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Induction Pegylated Interferon Alfa-2A and High Dose Ribavirin Do Not Increase SVR in Heavy Patients with HCV Genotype 1 and High Viral Loads

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Induction Pegylated Interferon Alfa-2A and High Dose Ribavirin Do Not Increase SVR in Heavy Patients with HCV Genotype 1 and High Viral Loads GASTROENTEROLOGY 2010;139:1972–1983 Induction Pegylated Interferon Alfa-2a and High Dose Ribavirin Do Not Increase SVR in Heavy Patients With HCV Genotype 1 and High Viral Loads K. RAJENDER REDDY,* MITCHELL L. SHIFFMAN,‡ MARIBEL RODRIGUEZ–TORRES,§ HUGO CHEINQUER,ʈ DJAMAL ABDURAKHMANOV,¶ IGOR BAKULIN,# VIACHESLAV MOROZOV,** GIOVANNI FARIA SILVA,‡‡ NATALIA GEYVANDOVA,§§ CAROL STANCIU,ʈʈ MICHAEL RABBIA,¶¶ MICHAEL McKENNA,## JAMES A. THOMMES,¶¶ and STEPHEN A. HARRISON*** on behalf of the PROGRESS Study Investigators *Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; ‡Liver Institute of Virginia, Bon Secours Health System, Newport News, Virginia; §Fundacion de Investigacion De Diego Santurce, Santurce, Puerto Rico; ʈHospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; ¶Moscow Medical Academy, Moscow, Russia; #Gastroenterology Department, Samara, Russia, and State Postgraduate Medical Institute, Ministry of Defense of the Russian Federation, Moscow, Russia; **Hepatology, Samara, Russia; ‡‡Botucatu School of Medicine, Botucatu, Brazil; §§No. 1 Stavropol State Medical Academy, Stavropol, Russia; ʈʈGastroenterology and Hepatology Institute, Iasi, Romania; ¶¶Roche, Nutley, New Jersey; ##Roche, Welwyn, England; and ***Brooke Army Medical Center, Houston, Texas BACKGROUND & AIMS: Patients infected with hepatitis varies and is influenced by patient and viral characteris- C virus (HCV) genotype 1, body weight Ն85 kg, and high tics. For example, SVR rates are higher in white patients PANCREAS, AND CLINICAL–LIVER, BILIARY TRACT baseline viral load respond poorly to standard doses of than in black and Hispanic patients and higher in those pegylated interferon (peginterferon) and ribavirin. We eval- infected with hepatitis C virus (HCV) genotype 2 or 3.1–5 uated intensified therapy with peginterferon alfa-2a plus It has been shown in one study that high viral load is ribavirin. METHODS: This double-blind randomized trial significantly associated with lower SVR rates, even when included HCV genotype 1-infected outpatients from hepa- a direct-acting antiviral agent is combined with peginter- Ն tology clinics with body weight 85 kg and HCV RNA titer feron and ribavirin.6 Obesity, hepatic steatosis, and insu- Ն ␮ 400,000 IU/mL. Patients were randomized to 180 g/wk lin resistance are some of the host characteristics that peginterferon alfa-2a for 48 weeks plus 1200 mg/day riba- have been associated with lower SVR rates in patients ϭ virin (standard of care) (group A, n 191) or 1400/1600 7–9 ϭ with chronic hepatitis C. More recently, host genetic mg/day ribavirin (group B, n 189). Additional groups polymorphisms have been shown to strongly influence included 360 ␮g/wk peginterferon alfa-2a for 12 weeks then the rate of SVR.10 Improved treatment strategies for pa- 180 ␮g/wk peginterferon alfa-2a for 36 weeks plus 1200 tients with “difficult-to-cure” characteristics are needed. mg/day ribavirin (group C, n ϭ 382) or 1400/1600 mg/day The use of higher doses of peginterferon alfa-2a, either ribavirin (group D, n ϭ 383). Follow-up lasted 24 weeks as a fixed-dose induction or for the full treatment dura- after treatment. RESULTS: Sustained virologic response rates (HCV RNA level Ͻ15 IU/mL at end of follow-up) in tion, as well as higher doses of ribavirin have been shown groups A, B, C, and D were 38%, 43%, 44%, and 41%, to increase the likelihood of achieving an SVR in small 11,12 ␮ respectively. There were no significant differences among pilot studies. A 12-week high-dose (360 g/wk) the 4 groups or between pooled peginterferon alfa-2a regi- peginterferon alfa-2a induction regimen produced higher ␮ mens (A ϩ BvsCϩ D: odds ratio [OR], 1.08; 95% confi- SVR rates than the standard 180- g/wk regimen in a dence interval [CI], 0.83–1.39; P ϭ .584) or pooled ribavirin study of nonresponders to conventional interferon ther- regimens (A ϩ CvsBϩ D: OR, 1.00; 95% CI, 0.79–1.28; apy (38% vs 18%).11 The objective of this large, random- P ϭ .974). CONCLUSIONS: In patients infected with ized, international study was to determine whether a HCV genotype 1 who are difficult to treat (high viral 12-week fixed-dose induction regimen of peginterferon load, body weight >85 kg), a 12-week induction regimen alfa-2a and/or a high-dose weight-based ribavirin dose of peginterferon alfa-2a and/or higher-dose ribavirin is regimen could increase SVR rates in patients weighing not more effective than the standard regimen. Ն85 kg with HCV genotype 1 infection and a baseline HCV RNA level Ն400,000 IU/mL. Keywords: Chronic Hepatitis C; Tolerability of High-Dose Pegylated Interferon; Steatosis and Response to HCV Therapy; Tolerability of High-Dose Ribavirin. Abbreviations used in this paper: cEVR, complete early virologic response; CI, confidence interval; HOMA-IR, homeostasis model of egylated interferon (peginterferon) alfa plus ribavirin assessment-insulin resistance; NAS, nonalcoholic fatty liver disease is currently the standard of care for treating chronic activity score; OR, odds ratio; peginterferon, pegylated interferon; RVR, P rapid virologic response; SVR, sustained virologic response. hepatitis C infection, with approximately 40% to 50% of © 2010 by the AGA Institute patients achieving a sustained virologic response (SVR).1 0016-5085/$36.00 The likelihood that any given patient will achieve an SVR doi:10.1053/j.gastro.2010.08.051 December 2010 INTENSIFIED PEGINTERFERON ALFA-2a/RIBAVIRIN 1973 Patients and Methods Blinding of the dose of peginterferon alfa-2a during Patient Selection the first 12 weeks of treatment was maintained by the provision of an identical volume of solution in all vials Eligible patients were aged 18 years or older and (180 ␮g/mL for patients in groups A and B and 360 had a body weight Ն85 kg, HCV genotype 1 infection, ␮ Ն g/mL in groups C and D) and by achieving dose reduc- and an HCV RNA titer 400,000 IU/mL. Patients were tions through changes in volume administered. Thus, a required to have a liver biopsy result within 24 months of 25% dose reduction from 180 ␮g/wk to 135 ␮g/wk in receiving study medication consistent with the diagnosis groups A or B, or from 360 ␮g/wk to 270 ␮g/wk in of chronic hepatitis C. Up to 20% of enrolled patients groups C or D, was achieved by an identical reduction in could have had a histologic diagnosis of transition to the administered volume from 1.0 mL to 0.75 mL. Blind- cirrhosis or cirrhosis provided that they had compen- ing of the dose of ribavirin was maintained by providing ␣ sated liver disease (Child–Pugh grade A), a serum -feto- 2 bottles of tablets containing placebo and drug and Ͻ protein level 100 ng/mL, and no evidence of hepatocellu- having each patient take the same number of tablets each lar carcinoma on ultrasonography, computed tomography, day. or magnetic resonance imaging scan performed within In the event of laboratory abnormalities or adverse the previous 2 months. Liver biopsy specimens were eval- events, the dose of either study drug could be reduced in uated by a central pathologist blinded to treatment as- a stepwise manner that maintained blinding. Treatment signment using the Ishak-modified histologic activity in- with peginterferon alfa-2a monotherapy could be contin- dex scoring system and, in addition, were graded for the ued if ribavirin therapy was interrupted; however, ribavi- degree of steatosis and nonalcoholic steatohepatitis us- rin monotherapy was not allowed. In addition to dose ing the nonalcoholic fatty liver disease activity score reductions, use of hematopoietic growth factors (granu- (NAS).13,14 locyte-colony stimulating factor or erythropoiesis-stimu- Patients were ineligible if they had previously received lating agents) was allowed during treatment at the dis- treatment with interferon, ribavirin, or an investigational cretion of the investigator. BILIARY TRACT CLINICAL–LIVER, agent for treatment of HCV infection; were infected with The study was conducted in accordance with the Dec- PANCREAS, AND hepatitis A or B virus or human immunodeficiency virus; laration of Helsinki, the protocol was approved by insti- had a history or evidence of a chronic liver disease other tutional review boards at each center, and each patient than chronic hepatitis C, a current or past history of provided written informed consent. chronic systemic disease including severe psychiatric dis- ease, or an increased baseline risk of anemia; and/or had Assessment of Efficacy Ͻ 3 an absolute neutrophil count 1500 cells/mm , a plate- Serum HCV RNA level was measured by real-time Ͻ 3 let count 90,000 cells/mm , a hemoglobin concentra- polymerase chain reaction assay (Cobas Ampliprep/Co- Ͻ Ͻ tion 12 g/dL if female or 13 g/dL if male, or a serum bas TaqMan HCV test; detection limit, 15 IU/mL; Roche Ͼ creatinine level 1.5 times the upper limit of normal. Diagnostics North America, Indianapolis, IN). Pregnant or breastfeeding women and male partners of Rapid virologic response (RVR) and complete early pregnant women were ineligible. virologic response (cEVR) were defined as undetectable HCV RNA (Ͻ15 IU/mL) by weeks 4 and 12 of treatment, Study Design respectively. SVR was defined as undetectable HCV RNA Patients eligible for this trial were randomized (Ͻ15 IU/mL) at the end of untreated follow-up (study (stratified by country) in a 1:1:2:2 ratio to 48 weeks of week 72). double-blind treatment with (A) subcutaneous peginter- The positive predictive value of an RVR or a cEVR was feron alfa-2a (40KD) (Pegasys; Roche, Basel, Switzerland) calculated as the proportion of patients with an RVR or 180 ␮g/wk plus oral ribavirin (Copegus; Roche) 1200 a cEVR who achieved an SVR. Conversely, the negative mg/day; (B) peginterferon alfa-2a 180 ␮g/wk plus ribavi- predictive value of an RVR or a cEVR was calculated as rin 1400 mg/day (body weight Ͻ95 kg) or 1600 mg/day the proportion of patients without an RVR or a cEVR (body weight Ն95 kg); (C) peginterferon alfa-2a 360 who did not achieve an SVR.
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