HCV genotypes 2 and 3 do not respond the same to interferon-based treatment

29th Jan 2008 By Liz Highleyman www.hivandhepatitis.com

Many clinical trials of hepatitis C treatment combine patients with HCV genotypes 2 and 3 when determining regimens and reporting results. Genotypes 2 and 3 are both considered "easier to treat" compared with genotype 1 and 4, but they are not as similar as often assumed, according to a study in the January 2008 Journal of Viral Hepatitis.

Researchers with the Canadian Pegasys Study Group re-assessed all treatment-naive patients with genotype 2 or 3 participating in a large non-randomized, open-label, expanded-access trial evaluating 180 mcg/week pegylated interferon alpha-2a (Pegasys) plus 800 mg/day ribavirin for 24-48 weeks. A total of 180 patients were analyzed, 72 (40%) with genotype 2 and 108 (60%) with genotype 3.

Results

Baseline characteristics of patients with genotypes 2 and 3 were similar, including the distribution of Metavir liver fibrosis scores.

The overall sustained virological response (SVR) rate was lower for genotype 3 patients compared with genotype 2 patients.

In a multivariate analysis, significant predictors of lack of SVR were genotype 3 (P= 0.030) and more advanced fibrosis (P = 0.014).

The negative impact of cirrhosis (Metavir stage F4) on treatment response was more pronounced among genotype 3 patients compared with genotype 2 patients (P = 0.027).

Conclusion
In conclusion, the authors wrote, "There is significant interaction between cirrhosis and genotype 3 leading to a poor antiviral response in such patients requiring an alternate management strategy."

Based on these findings, they suggested that genotype 2 and 3 patients should be analyzed separately in future clinical trials.

These results agree with those from a recent subanalysis of the POWeR study (see below), another Canadian trial that used pegylated interferon alfa-2b (PegIntron) plus ribavirin. In that study, too, genotype 3 patients had a lower SVR rate than genotype 2 patients, which was attributable to a lower end-of-treatment response rate. The POWeR investigators also recommended that researchers should avoid combining genotype 2 and 3 patients when reporting study results.

References
J Powis, KM Peltekian, SS Lee, and others (Canadian Pegasys Study Group). Exploring differences in response to treatment with peginterferon alpha 2a (40kD) and ribavirin in chronic hepatitis C between genotypes 2 and 3. Journal of Viral Hepatitis 15(1): 52-57. January 2008.

Future Studies Should Avoid Combining Genotype 2 and Genotype 3 Patients Due to Lower Response Rate in the Genotype 3 Population

Many studies of hepatitis C combine individuals with HCV genotype 2 and those with genotype 3 when reporting results. Genotype 2 and genotype 3 patients are both considered “easier to treat” compared to people with genotype 1, but the patient populations have some important differences.

In a subanalysis of the POWeR study, researchers evaluated the effect of fibrosis and baseline HCV viral load on sustained virological response (SVR) rates in treatment-naive genotype 2 and genotype 3 patients with chronic hepatitis C treated with weight-based pegylated interferon alfa-2b (PegIntron) and weight-based ribavirin. Findings were reported at the recent 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007) in Boston (November 2-6, 2007).

POWeR was an open-label observational trial conducted in community and academic clinics across Canada between 2002 and 2006. Patients with HCV genotype 2 or 3 received 1.5 mcg/kg/week PegIntron plus 800-1200 mg/day weight-based ribavirin for 24 weeks. SVR was defined as undetectable HCV RNA levels 24 weeks post-treatment.

Results

• 276 genotype 2 and 389 genotype 3 patients enrolled in POWeR (38% of all participants).

• Baseline viral load and fibrosis scores were available for 72% of genotype 2 patients and 37% of genotype 3 patients.

• Numerically, more genotype 3 than genotype 2 patients had high viral load (HVL; 49% vs 44%) and advanced fibrosis or cirrhosis (stage F3-F4) (40% vs 33%).

• Genotype 3 patients had lower SVR rates than genotype 2 patients (72% vs 79%; P = 0.04), attributable to a lower end-of-treatment response rate (77% vs 86%, P = 0.01);

• Relapse rates in genotype 2 and genotype 3 patients were identical (7%).

• Genotype 2 patients responded well to treatment regardless of baseline viral load and fibrosis score (Table).

• Genotype 3 patients with low viral load (LVL) attained SVR more often than those with high viral load (76% vs 65%, P = 0.03).

• An inverse relationship was observed between SVR and fibrosis score in genotype 3 patients.

• Less than 50% of genotype 3 patients with cirrhosis attained SVR.

Based on these findings, the study authors concluded:

• Genotype 2 and genotype 3 patients respond very differently to combination pegylated interferon alfa-2b plus ribavirin therapy.

• Genotype 2 patients respond well regardless of baseline characteristics.

• Conversely, lower response rates are observed in genotype 3 patients who have poor prognostic factors.

• The lower response rate in the genotype 3 population after 24 weeks of treatment may not be detected in smaller studies that combine genotype 2 and 3 patients for analysis.

• New treatment strategies such as increased dose or duration of treatment are needed for cirrhotic genotype 3 patients.

• Future studies should avoid combining genotype 2 and 3 patient populations when reporting results.

Royal Alexandra Hospital, Edmonton, AB, Canada; Toronto Western Hospital, Toronto, ON, Canada; Ottawa Hospital General Campus, Ottawa, ON, Canada; Jewish General Hospital, Montreal, QC, Canada; QEII Health Sciences Centre, Halifax, NS, Canada; Ontario Addiction Treatment Centers, Richmond Hill, ON, Canada; Schering-Plough Canada Inc, Pointe Claire, QC, Canada; London Health Sciences Centre, London, ON, Canada.

11/09/07

Reference
RJ Bailey, DK Wong, C Cooper, and others.Response to Peginterferon alfa-2b + Ribavirin Combination Therapy in Genotype 2 and 3 Patients With Poor Baseline Prognostic Factors: Results of the Canadian POWeR Program. 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007). Boston, MA. November 2-6, 2007. Abstract (poster) 246.