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Can Chronic Hepatitis C Patients with Genotypes 2 or 3 Benefit from Shorter Interferon Treatment?

SUMMARY: A shorter 12 to 16 week course of pegylated interferon plus ribavirin is not as effective overall for people with chronic hepatitis C virus (HCV) genotypes 2 or 3, according to a meta-analysis and 2 recent international trials. However, abbreviated treatment may be a viable option for selected patients with rapid virological response at 4 weeks, low HCV viral load, and inability to tolerate longer therapy.

HCV genotypes 2 and 3 are easier to treat than genotypes 1 or 4. The standard course of therapy for genotype 2 or 3 is pegylated interferon plus ribavirin for 24 weeks, increasing to 48 weeks for hard-to-treat genotype 1. Genotypes 2 and 3 also have a higher response rate of 70%-80% in most studies, compared with only about 50% for genotype 1.

Because chronic hepatitis C patients with genotypes 2 and 3 often respond rapidly to therapy -- and because interferon is expensive and can cause difficult side effects -- researchers have explored whether treatment for 12, 14, or 16 weeks might work as well as 24 weeks.

During hepatitis C treatment efficacy is assessed by measuring HCV viral load after 4 weeks (rapid virological response, or RVR), 12 weeks (early virological response, or EVR), 24 weeks (end-of-treatment response, or ETR), and 24 weeks after completion of therapy (sustained virological response, or SVR). Patients who experience RVR at week 4 are significantly more likely to go on to achieve SVR. People who still have undetectable viral load 24 weeks after finishing treatment are considered cured.

12-16 Weeks Meta-analysis

As reported in the September 2010 Journal of Clinical Gastroenterology, Ashwani Singal from the University of Texas Medical Branch in Galveston and colleagues performed a meta-analysis of prior studies of abbreviated treatment.

The study authors searched medical literature databases for studies that compared short-term (12 to 16 weeks) vs standard 24 week treatment using pegylated interferon plus 800 mg/day fixed-dose ribavirin for genotype 2 or 3 patients who had achieved RVR. They identified 6 relevant studies -- including a total of 2434 participants -- that reported data on ETR, SVR, and relapse rates.

After achieving RVR, patients treated for a total of 24 weeks were significantly more likely to achieve SVR than those treated for 16 weeks (79% vs 70%; P = 0.008). Conversely, 24 week patients had a significantly lower relapse rate (9% vs 23%, respectively; P < 0.00001). Results did not change when people with genotype 2 vs 3, or those with high vs low baseline viral load, were analyzed separately.

The pooled odds ratio for SVR using shorter treatment was 0.54, or about half as likely, while the pooled odds ratio for experiencing viral relapse was 3.12, or about 3 times more likely (P = 0.008 and < 0.00001, respectively).

However, people treated for 24 weeks were significantly more likely to discontinue therapy ahead of schedule than those receiving shorter-duration treatment (12% vs 5%; P < 0.0001). The researchers found that it would be cost-effective to reduce treatment duration to 12-16 weeks, and then re-treat patients who experience relapse with a second 24 week course of therapy.

"Advantages of short-term treatment include better patient compliance, lower rate of adverse effects, and cost," the authors concluded. "Short-term treatment may be an option for patients unable to tolerate treatment."

Scandinavian Trials

In the second study, published in the May 2010 European Journal Gastroenterology and Hepatology, Olav Dalgard from Rikshospitalet in Oslo and colleagues compared 14 vs 24 week treatment in chronic genotype 2 or 3 patients with RVR, defined as HCV RNA < 50 IU/mL after 4 weeks of therapy.

The analysis included participants in 2 Scandinavian studies, one a non-randomized pilot trial with 122 patients, the other a randomized controlled trial with 428 patients. In both trials, treatment-naive participants were treated with 1.5 mcg/kg/week pegylated interferon alpha-2b (PegIntron) plus 800-1400 mg/day weight-adjusted ribavirin (genotype 2 or 3 patients typically receive a fixed dose of 800 mg regardless of weight).

In the pilot trial, all patients with RVR were treated for 14 weeks, while in the larger trial participants with RVR were randomized to receive therapy for either 14 or 24 weeks.

In an analysis of all RVR patients treated per protocol, 91% of those who received 14 weeks of therapy achieved SVR, compared with 95% of those treated for 24 weeks. The difference of 4% fell well within the pre-determined 10% margin needed to show inferiority, allowing the researchers to conclude that 14 week treatment was non-inferior to 24 weeks.

The relapse rate was highest among participants older than 40 years, those with genotype 3, and those with a high baseline viral load. However, prolonging treatment from 14 to 24 weeks did not reduce the relapse rate substantially for any of these groups.

International Study

Finally, in the third study, described in the June 2010 issue of Hepatology, Moises Diago from Hospital General de Valencia in Spain and an international team of colleagues compared SVR and relapse rates among patients with RVR (again < 50 IU/mL) who were randomly assigned to receive treatment for 16 or 24 weeks in the ACCELERATE trial.

This study included 863 genotype 2 or 3 participants with RVR (66% of the initial 1309 eligible patients in the study). All were treated with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 800 mg/day ribavirin. The analysis included only those participants who took their assigned treatment for at least 80% of the planned duration.

The overall SVR rate was significantly higher among genotype 2 patients treated for 24 weeks rather than 16 weeks (91% vs 82%, respectively; P = 0.0006). The difference for participants with genotype 3, however, did not reach statistical significance (90% vs 84%, respectively; P = 0.1308). Among patients with low baseline viral load (HCV RNA <400.000 IU/mL), SVR rates with 24 or 16 weeks of treatment were also statistical equivalent (95% vs 91%, respectively; P = 0.2012).

Relapse rates were significantly lower among people randomized to 24 weeks of therapy vs 16 weeks, both overall (6% vs 15%; P < 0.0001) and when participants with genotype 2 (5% vs 17%; P = 0.0001) and those with genotype 3 (7% vs 14%; P = 0.0489) were analyzed separately.

Significant pre-treatment predictors of SVR included assigned treatment duration of 24 weeks (P = 0.0006), absence of advanced liver fibrosis or cirrhosis according to biopsy (P = 0.0032), lower HCV viral load (P = 0.0017), and lower body weight (P < 0.0001).

"The standard 24-week regimen of [Pegasys] plus ribavirin is significantly more effective than an abbreviated 16-week regimen in genotype 2/3 patients who achieve an RVR," the study authors concluded. "Abbreviated regimens may be considered in patients with a low baseline viral load who achieve an RVR."


In an editorial accompanying Singal's meta-analysis, Donald Jensen from the University of Chicago Medical Center attempted to make sense of the conflicting findings from studies to date of shorter treatment durations for genotype 2 or 3 patients. Even previous meta-analyses, which are intended to resolve such questions, have produced contradictory results.

Along with baseline viral load and genotype 2 vs 3, ribavirin dose may be an important factor, he suggested, since it reduces the chances of relapse after completion of treatment.

"In summary, finding convincing evidence to support RVR-guided duration shortening in all genotypes 2 and 3 subjects is still not available," Jensen wrote. "The difference in SVR rates, however, remains small (< 10%) and narrower still for those patients with low baseline viral load."

"As the authors point out, it may not be unreasonable in selected cases -- perhaps those with an RVR yet poorly tolerant of side effects -- to strongly consider shortening therapy and if relapse occurs, retreat for a longer duration," he concluded.

Investigator affiliations:

Singal study: Department of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX; Department of Gastroenterology and Hepatology, Michael DeBakey VA Medical Center, Baylor College of Medicine, Houston, TX.

Dalgard study: Medical Department, Rikshospitalet, Oslo, Norway. Diago study: Hepatology Section, Hospital General de Valencia, Valencia, Spain; Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA; Department of Hepatology and Gastroenterology, INSERM U724, CHU de Nancy, Vandoeuvre-les-Nancy, France; J.W. Goethe University Hospital, Frankfurt, Germany; Fundacion de Investigacion de Diego, Santurce, Puerto Rico; St Luke's Center for Liver Disease, Houston, TX; Roche, Basel, Switzerland; University of Florida, Gainsville, FL.



AK Singal and BS Anand. Tailoring Treatment Duration to 12 to 16 Weeks in Hepatitis C Genotype 2 or 3 With Rapid Virologic Response: Systematic Review and Meta-analysis of Randomized Controlled Trials. Journal of Clinical Gastroenterology 44(8): 583-587 (Abstract). September 2010.

O Dalgard, K Bjoro, H Ring-Larsen, and H Verbaan. In patients with HCV genotype 2 or 3 infection and RVR 14 weeks treatment is noninferior to 24 weeks. Pooled analysis of two Scandinavian trials. European Journal Gastroenterology and Hepatology 22(5): 552-556 (Abstract). May 2010.

M Diago, ML Shiffman, JP Bronowicki, and others. Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin. Hepatology 51(6): 1897-1903 (Abstract). June 2010.

DM Jensen. Treatment duration for genotypes 2 and 3: still confusing after all these years (Editorial). Journal of Clinical Gastroenterology 44(8): 527-528 (Free full text). September 2010.






















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