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Liu TW, Tsai PC, Huang CI, Tsai YS, Wang SC, Ko YM, Lin CC, Chen KY, Liang PC, Lin YH, Hsieh MY, Hou NJ, Huang CF, Yeh ML, Lin ZY, Chen SC, Dai CY, Chuang WL, Huang JF, Yu ML. Identification of treatment-experienced hepatitis C patients with poor cost-effectiveness of pegylated interferon plus ribavirin from a real-world cohort. J Formos Med Assoc 2018; 117:54-62. [PMID: 28389143 DOI: 10.1016/j.jfma.2017.02.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 02/21/2017] [Accepted: 02/23/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/PURPOSE Pegylated interferon (PegIFN) plus ribavirin (RBV) combination therapy has been the standard of care since 2002. Although a better viral response has been achieved among chronic hepatitis C (CHC) patients in Taiwan, approximately 25% of hepatitis C virus (HCV) genotype 1 (G1) patients and 15% of G2 patients failed to achieve a sustained virological response (SVR) at the first therapy. The actual cost-effectiveness of the retreatment remains elusive. The present study conducted a real-world cost-effectiveness analysis of a large cohort among different pre-specified subgroups of treatment-experienced CHC patients. METHODS A total of 117 patients with CHC who failed to achieve SVR at the first IFN-based therapy and received a second IFN-based therapy were enrolled. The inpatient and outpatient costs were acquired from National Health Insurance Research Database of Taiwan. The related medical care costs per treatment and per SVR were calculated. RESULTS We demonstrated that the average cost per SVR achieved was $13,722 in treatment-experienced CHC patients. Especially, patients with HCV G1 infection, baseline viral loads > 400,000 IU/mL, advanced hepatic fibrosis, not achieving a rapid viral response at week 4 or complete early viral response at week 12, had poorer cost-effectiveness for PegIFN/RBV retherapy, ranging from around $15,520 to as high as $72,546 per SVR achieved. CONCLUSION In the current study, we explored the real-world cost-effectiveness data of PegIFN/RBV for different subgroups of treatment-experienced HCV patients. These findings provide information for policy-makers for making decisions on treatment strategies of costly direct-acting antiviral agents for retreating CHC patients.
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Affiliation(s)
- Ta-Wei Liu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Pei-Chien Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ching-I Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Shan Tsai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Shu-Chi Wang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yu-Min Ko
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ching-Chih Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Kuan-Yu Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Nai-Jen Hou
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
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Hunyady B, Gervain J, Horváth G, Makara M, Pár A, Szalay F, Telegdy L, Tornai I. [Diagnosis, treatment, and follow-up of hepatitis C-virus related liver disease. Hungarian national consensus guideline]. Orv Hetil 2014; 155 Suppl:3-24. [PMID: 24631886 DOI: 10.1556/oh.2013.29893] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Approximately 70 000 people are infected with hepatitis C virus in Hungary, more than half of whom are not aware of their infection. Early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases (liver cirrhosis and liver cancer) and its complications. In addition, it may increase work productivity and life expectancy of infected individual, and can prevent further viral transmission. Early recognition can substantially reduce the long term financial burden of related morbidity from socioeconomic point of view. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can kill the virus in 40-45% of previously not treated (naïve), and in 5-21% of previous treatment-failure patients. Addition of two direct acting first generation protease inhibitor drugs (boceprevir and telaprevir) to the dual therapy increased the chance of sustained clearance of virus to 63-75% and 59-66%, respectively. These two protease inhibitor drugs are available and financed for a segment of Hungarian patients since May 2013. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and/or fibrosis in the liver. For initiation of treatment as well as for on-treatment decisions accurate and timely molecular biology tests are mandatory. Staging of liver damage (fibrosis) non-invasive methods (transient elastography and biochemical methods) are acceptable to avoid concerns of patients related to liver biopsy. Professional decision for treatment is balanced against budget limitations in Hungary, and priority is given to those with urgent need using a national Priority Index system reflecting stage of liver disease as well as additional factors (activity and progression of liver disease, predictive factors and other special circumstances). All naïve patients are given a first chance with dual therapy. Those with genotype 1 infection and with on-treatment or historic failure to dual therapy are eligible to receive protease inhibitor based triple therapy provided, they reach financial cutoff eligibility based on Priority Index. Duration of therapy is usually 48 weeks in genotype 1 with a response-guided potential to reduce duration for non-cirrhotic patients. Patients with non-1 genotypes are treated with dual therapy (without protease inhibitors) for a genotype and response driven duration of 16, 24, 48, or 72 week. Careful monitoring for early recognition and management of side-effects as well as viral response and potential breakthrough during protease-inhibitor therapy are recommended.
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Affiliation(s)
- Béla Hunyady
- Somogy Megyei Kaposi Mór Oktató Kórház Belgyógyászati Osztály Kaposvár Tallián Gyula u. 20-32. 7400 Pécsi Tudományegyetem, Általános Orvostudományi Kar I. Belgyógyászati Klinika Pécs
| | - Judit Gervain
- Szent György Egyetemi Oktató Kórház I. Belgyógyászat és Molekuláris Diagnosztikai Laboratórium Székesfehérvár
| | - Gábor Horváth
- Szent János Kórház és Észak-budai Egyesített Kórházak Hepatológiai Szakrendelés Budapest
| | - Mihály Makara
- Egyesített Szent István és Szent László Kórház Budapest
| | - Alajos Pár
- Pécsi Tudományegyetem, Általános Orvostudományi Kar I. Belgyógyászati Klinika Pécs
| | - Ferenc Szalay
- Semmelweis Egyetem, Általános Orvostudományi Kar I. Belgyógyászati Klinika Budapest
| | | | - István Tornai
- Debreceni Egyetem, Általános Orvostudományi Kar, Orvos- és Egészségtudományi Centrum Belgyógyászati Intézet Debrecen
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Clinical Aspects of Hepatitis C Virus Infection. Antiviral Res 2014. [DOI: 10.1128/9781555815493.ch14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Cho HC, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Yoo BC, Paik SW. Pegylated interferon and ribavirin in the retreatment of chronic hepatitis C in Korea. Gut Liver 2013; 7:585-93. [PMID: 24073317 PMCID: PMC3782674 DOI: 10.5009/gnl.2013.7.5.585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 02/14/2013] [Accepted: 02/25/2013] [Indexed: 11/19/2022] Open
Abstract
Background/Aims Pegylated interferon (peginterferon) and ribavirin is the current standard therapy for chronic hepatitis C. The aims of this study were to evaluate the efficacy of peginterferon and ribavirin and to identify predictors of a sustained virological response (SVR) to the retreatment of chronic hepatitis C in Korea. Methods The clinical records of 91 patients with chronic hepatitis C who were retreated with peginterferon and ribavirin were retrospectively analyzed. None of the patients had previously attained a SVR, and the patients were categorized according to their previous responses (nonresponder, relapser, or inadequate treatment) to conventional interferon/ribavirin. Results The overall SVR rate was 54.9%. Independent predictors of a SVR were genotypes 2 and 3, relapse, an adherence to peginterferon of over 80%, and an early virological response (EVR). For genotype 1 patients, an adherence to peginterferon of over 80% was an independent predictor of a SVR. Conclusions Peginterferon and ribavirin therapy is effective for the retreatment of Korean chronic hepatitis C patients who have failed interferon/ribavirin, especially in patients with genotypes 2 and 3, relapse, an adherence to peginterferon over 80%, and an EVR. For genotype 1 patients, retreatment was effective in patients with an adherence to peginterferon over 80%.
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Affiliation(s)
- Hyun Chin Cho
- Division of Gastroenterology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
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Huang CF, Dai CY, Yeh ML, Huang JF, Huang CI, Hsieh MY, Lin ZY, Chen SC, Wang LY, Juo SHH, Chuang WL, Lin YC, Yu ML. Virological predictors of response to retreatment in hepatitis C genotype 2 infected patients. PLoS One 2013; 8:e58882. [PMID: 23527043 PMCID: PMC3602580 DOI: 10.1371/journal.pone.0058882] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 02/07/2013] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND/AIMS The impact of virological factors and interleukin-28B (IL-28B) genetic variants on retreatment of hepatitis C virus genotype 2 (HCV-2) treatment-experienced patients remains unknown. METHODS On-treatment virological responses and IL-28B rs8099917 genotype were determined in 46 HCV-2 treatment-experienced patients (42 previous relapsers; four previous non-responders) retreated with 24-week peginterferon/ribavirin. RESULTS Forty (87.0%) patients carried the rs8099917 TT genotype and 6 patients (13.0%) carried the TG/GG genotype. The sustained virological response (SVR; seronegativity of HCV RNA throughout 24 weeks of the post-treatment follow-up period) rate was 71.7%. Compared with previous non-responders, previous relapsers had a significantly higher SVR rate (78.6% vs. 0%, P = 0.004) and a lower relapse rate (17.5% vs. 100%, P = 0.04). All the previous non-responders were with the rs8099917 TT genotype. As for those who relapsed, treatment responses, including the rates of rapid virological response (RVR, 80.6% vs. 66.7%, P = 0.59), early virological response (EVR, 97.2% vs. 83.3%, P = 0.27), end-of-treatment virological response (97.2% vs. 83.3%, P = 0.27) and SVR (80.6% vs. 66.7%, P = 0.59) and relapse rate (17.1% vs. 20.0%, P = 1) did not differ significantly between patients with the rs8099917 TT and those with the non-TT genotype. Multivariate analysis revealed that the most important factor predictive of an SVR in the retreatment of HCV-2 was previous relapse; the only factor predictive of an SVR for previous relapsers was the achievement of an EVR. Compared with the achievement of a RVR, the attainment of an EVR was more accurate in predicting an SVR (88% vs. 74%). CONCLUSIONS Peginterferon/ribavirin is effective in the retreatment of HCV-2 relapsers, especially among those who achieved an EVR.
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Affiliation(s)
- Chung-Feng Huang
- Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ching-I Huang
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Liang-Yen Wang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Suh-Hang Hank Juo
- Department of Medical Genetics, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Ching Lin
- Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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The effectiveness of retreatment with peginterferon alfa and ribavirin in patients with chronic viral hepatitis C genotype 2 and 3: a prospective cohort study in Brazil. BMC Infect Dis 2012; 12:377. [PMID: 23270376 PMCID: PMC3548710 DOI: 10.1186/1471-2334-12-377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 12/13/2012] [Indexed: 12/24/2022] Open
Abstract
Background More than 50% of patients infected with chronic hepatitis C virus (HCV) do not respond to treatment with conventional interferon (IFN) combined with ribavirin (RBV). The aim of our study was to evaluate the effectiveness of retreatment with peginterferon alfa-2a or 2b (PEG-IFN 2a or 2b) concomitantly with RBV in patients with HCV genotype 2 and 3, which were non-responders or relapsers to initial treatment with IFN / RBV and to identify possible predictors of sustained virological response (SVR). Methods From September 2003 to March 2009 a cohort of 216 patients who had previously failed therapy with a regimen of standard interferon and ribavirin, were followed in a specialized service implemented in the Brazilian Unified Health System, Rio Grande do Sul. All patients were retreated with PEG-IFN 2a or 2b per week, associated with RBV, through oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 Kg and 1,250 mg if ≥ 75 Kg) per day for 48 weeks. The HCV-RNA was tested by Polymerase Chain Reaction (PCR). Virological Response (VR) within 48 weeks and SVR in the 72 weeks was considered for evaluation of treatment efficacy. Analyses were performed in patients who received at least one dose of PEG-IFN. Results The SVR rate for non-responders to previous treatment was 34.4% and for relapsers was 50% (p = 0.031). As predictive factors that contribute to improve SVR, were identified the age (p = 0.005), to be relapsers to previous treatment (p = 0.023) and present liver biopsy examination Metavir F0-F2 (p = 0.004). In assessing the safety profile, 51 patients (23.6%) discontinued treatment prematurely. Conclusions This alternative retreatment for patients who have failed prior therapies for anti-HCV, has demonstrated promising SVR rate, provided that it includes a careful selection of patients with predictors of response and adverse events monitored.
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Stern C, Martinot-Peignoux M, Ripault MP, Boyer N, Castelnau C, Valla D, Marcellin P. Impact of ribavirin dose on retreatment of chronic hepatitis C patients. World J Gastroenterol 2012; 18:2966-72. [PMID: 22736920 PMCID: PMC3380324 DOI: 10.3748/wjg.v18.i23.2966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2011] [Revised: 02/15/2012] [Accepted: 02/26/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the efficacy and factors associated with a sustained virological response (SVR) in chronic hepatitis C (CHC) relapsing patients.
METHODS: Out of 1228 CHC patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV), 165 (13%) had a relapse. Among these, 62 patients were retreated with PEG-IFN-α2a or -α2b and RBV. Clinical, biological, virological and histological data were collected. Initial doses and treatment modifications were recorded. The efficacy of retreatment and predictive factors for SVR were analyzed.
RESULTS: An SVR was achieved in 42% of patients. SVR was higher in young (< 50 years) (61%) than old patients (27%) (P = 0.007), and in genotype 2 or 3 (57%) than in genotype 1 or 4 (28%) patients (P = 0.023). Prolonging therapy for at least 24 wk more than the previous course was associated with higher SVR rates (53% vs 28%, P = 0.04). Also, a better SVR rate was observed with RBV dose/body weight > 15.2 mg/kg per day (70% vs 35%, P = 0.04). In logistic regression, predictors of a response were age (P = 0.018), genotype (P = 0.048) and initial RBV dose/body weight (P = 0.022). None of the patients without a complete early virological response achieved an SVR (negative predictive value = 100%).
CONCLUSION: Retreatment with PEG-IFN/RBV is eff-ective in genotype 2 or 3 relapsers, especially in young patients. A high dose of RBV seems to be important for the retreatment response.
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Consensus interferon used to treat prior partial-responders to pegylated interferon plus ribavirin. Dig Dis Sci 2011; 56:3032-7. [PMID: 21879283 DOI: 10.1007/s10620-011-1869-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 08/12/2011] [Indexed: 01/08/2023]
Abstract
BACKGROUND The response to pegylated interferon (peg-IFN) plus ribavirin therapy remains less than ideal with 40-50% of treated subjects failing to clear the virus. Moreover, retreatment is only minimally effective. Consensus interferon (c-IFN) has been shown to be efficacious in HCV genotype 1 patients who have failed therapy with peg-IFN. AIM To evaluated the response to re-treatment of peg-IFN plus ribavirin partial-responders with c-IFN plus ribavirin. METHODS Forty-two subjects who had previously failed to clear virus after treatment with peg-IFN plus ribavirin were treated with c-IFN (15 μg/day) plus ribavirin (800-1,200 mg/day) until 12 months of therapy or a total of six consecutive months of PCR negativity was achieved. RESULTS The study population consisted predominantly of males (71%), Caucasians (76%), with African Americans comprising the remaining 24%, subjects with HCV genotype 1 infection (81%) and 21% had cirrhosis by liver biopsy. The overall SVR rate was 29%. The only pretreatment variable that distinguished responders from partial-responders was the serum triglyceride level. CONCLUSIONS The use of c-IFN plus ribavirin in the retreatment of prior peg-IFN plus ribavirin partial responders is essentially twice that achieved in prior re-treatment regimens consisting of a second course of peg-IFN plus ribavirin. These results will need to be evaluated against the use of triple therapy consisting of a peg-IFN plus ribavirin and a protease inhibitor. More studies utilizing c-IFN plus ribavirin with either a protease inhibitor or polymerase inhibitor need to be performed as well.
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Lindh M, Arnholm B, Eilard A, Färkkilä M, Hellstrand K, Lagging M, Langeland N, Mørch K, Nilsson S, Pedersen C, Buhl MR, Wahlberg T, Wejstål R, Westin J, Norkrans G. Hepatitis C treatment response kinetics and impact of baseline predictors. J Viral Hepat 2011; 18:400-7. [PMID: 20500548 DOI: 10.1111/j.1365-2893.2010.01323.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The optimal duration of treatment for hepatitis C virus (HCV) infections is highly variable but critical for achieving cure (sustained virological response, SVR). We prospectively investigated the impact of age, fibrosis, baseline viraemia and genotype on the early viral kinetics and treatment outcome. Patients treated with peginterferon alfa-2a and ribavirin in standard dosing were included: 49 with genotype 1 treated for 48weeks and 139 with genotype 2 or 3 treated for 24weeks. The reduced SVR rates in patients older than 45years, with severe liver fibrosis or pretreatment viraemia above 400,000IU/mL were strongly associated with slower second phase declines of HCV RNA. Genotype 2/3 infections responded more rapidly than genotype 1, reaching week 4 negativity (RVR) in 59%vs 22%. We conclude that baseline response predictors such as age, fibrosis and viral load were well reflected by the early viral kinetics as assessed by repeated HCV RNA quantifications. The kinetic patterns and the high relapse rate in genotype 2/3 patients without RVR suggest that this group might benefit from treatment durations longer than 24weeks.
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Affiliation(s)
- M Lindh
- Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden
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Halfon P, Pérusat S, Bourlière M, Bronowicki JP, Trimoulet P, Benhamou Y, Leroy V, Marcellin P, Foucher J, Penaranda G, Chêne G, Couzigou P. Neutralizing antibodies to interferon-α and circulating interferon in patients with chronic hepatitis C non-responding to pegylated interferon plus ribavirin re-treated by pegylated interferon-α-2a and ribavirin (ANRS HC16 GAMMATRI substudy). J Med Virol 2011; 82:2027-31. [PMID: 20981789 DOI: 10.1002/jmv.21909] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
A lack of antiviral response in patients with chronic hepatitis C treated with pegylated (PEG)-interferon (IFN)-α-2a + ribavirin (RIBA) may be explained by neutralizing antibodies to IFN-α-2a. The aim of this study was to assess neutralizing antibodies to IFN-α-2a and IFN levels in non-responder patients who were re-treated by PEG IFN-α-2a and RIBA for 12 weeks. Non-responders to a first-line treatment of PEG IFN-α-2a + RIBA were included for treatment with PEG IFN-α-2a (180 µg/week) + RIBA (1,000 mg/day if <75 kg, 1,200 mg otherwise) for 48 weeks. HCV RNA was measured at week 12. IFN levels and neutralizing antibodies to IFN-α-2a were measured retrospectively on stored sera at baseline and weeks 4 and 12, using a quantitative sandwich ELISA for neutralizing antibodies to IFN-α-2a. Twenty-three patients were non-responders and 19 patients were responders at week 12 of the initial phase of the second-line treatment. Non-responders and responders did not differ statistically: baseline age (median age 47 vs. 50 years), HCV RNA (median 6.8 vs. 6.4 log(10) copies/ml), gender (70% vs. 73% males), genotype (genotype 1: 91% vs. 80%). The median IFN-α-2a levels (pg/ml) at weeks 0, 4, and 12 (interquartile range) did not differ between the 19 responders to initial phase of second-line treatment and the 23 non-responders: <3.3 (<3.3-371.4), 1457.3 (106.8-3284.8), and 1,652 (90.8-5,000); 84.5 (3.3-277.4), 1407.4 (120.2-2443.4), and 1620.1 (120.2-2287.1), respectively. Among non-selected consecutive non-responder patients, re-treatment with PEG IFN-α-2a + RIBA is associated with virological response regardless of the presence of antibody-mediated resistance to conventional IFN treatment.
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Affiliation(s)
- Philippe Halfon
- Alphabio Laboratory, Ambroise Paré Hospital, Marseille, France.
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Brook G, Main J, Nelson M, Bhagani S, Wilkins E, Leen C, Fisher M, Gilleece Y, Gilson R, Freedman A, Kulasegaram R, Agarwal K, Sabin C, Deacon-Adams C. British HIV Association guidelines for the management of coinfection with HIV-1 and hepatitis B or C virus 2010. HIV Med 2010; 11:1-30. [PMID: 20059574 DOI: 10.1111/j.1468-1293.2009.00781.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- G Brook
- British HIV Association (BHIVA), BHIVA Secretariat, Mediscript Ltd, London, UK.
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12
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Morisco F, Stroffolini T, Medda E, Amoruso DC, Almasio PL, Villa E, Zuin M, Paris B, Stanzione M, Caporaso N. Retrospective, observational, multicentre study on an Italian population affected by chronic hepatitis C who failed to clear HCV-RNA after the combined therapy (PEG-IFN and ribavirin): NADIR study. J Viral Hepat 2010; 17:427-34. [PMID: 19780939 DOI: 10.1111/j.1365-2893.2009.01200.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
There is a lack of information on the characteristics of patients with chronic hepatitis C virus infection (HCV) who fail to respond to antiviral treatment. We studied HCV-positive subjects with chronic liver diseases treated with pegylated-interferon (PEG-IFN) and ribavirin (RBV) who failed to clear HCV in routine clinical practice. A total of 2150 consecutive adult patients treated with PEG-IFN plus RBV therapy in 46 Italian centres between 1 July 2004, and 30 June 2005, were studied. Of the 2150 patients, 923 (42.9%) (M/F 585/335, mean age 54.8 years) failed to achieve a serum HCV-RNA clearance. Of these 923 patients, 429 (46.5%) were nonresponders, 298 (32.3%) relapsers, 168 (18.2%) drop-outs for noncompliance or adverse events and 28 (3.0%) were lost during follow-up. Overall, 642 (70.6%) patients received adequate therapy (defined as more than 80% of the drug doses for >80% of the time). Genotypes 1-4 were observed in 76.9% of cases; genotypes 2-3 in 21.2% and mixed in 1.9%, respectively. Multiple logistic regression analysis identified genotypes 1 and 4 as the sole independent predictors of the likelihood of nonresponse to therapy compared with relapse (OR: 4.38; 95% CI = 2.28-8.4). Age older than 65 years was the sole independent factor associated with no adherence to therapy (OR: 2.22; 95% CI = 1.36-3.62). Patients who fail to respond to treatment are a nonhomogeneous population with different features, and the sole factor that discriminates nonresponse from relapse is the distribution of genotypes 1-4. Co-morbidities are unable to determine the type of treatment failure and inadequate adherence to therapy mostly affects patients older than 65 years of age.
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Affiliation(s)
- F Morisco
- Clinical and Experimental Medicine, Gastroenterology Unit, University of Naples Federico II, Naples, Italy.
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13
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Abstract
Chronic infections with HBV and HCV are a major cause of liver-associated morbidity and mortality worldwide. An increased knowledge of HBV and HCV virology, natural history and predictors of virological response has led to the development of new strategies to improve treatment outcomes. The use of new antiviral agents with greater potency and a high genetic barrier to resistance, as well as on-treatment monitoring of virological response, may result in improved outcomes in HBV therapy. A greater understanding of predictors of virological response has led to the ability to individualize therapy in chronic HCV infection. Several new antiviral agents specifically targeting HCV are in development and should have a major impact on treatment response rates over the next few years.
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Affiliation(s)
- Stevan A Gonzalez
- Division of Gastroenterology & Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304-1509, USA
| | - Emmet B Keeffe
- Division of Hepatology, Baylor All Saints Medical Center, 1400 8th Avenue, Building C, 1st Floor, Fort Worth, TX 76104, USA
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14
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Poynard T, Colombo M, Bruix J, Schiff E, Terg R, Flamm S, Moreno-Otero R, Carrilho F, Schmidt W, Berg T, McGarrity T, Heathcote EJ, Gonçales F, Diago M, Craxi A, Silva M, Bedossa P, Mukhopadhyay P, Griffel L, Burroughs M, Brass C, Albrecht J. Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed interferon alfa/ribavirin therapy. Gastroenterology 2009; 136:1618-28.e2. [PMID: 19208349 DOI: 10.1053/j.gastro.2009.01.039] [Citation(s) in RCA: 192] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2007] [Revised: 11/26/2008] [Accepted: 01/15/2009] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. METHODS This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 microg/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigator's request. RESULTS Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (< or =600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. CONCLUSIONS Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.
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Affiliation(s)
- Thierry Poynard
- Service d'hepatologie, Université Pierre et Marie Curie Liver Center, Hôpital La Pitié Salpêtrière, Paris, France.
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15
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Wagner R, Larson DP, Beno DWA, Bosse TD, Darbyshire JF, Gao Y, Gates BD, He W, Henry RF, Hernandez LE, Hutchinson DK, Jiang WW, Kati WM, Klein LL, Koev G, Kohlbrenner W, Krueger AC, Liu J, Liu Y, Long MA, Maring CJ, Masse SV, Middleton T, Montgomery DA, Pratt JK, Stuart P, Molla A, Kempf DJ. Inhibitors of Hepatitis C Virus Polymerase: Synthesis and Biological Characterization of Unsymmetrical Dialkyl-Hydroxynaphthalenoyl-benzothiadiazines. J Med Chem 2009; 52:1659-69. [DOI: 10.1021/jm8010965] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Rolf Wagner
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Daniel P. Larson
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - David W. A. Beno
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Todd D. Bosse
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - John F. Darbyshire
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Yi Gao
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Bradley D. Gates
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Wenping He
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Rodger F. Henry
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Lisa E. Hernandez
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | | | - Wen W. Jiang
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Warren M. Kati
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Larry L. Klein
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Gennadiy Koev
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - William Kohlbrenner
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - A. Chris Krueger
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Jinrong Liu
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Yaya Liu
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Michelle A. Long
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Clarence J. Maring
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Sherie V. Masse
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Tim Middleton
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Debra A. Montgomery
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - John K. Pratt
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Patricia Stuart
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Akhteruzzaman Molla
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
| | - Dale J. Kempf
- Global Pharmaceutical Research and Development, Abbott, Abbott Park, Illinois 60064
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16
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Iminosugars in combination with interferon and ribavirin permanently eradicate noncytopathic bovine viral diarrhea virus from persistently infected cells. Antimicrob Agents Chemother 2008; 52:1820-8. [PMID: 18316522 DOI: 10.1128/aac.01181-07] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We evaluated interferon (IFN) and ribavirin (RBV) as dual therapy and as part of triple-combination therapies with the iminosugars N-butyl-deoxynojirimycin (NB-DNJ), N-nonyl-deoxynojirimycin, and N-7-oxanonyl-6-deoxymethyl-galactonojirimycin. The ability of these compounds to clear bovine viral diarrhea virus (BVDV), a surrogate model for hepatitis C virus (HCV), from a persistently infected Madin-Darby bovine kidney cells cell line was determined by monitoring the secretion of viral RNA and the infectivity of secreted virions. In the BVDV system, after treatment with IFN-RBV alone, viral rebound was observed immediately after removal of the drugs. In contrast, we demonstrate that a triple drug combination of IFN, RBV, and an iminosugar eradicated the BVDV infection in a time- and a dose-dependent manner, leading to sustained viral clearance. Importantly, in the case of NB-DNJ, the sustained viral clearance was achieved by using physiologically relevant and tolerated drug concentrations. Therefore, the use of a triple-combination therapy that includes an iminosugar may prove to be of greater therapeutic value for the treatment of HCV infection than the use of IFN-RBV alone.
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Hmaied F, Legrand-Abravanel F, Nicot F, Garrigues N, Chapuy-Regaud S, Dubois M, Njouom R, Izopet J, Pasquier C. Full-length genome sequences of hepatitis C virus subtype 4f. J Gen Virol 2007; 88:2985-2990. [PMID: 17947520 DOI: 10.1099/vir.0.83151-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Hepatitis C virus genotype 4 (HCV-4) is very common in central Africa, prevalent in the Middle East, and is becoming increasingly frequent among southern Europeans. We have determined the complete nucleotide sequences of HCV-4f strains and investigated their phylogenetic relationships with other genotypes. We amplified the complete genome of two HCV subtype 4f strains, IFBT84 and IFBT88. The HCV-4f strains have a total of 9181 and 9304 nt, respectively, including the 5' untranslated region followed by a single open reading frame. There was no evidence of genomic recombination in the IFBT84 and IFBT88 strains. The sequences of the HCV-4f strain genomes are closer to those of HCV-1b than to genotypes 2, 3, 5 and 6. It is important to know the full-length sequences of HCV-4 subtypes in order to classify them correctly and to obtain more detailed knowledge about HCV epidemiology and sensitivity to interferon.
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Affiliation(s)
- Fatma Hmaied
- Facultés de Médecine et de Pharmacie, Université Toulouse III Paul-Sabatier, F-31400 Toulouse, France
- Service de Virologie, CHU de Toulouse, Institut Fédératif de Biologie, F-31059 Toulouse, France
| | - Florence Legrand-Abravanel
- Facultés de Médecine et de Pharmacie, Université Toulouse III Paul-Sabatier, F-31400 Toulouse, France
- INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France
- Service de Virologie, CHU de Toulouse, Institut Fédératif de Biologie, F-31059 Toulouse, France
| | - Florence Nicot
- Facultés de Médecine et de Pharmacie, Université Toulouse III Paul-Sabatier, F-31400 Toulouse, France
- INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France
- Service de Virologie, CHU de Toulouse, Institut Fédératif de Biologie, F-31059 Toulouse, France
| | - Natalie Garrigues
- Facultés de Médecine et de Pharmacie, Université Toulouse III Paul-Sabatier, F-31400 Toulouse, France
| | - Sabine Chapuy-Regaud
- Facultés de Médecine et de Pharmacie, Université Toulouse III Paul-Sabatier, F-31400 Toulouse, France
- INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France
- Service de Virologie, CHU de Toulouse, Institut Fédératif de Biologie, F-31059 Toulouse, France
| | - Martine Dubois
- INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France
- Service de Virologie, CHU de Toulouse, Institut Fédératif de Biologie, F-31059 Toulouse, France
| | - Richard Njouom
- Laboratoire de Virologie, Centre Pasteur du Cameroun, Cameroon
- Facultés de Médecine et de Pharmacie, Université Toulouse III Paul-Sabatier, F-31400 Toulouse, France
- Service de Virologie, CHU de Toulouse, Institut Fédératif de Biologie, F-31059 Toulouse, France
| | - Jacques Izopet
- Facultés de Médecine et de Pharmacie, Université Toulouse III Paul-Sabatier, F-31400 Toulouse, France
- INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France
- Service de Virologie, CHU de Toulouse, Institut Fédératif de Biologie, F-31059 Toulouse, France
| | - Christophe Pasquier
- Facultés de Médecine et de Pharmacie, Université Toulouse III Paul-Sabatier, F-31400 Toulouse, France
- INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31300 Toulouse, France
- Service de Virologie, CHU de Toulouse, Institut Fédératif de Biologie, F-31059 Toulouse, France
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