AASLD: Upping Ribavirin Dose Does Not Increase Interferon Effectiveness in HIV/HCV Coinfected Patients

Liz Highleyman | Content provided by hivandhepatitis.com

Published Tuesday, 22 November 2011

Starting hepatitis C treatment with a double dose of ribavirin plus erythropoietin to manage anemia did not lead to higher rates of sustained response to interferon-based therapy in HIV/HCV coinfected people, researchers reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2011) this month in San Francisco.

An estimated one-third of HIV positive people are coinfected with hepatitis C virus (HCV), and dual infection is associated with faster liver disease progression and poorer response to interferon-based therapy.

Vincent Soriano from Hospital Carlos III in Madrid and colleagues conducted a study to determine whether increasing the usual dose of ribavirin might improve virological response in this patient population.

Ribavirin promotes sustained virological response (SVR) because it reduces the risk of relapse after the end of treatment. Studies have shown that 1000-1200 mg/day weight-adjusted ribavirin works better than a fixed 800 mg/day dose, but the effect of even higher doses is not well understood. Ribavirin can cause hemolytic anemia (destruction of red blood cells), so higher-than-normal doses must be used with caution.

The PERICO study included 357 HIV/HCV coinfected participants who had not previously received interferon for hepatitis C. About three-quarters were men and the average age was 43 years. About 60% had HCV genotype 1, 19% had genotype 3, 17% had genotype 4, and only 6% had genotype 2. About half had advanced liver fibrosis/cirrhosis, 43% had the favorable IL28B CC gene pattern, and 72% had high baseline HCV RNA > 500,000 IU/mL. Most were on antiretroviral therapy with undetectable HIV viral load, and the mean CD4 T-cell count was about 550 cells/mm³.

All participants received the standard 180 mcg/week dose of pegyalted interferon alfa-2a (Pegasys). In addition, they were randomly assigned to receive either standard 1000-1200 mg/day weight-adjusted ribavirin for the full course of treatment, or else a 2000 mg/day induction dose for the first 4 weeks along with weekly subcutaneous injections of 50,000 IU erythropoietin (Procrit or Epogen), then dropping down to the standard ribavirin dose and discontinuing erythropoietin.

Patients with rapid virological response (RVR) at week 4 were treated for the standard duration of 24 weeks for genotypes 2 and 3 or 48 weeks for genotypes 1 and 4. People without RVR were treated for 48 or 72 weeks, respectively. Participants with inadequate response at weeks 12 or 24 stopped treatment early.

Results

• In an intent-to-treat analysis, 43% of participants in the high-dose ribavirin induction arm achieved SVR 24 weeks after the end of treatment, compared with 47% in the standard therapy arm, not a significant difference.
• In an on-treatment analysis, the corresponding rates were 53% vs 57%, again not a significant difference.
• Premature treatment discontinuation occurred with similar frequency in both arms -- 51% vs 53%, respectively -- mostly due to virological failure.
• Other response predictors were associated with higher sustained response rates, as expected:
  • HCV genotype: 82% for genotypes 2 and 3, 42% for genotype 1b, 34% for genotype 4, and 31% for genotype 1a;
  • IL28B gene pattern: 74% for CC vs 35% for CT or TT;
  • Treatment completion: 80% for completion vs 31% for early discontinuation.
• In a multivariate analysis, SVR was significantly associated with HCV genotypes 2 and 3, IL28B CC, and low baseline HCV RNA.
• RVR was the best predictor of SVR.
• Despite differing doses, ribavirin plasma trough levels (lowest between doses) at week 4 were the same in both arms, at 2.3 mcg/mL.

Based on these findings, the investigators concluded, "Induction therapy with high ribavirin dosing along with erythropoietin does not improve SVR rates in HIV/HCV coinfected patients."

To explain the unexpected similar ribavirin levels regardless of dose, they suggested that pre-emptive erythropoietin "might blunt the benefit of ribavirin overdosing by enhancing erythrocyte uptake of plasma ribavirin."

Investigator affiliations: Infectious Diseases, Hospital Carlos III, Madrid, Madrid, Spain; Hospital Clínico San Cecilio, Granada, Spain; Hospital San Pablo, Barcelona, Spain; Hospital Gregorio Marañón, Madrid, Spain; Hospital 12 de Octubre, Madrid, Spain; Hospital Clinico San Carlos, Madrid, Spain; Hospital Virgen de La Victoria, Malaga, Spain; H Virgen Macarena, Sevilla, Spain; Hospital Universitario de Valme, Sevilla, Spain; Hospital Txagorritxu, Vitoria, Spain; Hospital Gral de Jerez, Jerez, Spain; Hospital do Meixoeiro, Vigo, Spain; Hospital Xeral-Cies, Vigo, Spain; Hospital Cruces, Bilbao, Spain; Hospital La Princesa, Madrid, Spain; Hospital Central de Asturias, Oviedo, Spain.

11/22/11

Reference

P Labarga, M Téllez, P Barreiro, V Soriano, et al. The Perico Trial: A Multicenter Randomized Controled Trial Comparing High Ribavirin (RBV) Induction vs Standard RBV Dosing in the Treatment of Chronic Hepatitis C in HIV-Coinfected Patients. 62nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2011). San Francisco, November 4-8. 2011. Abstract 247.

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