undetectable HCV RNA at weeks 4 and 8. Ninety-five of 122 patients (78%) fulfilled these early virologic response criteria, and 85 of the 95 patients achieved a sustained virologic response.16 Mangia et al observed a sustained virologic response rate of 89% in mainly HCV-2-infected patients who received peginterferon-α-2b (1.0 μg/kg once per week) plus ribavirin (1000-1200 mg according to body weight) for a total duration of 12 weeks if they were HCV RNA negative at week 4.17

In conclusion, patients chronically infected with HCV-2 (independent from pretreatment viremia) and those infected with HCV-3 and a pretreatment HCV RNA level equal or below 800,000 IU/mL, who can achieve a rapid virologic response defined as HCV RNA below 600 IU/mL at week 4, can be treated for only 16 weeks with peginterferon-α-2a and ribavirin without compromising the chances for a sustained virologic response. The data of the present study are less conclusive for HCV-3-infected patients with a pretreatment viremia above 800,000 IU/mL, who achieve a rapid virologic response as well as for those patients who cannot achieve a rapid virologic response. Additional trials are required to optimize treatment duration in these patients.

Etanercept Treatment to Slow Fibrosis Progression Shows No Histological or Biochemical Improvement in Chronic HCV Genotype 1 Nonresponders to Peginterferon/Ribavirin

There is no established treatment that prevents the progression of fibrosis in patients who fail interferon-based combination antiviral treatment. Tumor necrosis factor (TNF) alpha is an important mediator in the development of fibrosis, thereby implicating a possible role for the inhibition of TNF alpha (etanercept) in the treatment of chronic Hepatitis C (CHC). 

The aim of the current study was to asses the efficacy of etanercept treatment on the necroinflammatory and fibrotic change in patients with CHC infection, genotype 1, nonresponders to interferon-based combination antiviral treatment.

Ten patients with CHC genotype 1, nonresponders to antiviral treatment with pegylated interferon and ribavirin, were enrolled. Active HCV infection was documented by a positive HCV RNA by PCR (Cobas  Amplicor).

Etanercept was administered for 24 weeks duration at a dose of 25 mg subcutaneously twice weekly.

A liver biopsy prior and post etanercept treatment was obtained and reviewed by an independent pathologist using the METAVIR score.

Patients were followed monthly for evaluation of side effects and liver related blood tests for a period of 32 weeks.

Results

·         Of the ten patients enrolled, 50% (5/10) were women of mean age 50 years, and 50% (5/10) were men of mean age 40 years.

·         One patient was withdrawn due to abnormal elevation in serum alanine aminotransferase (ALT); one patient was lost to follow up.

·         Eight post treatment liver biopsies were evaluated;

·         12% (1/8) had an improvement in the stage of fibrosis, 88% (7/8) had no change in fibrosis.

·         The mean baseline platelet count (PLT) and ALT level were (177,000 MCL/120 U/L) respectively.

·         None of the differences between platelet count and ALT levels at baseline and at follow up achieved statistical significance (p >0.05).

·         Even though one patient had an improvement in the stage of biopsy after treatment, these results did not reach statistical significance.

Conclusion

This is the first analysis of etanercept treatment for inhibition of hepatic fibrosis in patients with chronic HCV, genotype 1, nonresponders to combination antiviral therapy.  There was no significant histological or biochemical improvement.

06/01-05

Reference
R J Marrero and others. A Pilot Study Of Etanercept Treatment for Inhibition of Fibrotic Progression in Chronic Hepatitis C Infection. Abstract S1557. DDW 2005. May 14-18, 2005. Chicago, IL.

Predictors of Treatment Failure in Patients with Hepatitis C Genotypes 2 or 3

Sustained virologic response (SVR) following antiviral therapy in genotype 2 and 3 HCV patients is accomplished in most cases, although a small number of patients fail to respond (NR) or relapse (Rel) after discontinuation of therapy.

Understanding predictors of treatment failure in this “highly treatment-sensitive” population may allow the development of novel therapeutic approaches. The aim of the present study, presented at DDW 2005, was to assess predictors of treatment failure (NR and Rel) in patients with HCV genotypes 2 and 3.

All treatment-naive Caucasian patients with chronic HCV genotype 2 and 3 infection at The Cleveland Clinic Foundation between 2001 and 2004 were identified (59 patients).

Those who received at least one dose of peginterferon (fixed dose PEG 2a [Pegasys] or weight-based PEG 2b) [PegIntron] and ribavirin were included whereas liver transplant recipients, co-infected hepatitis B and/or HIV patients were excluded.

Identification of variables associated with treatment failure was done by comparing variables of interest between SVR and non-SVR groups using Wilcoxon test for continuous variables and Chi-Square for categorical variables.

Individual logistic regression was done to obtain Odds Ratios (OR).

Multivariate modeling was done to identify independent predictors of treatment failure.

Results

·         Overall, 14/59 (24%) patients failed to achieve SVR (7 NR and 7 Rel).

·         Male gender, history of alcohol abuse, non-weight-based therapy, and presence of histologically advanced disease were identified as predictors of failure to achieve SVR by univariate analysis.

·         Multivariable logistic regression analysis model (whole model p=0.0006) identified history of alcohol abuse and non-weight-based treatment as significant independent predictors of failure to achieve SVR in these patients.

·         More patients with genotype 3 failed to achieve SVR, although not statistically significant.

Conclusions

The authors conclude, “A subgroup of Caucasian HCV patients with genotype 2 and 3 infections less likely to achieve SVR may potentially benefit from weight-based peginterferon therapy.”

“Excessive alcohol intake appears to contribute to treatment failure in patients infected with HCV genotype 2 or 3 infections”

“Novel therapeutic approaches such as longer duration of treatment may lead to better outcomes in this population.”

06-01-05

Reference
A M Qadri and others. Predictors Of Treatment Failure in Patients With Hepatitis C Genotypes 2 or 3 Infections. Abstract S1565. DDW 2005. May 14-18, 2005. Chicago, IL.

Enrollment Completed for Phase IIb Trial of Valopicitabine plus Pegasys Combination Therapy for HCV Genotype 1 Patients Non-responsive to Peginterferon/Ribavirin

Idenix Pharmaceuticals announced that it has completed enrollment of its phase IIb clinical trial of valopicitabine (NM-283) with more than 170 treatment refractory hepatitis C genotype 1 patients. The company believes that this is the first time an antiviral experimental drug that acts directly against the hepatitis C virus has reached this stage of clinical testing.

"Today, there are very limited treatment options for treatment refractory hepatitis C patients, or patients that have failed prior treatment with existing hepatitis C therapies. Among this patient population, approximately 10 percent respond to re-treatment with the current standard of care, pegylated interferon plus ribavirin," said Jean-Pierre Sommadossi, Ph.D., Idenix's chairman and chief executive officer. "Since standard treatment is only effective in about half of genotype 1 patients, it is estimated that 30,000 - 40,000 patients in the US will fail treatment each year. Our development program for valopicitabine is seeking first to address this major, growing, unmet need."

Phase IIb Trial Design

Valopicitabine is being evaluated in a phase IIb clinical trial in patients who have previously failed treatment with pegylated interferon plus ribavirin. This six-month head-to-head trial, comparing the combination of valopicitabine plus Pegasys to ribavirin plus Pegasys, is evaluating more than 170 hepatitis C genotype 1 patients who have previously failed at least 3 months of treatment with pegylated interferon plus ribavirin. Idenix expects to report initial clinical data from this phase IIb trial in the fall of 2005. Currently, the company anticipates initiating a phase III clinical trial in this patient population in the first half of 2006.

About Valopicitabine (NM283)

Valopicitabine (NM283) is an oral, novel nucleoside analog that was co- discovered by Idenix and the University of Cagliari through a cooperative laboratory agreement under the direction of Dr. Paolo LaColla, Director of the Department of Biomedical Sciences and Technologies of the University. Valopicitabine (NM283) is currently being developed in combination with pegylated interferon for use in both HCV treatment refractory and HCV treatment-naive patient populations.

About Hepatitis C

There are approximately 170 million people worldwide with chronic hepatitis C virus (HCV) infection, of which approximately 2.7 million are in the United States. Chronic HCV infection accounts for 40 percent of end-stage cirrhosis, 60 percent of liver cancer and 30 to 40 percent of liver transplants in the United States and other industrialized countries.

Responses to current treatment options are frequently inadequate due to the inability of some patients to tolerate these treatments and by their limited effectiveness, particularly in patients infected with HCV genotype 1. The genotype 1 strain of HCV is the most treatment-resistant HCV genotype and is estimated to cause more than 70 percent of the reported cases of hepatitis C in the US and Japan, and more than 65% of the reported cases of hepatitis C in Western Europe.

About Idenix

Idenix Pharmaceuticals is a biopharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of human viral and other infectious diseases. Idenix's current focus is on the treatment of infections caused by hepatitis B virus, hepatitis C virus and human immunodeficiency virus (HIV). Idenix's headquarters are located in Cambridge, Massachusetts. The company also has drug discovery and development operations in Montpellier, France and drug discovery operations in Cagliari, Italy. For further information about Idenix, please visit http://www.idenix.com.

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06/03/05

Source
Idenix Pharmaceuticals. Idenix Pharmaceuticals Completes Enrollment of Valopicitabine (NM283) Phase IIb Trial in Treatment-refractory Hepatitis C Genotype 1 Patients. Press Release. May 31, 2005.