Genotypes 1 and 4 do not respond to treatment as well as genotypes 2 and 3, regardless of the type of interferon used (Berg 2003; Fried 2002a; S. Lee 2002; McHutchison 1998; Poynard 1998). In their meta-analysis of data from three trials of pegylated interferon alfa-2a, Lee and colleagues found a non-1 genotype to be the strongest independent predictor of SVR (OR, 4.11; 95% CI, 2.90-5.86; P=0.0001) (S. Lee 2002). A 24-week course of treatment for individuals with genotypes 2 and 3 appears to be sufficient; a 48-week course of treatment is recommended for individuals with genotypes 1 and 4 (Di Bisceglie 2002; Hadziyannis 2004).

Genotype 3 does not appear to be as sensitive to treatment as genotype 2 (Mangia 2004: Zeuzem 2003). Zeuzem and colleagues treated 224 individuals with HCV-2 or HCV-3 with 1.5 µg/kg of pegylated interferon alfa-2b plus weight-based rivavirin (800 to 14,000 mg/day) for 24 weeks. Overall, 81% achieved sustained virological response, but SVR rates were lower in those with genotype 3 (79% [143/182]) than in genotype 2 (93% [39/42]). Relapse rates were higher in genotype 3 (14% vs. 7% in genotype 2). The difference in response rates may be attributed in part to steatosis and high baseline viral load. Steatosis was significantly more prevalent in genotype 3 (P=0.003), and it was associated with a high baseline viral load (P=0.001). Steatosis of <5% was significantly associated with SVR (P=0.015) (Zeuzem 2003).

Genotype 4 may be more responsive to treatment than genotype 1. Sustained virological response rates from two studies that used 48 weeks of pegylated interferon plus ribavirin have ranged from 40% to 61% (Esmat 2003; Hassan 2003).

The viral kinetics of hepatitis C during early treatment differ depending on the genotype of HCV (A. U. Neumann 2000; Pawlotsky 2002; Zeuzem 2001). Frequent blood sampling from 12 individuals with HCV genotypes 1a, 1b, 2a, and 2b over the first 14 days of high-dose interferon revealed significant differences. Individuals with genotypes 2a and 2b had larger and more rapid decreases in HCV RNA after 48 hours than those with genotypes 1a and 1b (2.95 log copies/mL vs. 1.65 log copies/mL; t1/2 = 2.0 ± 0.5 hours vs. t1/2 = 3.0 ± 1.0 hours). At the end of 14 days, a significantly larger proportion of individuals with genotypes 2a and 2b had undetectable HCV RNA (P=0.03) (A. U. Neumann 2000). An examination of first and second-phase viral kinetics by genotype and mode of treatment (standard or pegylated interferon monotherapy) revealed more rapid first-phase and second-phase viral decay slopes for non-1 genotypes treated with pegylated interferon (Zeuzem 2001). Pawlotsky and colleagues observed less marked decreases in second-phase viral decay in genotypes 1 and 4 vs. genotype 3. At four weeks of treatment, individuals with genotypes 1 and 4 were less likely to be classified as rapid responders (individuals with decreases ≥0.3 log per week) (Pawlotsky 2002).

http://www.aidsinfonyc.org/tag/coinf/hcv2004/chap5.html

24 weeks of peginterferon alfa-2a plus ribavirin as effective as 48 weeks with higher-dose ribavirin for HCV genotype 2 and 3

By Jillian L. Lokere, MS

November 3, 2004 — The current recommendation that patients infected with hepatitis C virus (HCV) genotype 2 or 3 receive 24 weeks of peginterferon plus low-dose ribavirin is appropriate, regardless of baseline viral load, and the duration need not be extended to 48 weeks. These results were presented by Mario Rizzetto, Universita di Torino, Torino, Italy, and colleagues at the 55th Annual Meeting of the American Association for the Study of Liver Diseases.

The standard of care for patients with HCV genotype 2 or 3 infection is 24 weeks of therapy with peginterferon plus ribavirin 800 mg/d. Although this regimen provides high rates of sustained virologic response, some have thought that longer treatment or a higher dose of ribavirin might increase SVR rates.

Rizzetto and colleagues analyzed combined data from 2 large, international phase 3 trials by Fried and colleagues and Hadziyannis and colleagues. They compared SVR rates in patients infected with genotypes 2 and 3 and the efficacy of different durations and doses of ribavirin. They also investigated the effects of baseline HCV RNA level on SVR.

A total of 258 patients infected with genotype 2 and 374 patients infected with genotype 3 were included in the study. Eligible patients were treatment naive and had detectable serum HCV RNA greater than 2000 copies/mL, elevated alanine aminotransferase (ALT) levels, and compensated liver disease. The study population was predominantly white and male.

Patients were randomized to receive peginterferon alfa-2a 180 µg weekly plus ribavirin at a low dose (800 mg/d) or a high dose (1000 or 1200 mg/d) for either 24 or 48 weeks. Thus, the 4 study arms were low dose for 24 weeks, high dose for 24 weeks, low dose for 48 weeks, and high dose for 48 weeks.

There was a nonsignificant trend toward higher SVR rates in patients infected with genotype 2 compared to 3. The overall SVR rate was 82% for patients infected with genotype 2 vs 77% for patients infected with genotype 3. No consistent trend in SVR was noted high (greater than 800,000 IU/mL) and low baseline viral load groups were compared. Prolonging treatment or increasing the daily dose of ribavirin also did not increase SVR rates, which were similar among the 4 treatment arms.

The investigators concluded that the current recommendation of 24 weeks of treatment for patients infected with HCV genotype 2 or 3 appears to be appropriate, regardless of baseline HCV RNA level. These data contrast with a recent study of peginterferon alfa-2b and ribavirin, which indicated that patients infected with genotype 3 who have a high viral load should receive 48 weeks of treatment.

Reference

Rizzetto M, Hadziyannis S, Ackrill AM. Sustained virological response to peginterferon alfa-2a plus ribavirin: comparison of outcomes in patients infected with HCV genotype 2 and 3. Program and abstracts of the 55th Annual Meeting of the American Association for the Study of Liver Diseases; October 29 - November 2, 2004; Boston, Massachusetts. Abstract 198.

Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.

Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355.

http://clinicaloptions.com/hep/news/news_AASLD2004_198.asp

Peginterferon Alfa- 2b (Peg-Intron) and Ribavirin Combination Therapy in Chronic HCV Genotype 4

Pegylated interferons have replaced conventional interferon for treatment of chronic hepatitis C due to their high efficacy in inducing sustained virological response. The current randomized, parallel-group, double-blind trial was designed to assess the efficacy and safety of 24 or 48 weeks of treatment with peginterferon-alpha2b in chronic hepatitis C genotype 4.

148 patients with chronic hepatitis C genotype 4 matched for age, gender, duration and stage of liver disease at enrollment were randomly assigned to receive peginterferon alfa-2b ( 1.5 microg/kg) once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight) for 24 (Group A: n=48). 36 (Group B=50) or 48 weeks (Group C: n=60).

Liver functions, HCV-RNA titers and viral kinetics were evaluated before, during and after therapy. Liver biopsies and histopathological evaluation are performed before therapy induction and at end of follow-up.

The primary treatment endpoint was to achieve sustained virologic response marked by undetectable HCV RNA concentration at the end of 24 weeks of follow-up after cessation of therapy. Secondary end-points are end of treatment virological responses and histological response.

Results

In patients infected with HCV genotype 4, sustained virologic response was achieved in 46/60 subjects (76%), 37/50 (74%) and 23/48 (48%) treated with peginterferon-alpha2b and ribavirin for 48, 36, 24 weeks respectively. Overall 48 and 36 weeks of treatment were statistically superior to 24 weeks (P=0.02).

The difference in sustained virologic response rates between 48 and 36 weeks of treatment was not statistically significant (p=0.3). The decrease in viral load 24 h after therapy was greater in virological responders (1.06 log) than in nonresponders (NR) (0.26 ; P=0.002).

An initial decline > 1.5 log was detected in all sustained responders. Pair-wise comparison of the histological scores for the initial and the follow-up biopsies showed no deterioration in the total HAI index in any patient and an improvement (>2 point HAI score improvement) in 110 patients (74%), regardless of duration of therapy.

Improvement in the histological score was more marked in sustained virological responders who showed a 3-5 points decrease in mean HAI activity scores.

The overall safety profiles of the three treatment regimens were similar.

Conclusion

In conclusion, the authors write, “In patients with chronic hepatitis C genotype 4, once-weekly peginterferon alfa-2b plus ribavirin was tolerated and produced significant improvements in the rate of sustained virologic response, as well as histological response.”

“Patients with HCV genotype 4 seem to be adequately treated with peginterferon alfa-2b plus ribavirin for 36 weeks.”

11/08/04

Reference
S M Kamal and others. PEGINTERFERON-ALPHA2B AND RIBAVIRIN COMBINATION THERAPY IN CHRONIC HEPATITIS C GENOTYPE 4: IMPACT OF TREATMENT DURATION ON SUSTAINED VIROLOGIC REAPONSE. Abstract 366 (poster). 55^th AASLD. October 29-November 2, 2004. Boston, MA.

http://www.hivandhepatitis.com/2004icr/aasld/docs/hcv/110804_f.html

Presentation Time: 11/1/2004 5:45:00 PM Program#/Poster#: 197

SHORT (14 WEEKS) TREATMENT WITH PEGYLATED INTERFERON ALPHA-2B AND RIBAVIRIN IN PATIENTS WITH HEPATITIS C GENOTYPE 2/3 VIRUS INFECTION AND EARLY VIROLOGICAL RESPONSE

Olav Dalgard, Aker University Hospital, Oslo, Norway; Kristian Bjøro, Rikshospitalet, Oslo, Norway; Kjell Hellum, Akershus University Hospital, Nordbyhagen, Norway; Bjørn Myrvang, Ullevål University Hospital, Oslo, Norway; Ståle Ritland, Buskerud Hospital, Drammen, Norway; Kjell Skaug, Nils Raknerud, Helge Bell, Aker University Hospital, Oslo, Norway.

Aim:

To determine the efficacy of 14 weeks treatment to patients infected with hepatitis C virus (HCV) genotype 2 or 3 experiencing early virological response.

Material and methods:

Multicenter trial. 122 treatment naïve patients received pegylated interferon alfa-2b 1,5μg/kg subcutaneously once weekly and ribavirin 800-1400 mg/day based on body weight. Treatment was stopped at week 14 in those with an early response, defined as undetectable HCV RNA at week 4 and 8. Patients without early response were assigned to 24 weeks treatment. The primary endpoint was sustained virological response (SVR), defined as undetectable HCV RNA 24 weeks after end of treatment.

Results:

Among 122 included patients, 95 (78%) had an early response and received 14 weeks of treatment. The remaining 27 (22%) patients were treated for 24 weeks. SVR was obtained in 85/95 patients (90%) in the 14 weeks treatment group and 15/27 (56%) in the 24 weeks treatment group. Altogether, SVR was obtained in 100/122 of the patients (82%, 95 CI: 75-89). In comparison Zeuzem et al ( J Hepatol 2004) obtained SVR in 81% after 24 weeks of HCV treatment to 224 genotype 2/3 patients. Logistic regression analysis of the present study showed that absence of bridging fibrosis/cirrhosis and receiving at least 80% of both drugs at least 80% of the planned time were predictors of SVR.

Conclusion:

Our findings suggest that 14 weeks of HCV treatment is effective in patients with HCV genotype 2 or 3 infection and early treatment response. This treatment approach should be further assessed in a andomized controlled trial.

http://www.hcvadvocate.org/news/reports/AASLD_2004/Posters_AASLD_2004.htm#B85

HCV Genotype 2 and 3 Have Similar SVR to Peginterferon alfa-2a plus Ribavirin, Regardless of Length of Treatment, Ribavirin Dose, or Baseline Viral Load

Retrospective analysis of combined patient data from 2 randomized, prospective, multinational, phase 3 studies

Summary of Key Conclusions

Overall sustained virologic response (SVR) with peginterferon plus ribavirin similar for patients with hepatitis C virus (HCV) genotype 2 and 3 infection
No statistical difference between SVR rates for genotype 2/3 patients regardless of HCV viral load
Relapse rates with genotype 3 infection similar regardless of treatment regimen

Background

Phase 3 trials showed 79% to 84% SVR with peginterferon alfa-2a and ribavirinin patients with HCV genotype 2 or 3 infection
Based on these trial results, treatment guidelines recommend ribavirin 800 mg/day for 24 weeks for HCV genotype 2- and 3-infected patients
However, a recent study suggested that patients with genotype 3 and high HCV RNA levels (> 600,000 IU/mL) have a higher treatment relapse rate
- Patients were treated with peginterferon alfa-2b (12kd) and ribavirin
- Treatment relapse was lower for:
  - Genotype 2 infection
  - Genotype 3 infection and low baseline HCV RNA levels

Summary of Study Design

Study aims:
- To compare SVR rates in patients with genotype 2 and 3 treated with peginterferon alfa-2a and ribavirin for 24 and 48 weeks
- Examine the effect of baseline HCV RNA levels on SVR
Patients treated with 1 of 4 regimens
- Low-dose ribavirin, 24 weeks
- Low-dose ribavirin, 48 weeks
- Standard-dose ribavirin, 24 weeks
- Standard-dose ribavirin, 48 weeks
- All patients received peginterferon alfa-2a 180 µg/week plus either:
  - Low-dose: ribavirin 800 mg/day
  - Standard dose: ribavirin 1000-1200 mg/day
SVR defined as undetectable HCV RNA, < 50 IU/mL (COBAS Amplicor HCV test, v2.0)
High HCV titer defined as > 800,000 IU/mL (>2 x 10<sup>6</sup> copies/mL)

Baseline Characteristics

Characteristics	Value
	(n = 632)
Male, n (%)	426 (67.4)
White, n (%)	573 (90.7)
Age, yrs	41.5 ± 9.2
Weight, kg	76.9 ± 15.8
BMI, kg/m²	26.0 ± 4.6
Genotype 2, n (%)	258 (40.8)
Genotype 3, n (%)	374 (59.2)
Cirrhosis, n (%)	128 (20.3)
HCV RNA level, 10⁶ copies/mL	7.6 ± 8.8

Main Findings

Overall SVR
- 82% for genotype 2
- 77% for genotype 3
- No statistically significant differences in terms of regimen and duration
Similarly, no significant differences in SVR by regimen and genotype

	SVR
Genotype	Low-dose x 24 Wks	Standard-dose x 24 Wks	Low-dose x 48 Wks	Standard-dose x 48 Wks
2 (n=258)	90%	85%	87%	77%
3 (n=374)	81%	79%	72%	76%

No statistical differences in SVR for genotype 2 or 3 patients regardless of HCV viral load
For genotype 3 patients, relapse rates comparable among regimens
- Standard-dose 48-week regimen: 12.8%
- Low-dose 24-week regimen: 11.4%

http://clinicaloptions.com/hep/conf/aasld2004/cs/198.asp

Reviewed Nov 14 2004