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In conclusion, the care of HIV–HCV coinfected patients changed significantly in “real life” in France between 2004 and 2009. These results underline the importance of continuing efforts to educate physicians and patients about increasing the access of coinfected patients to HCV treatment. Efforts should be made to improve the care of these patients, such as increasing the access to and the number of patients receiving treatment for HCV infection, the possibility of starting HCV treatment earlier (i.e. before the presence of a high liver fibrosis score), the introduction of HCV treatment even in patients with low CD4 cell counts, and earlier referral of patients with cirrhosis to a liver transplant unit.....RESULTS: The rate of liver biopsy decreased (14% vs. 38% vs. 56%), while the use of non-invasive liver damage tests increased (47% vs. 24% vs. ND) in the 2009, 2006, and 2004 surveys, respectively. The rate of patients that had never been treated for HCV infection progressively decreased in the 2009, 2006, and 2004 surveys (37%, 42%, and 54%). The main reasons for HCV non-treatment changed as HCV treatment was deemed less questionable and the lack of liver biopsy became a very rare reason (6%, 18%, and 34%). Among patients treated for HCV infection, the rate of sustained virological response increased (49%, 29%, and 29%). The main factors independently associated with HCV treatment were a liver fibrosis score >F2 (odds ratio=3.5; 95% CI 2.1–5.7), a liver biopsy activity grade A2 (2.7; 1.4–5.3), a CD4 cell count 350ml (2.7; 1.6–4.4), European origin (2.1; 1.3–3.4), daily alcohol consumption<30g (2.1; 1.2–3.8), and male gender (2.0; 1.2–3.3)."
Articles in Press
Care of hepatitis C virus infection in human immunodeficiency virus-infected patients: Modifications in three consecutive large surveys between 2004 and 2009
Journal of Hepatology June 2010
Patrice Cacoub12, Philippe Halfon3, Eric Rosenthal4, François Bailly5, Firouze Bani Sadr6, Yves Benhamou7, Stéphane Chevaliez8, Jean Michel Pawlotsky8, Lionel Piroth9, Yazdan Yazdanpanah10, Stanislas Pol11
Received 30 November 2009; received in revised form 9 February 2010; accepted 15 March 2010. published online 05 May 2010.
Corrected Proof
ABSTRACT
Background & Aims
To analyze the care of HCV infection in HIV–HCV coinfected patients and its progression between 2004 and 2009.
Patients and methods
Three hundred eighty HIV–HCV coinfected patients were prospectively included from November 22 to 29, 2004 (2004 survey), 416 patients from April 3 to 10, 2006 (2006 survey), and 419 patients from June 15 to 22, 2009 (2009 survey).
Results
The rate of liver biopsy decreased (14% vs. 38% vs. 56%), while the use of non-invasive liver damage tests increased (47% vs. 24% vs. ND) in the 2009, 2006, and 2004 surveys, respectively. The rate of patients that had never been treated for HCV infection progressively decreased in the 2009, 2006, and 2004 surveys (37%, 42%, and 54%). The main reasons for HCV non-treatment changed as HCV treatment was deemed less questionable and the lack of liver biopsy became a very rare reason (6%, 18%, and 34%). Among patients treated for HCV infection, the rate of sustained virological response increased (49%, 29%, and 29%). The main factors independently associated with HCV treatment were a liver fibrosis score >F2 (odds ratio=3.5; 95% CI 2.1–5.7), a liver biopsy activity grade A2 (2.7; 1.4–5.3), a CD4 cell count 350ml (2.7; 1.6–4.4), European origin (2.1; 1.3–3.4), daily alcohol consumption<30g (2.1; 1.2–3.8), and male gender (2.0; 1.2–3.3).
Conclusion
Compared to the 2004 and 2006 surveys, the 2009 coinfected patients had liver damage assessment more frequently, more patients had received HCV treatment and more patients had achieved a sustained virological response.
Introduction
Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is a frequent and particularly serious problem [1], [2], [3], [4], [5], [6]. About 30% of HIV-infected patients in France are also infected with HCV, i.e. close to 30,000 patients [1], [2], [5], [6]. Since the widespread use of combined antiretroviral therapy (cART) was begun, AIDS mortality has progressively decreased, while chronic liver disease, linked primarily to HCV, has become one of the leading causes of morbidity and mortality [2], [4], [6].
Considerable therapeutic progress has been achieved in HCV-infected patients due to combination therapy with pegylated interferon and ribavirin, resulting in a 55–60% sustained virological response (SVR) in HCV mono-infected patients (40–50% in HCV genotype 1, the most frequent HCV genotype worldwide) [7]. Results from large therapeutic trials in HIV–HCV coinfected patients have provided important information. A particularly encouraging result was that the pegylated interferon and ribavirin combination achieved an SVR in 27–44% of coinfected patients [8], [9], [10], [11], resulting in histopathological improvement in most of them. Recent results report similar SVR rates in coinfected more than in HCV mono-infected patients [12], [13], [14], [15]. HCV treatment, however, is given to a small number of HIV–HCV coinfected patients for many reasons, e.g., HCV treatment deemed questionable (minimal hepatic lesions, alcohol abuse, active drug use), lack of available liver biopsy, psychiatric contraindication, and physicians’ conviction of poor patient compliance [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]. Following the First European Consensus Conference on the treatment of chronic hepatitis B and C in HIV-infected patients in 2005, the coinfection guidelines in HIV medicine from the European AIDS Society in 2008 as well as their recent update at the European AIDS Clinical Society conference, it may be assumed that differences in the guidelines may have had an impact on treatment compliance and management standards [26], [27].
The aim of the present study was to analyze the care of HIV–HCV coinfected patients in France in 2009 (including initial workup, mode of treatment, follow-up modalities, and virological response) through a survey and to compare results with surveys conducted in 2004 and 2006 [17], [22].
Patients and methods
The same methodology was used in the three surveys, and details have been published elsewhere [17], [22]. In brief, physicians involved in the management of HIV-infected patients were recruited from 50 specialized centers from all of metropolitan France. These centers were representative of those providing the standard of care in HIV cART in France. Each physician was asked to prospectively fill out a standardized data collection form for all HIV–HCV coinfected patients seen between November 22 and 29, 2004 (2004 survey), April 3 and 10, 2006 (2006 survey) and June 15 and 22, 2009 (2009 survey). The form included sociodemographic data of the patient and physician, the HIV and HCV virological status, information regarding the pre-therapeutic workup of HCV infection, the type of HCV treatment, and its follow-up. In the 2006 and 2009 surveys, some questions were added to obtain more details on current addiction (alcohol consumption, IVDU, and substitution), liver damage assessment (biopsy or non-invasive tests), modalities of the follow-up of patients with cirrhosis, HCV treatment modalities and their virological results [sustained virologic response (SVR) was defined as an undetectable HCV-RNA (<50IU/ml) sixmonths after the end of HCV treatment], use of erythropoietin, use of anti-depressants, and the type of HIV treatment. This form had been pre-tested by four physician specialists managing HIV–HCV coinfected patients in order to optimize the type and means of data collection.
Discussion
In the last decade, chronic liver disease, linked primarily to HCV, has become one of the leading causes of morbidity and mortality in HIV-infected patients [2], [4], [6]. In the present study we had the opportunity to analyze the care of HIV–HCV coinfected patients in France in 2009 (including initial workup, mode of treatment, follow-up modalities, and virological response) and to compare the results with those obtained in the 2004 and 2006 surveys. We showed that the care of HIV–HCV coinfected patients has changed significantly in “real life”: (1) patients had more liver damage assessment; (2) more patients had received HCV treatment; and (3) more patients achieved a sustained virological response.
The complete workup of HCV infection in coinfected patients has progressed dramatically, mostly due to better liver damage assessment. In the 2009 and 2006 surveys, non-invasive liver tests had been done in 72% vs. 45% of patients using serum biomarkers (52% vs. 67%), transient elastography (63% vs. 11%), or both (25% vs. 22%). Numerous groups in France have been leaders in the development of non-invasive techniques for liver fibrosis assessment and this may partially explain the increased use in our surveys. The absence of liver biopsy was given as one of the main reasons for non-treatment in the 2004 survey, while this reason was given in only a small percentage of patients in the 2006 and 2009 surveys. Fibrometer, Hepascore, and FibroTest were shown to be able to stage liver fibrosis in HIV–HCV coinfected patients with area-under-the receiver operating characteristic curves (AUROCs) of 0.89, 0.84, and 0.78 for the diagnosis of >F2, respectively [28]. In 114 HIV–HCV coinfected patients with liver biopsy performed before and sixmonths after the end of HCV treatment, non-invasive biological scores showed a significant decrease in SVR patients [29]. Evaluations of liver stiffness using transient elastography have shown cut-off values from 4.5 to 7.2kPa for the diagnosis of significant fibrosis, with AUROCs from 0.72 to 0.83; performances were even better for the diagnosis of cirrhosis with AUROCs from 0.95 to 0.97 [30], [31]. The dual combination approach of serum biomarkers and transient elastography for the diagnosis of significant fibrosis could avoid the use of liver biopsy. Other methods have also been developed, including a novel panel of blood markers [32] and a genomics-based approach [33].
The percentage of coinfected patients who had never received HCV treatment decreased from 54% to 37% between 2004 and 2009, while the number of reasons cited by physicians for non-treatment decreased from 2.4 to 1.8 (out of the 11 choices presented on the data collection form). The reasons for non-treatment were numerous and their profile also changed [34], [35], [36], [37], [38], [39]. HCV treatment was deemed less questionable, the absence of liver biopsy no longer seemed to be a major barrier, and the number of contraindications to HCV treatment decreased (mainly due to fewer psychiatric reasons). Barriers to HCV treatment were more frequent in HIV–HCV coinfected than in HCV mono-infected patients, mainly due to depression and ongoing alcohol and injection drug use [19], [24], [40]. Fleming et al. [16] reported a cohort of 149 HIV–HCV coinfected patients, 70% of whom were ineligible for HCV treatment mainly due to non-compliance with medical visits, drug or alcohol use, and active psychiatric disease. Maida et al. [36] reported that only 40.1% of 405 coinfected patients had already been exposed to interferon-based therapies. Other groups found even smaller proportions (<2–33%) of coinfected patients who had undergone HCV treatment [24], [37], [38]. More recent data from the EuroSIDA group however showed results quite similar to those found in the present study. In European countries, the incidence of starting HCV treatment in HIV–HCV coinfected patients increased from 3.9 per 1000 patients prior to 1998 to 32.6 per 1000 patients in the year follow-up after 2004. In multivariate analysis, an estimated 23% annual increase in the incidence of starting HCV treatment was found when adjusting for baseline factors [39]. Programs are successfully integrating hepatitis C care for IVDUs into health-care settings [20]. Studies in methadone maintenance patients showed rates of SVR in 28–94% of patients with excellent completion rates of HCV treatment (72–100%) [41]. Many aspects of the barriers to HCV treatment can be overcome with direct treatment, such as the anti-depressant drugs used in only 20% and 22% of patients in the 2006 and 2009 surveys, respectively [21], [41], [42], [43]. Asthenia may be a consequence of treatment-related anemia during HCV therapy [44], [45]. Erythropoietin treatment should then be considered to maximize SVR in HCV therapy; it had been used in 7% of patients in the 2006 survey and 34% in the 2009 survey. Its use may help to maintain full doses of standard of care treatment, especially ribavirin, by improving the quality of life during the treatment [46], [47].
A dramatic increase in the SVR rates in coinfected patients between 2004 and 2009 was seen in the present study. In the 2004 survey, we did not have specific data available concerning the duration and type of HCV treatment. In the 2009 and 2006 surveys; however, most treated patients (94% vs. 80%, respectively) had received the combination of pegylated interferon and ribavirin. It is striking to note that an SVR was obtained in 29% of patients in the 2004 and 2006 surveys and in 49% of those in the 2009 survey. This figure is very close to that reported (up to 54%) in recently published large randomized trials [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [47]. Based on data from large therapeutic trials and clinical studies (reflecting a more pragmatic attitude) [48], about half of HIV–HCV coinfected patients receiving HCV treatment will have an SVR. In terms of coinfection and its particular seriousness [49], [50], [51], [52], these results seem particularly encouraging [27].
In HIV–HCV coinfected patients with end-stage liver disease, liver transplantation shows promise as a potential therapeutic option. In one study [53], 2- and 5-year survival rates after liver transplantation were 73% and 51%, and 91% and 81% in 35 coinfected and 44 mono-infected patients, respectively. In another study [54], survival at 1, 2, and 3years was 83%, 75%, and 62% in the 12 coinfected vs. 98%, 89%, and 84% in the 59 mono-infected patients, respectively. However, more recent data showed the 5-year survival rate to be significantly lower in coinfected vs. mono-infected subjects, with liver complications secondary to HCV recurrence as the main driver of this poor outcome [55]. Thus, it does not seem that transplantation may be the final solution for most decompensated cirrhotic patients with HIV–HCV. Earlier referral of these patients to a liver transplant unit after the first episode of liver decompensation (which was rarely the case in the two more recent surveys), the use of new drugs that are effective against HCV, and the avoidance of drug toxicity (i.e. cART-related hepatotoxicity) are mandatory for improving the results of this challenging indication for liver transplantation.
In the present study, the immuno-virological control of HIV infection from 2004 to 2009 showed increased rates of undetectable HIV viral load (63–79%) and CD4 level counts >350/ml (49–71%). This control was even better in the sub-group of patients who received HCV treatment [25]. Pegylated interferon and ribavirin responses tended to increase with higher CD4 counts with similar rates of side effects [56], although there are conflicting results [57]. High CD4 cell counts, the lack of markers of severe liver disease and therapy against HCV were factors associated with a better hepatic outcome in HIV–HCV coinfected patients treated with cART [58], [59]. However, more data are needed in order to better define the impact of different cART on SVR rates after HCV treatment in such patients [60], [61].
In conclusion, the care of HIV–HCV coinfected patients changed significantly in “real life” in France between 2004 and 2009. These results underline the importance of continuing efforts to educate physicians and patients about increasing the access of coinfected patients to HCV treatment. Efforts should be made to improve the care of these patients, such as increasing the access to and the number of patients receiving treatment for HCV infection, the possibility of starting HCV treatment earlier (i.e. before the presence of a high liver fibrosis score), the introduction of HCV treatment even in patients with low CD4 cell counts, and earlier referral of patients with cirrhosis to a liver transplant unit.
Results
Sixty-two, 58, and 71 physicians following HIV–HCV coinfected patients participated in the 2009, 2006, and 2004 studies, respectively (two-thirds of physicians participated in all surveys). The profiles of these physicians did not differ in the three surveys, as they practiced in university hospitals (70–74%), general hospitals (22–25%), or other areas (3–7%). They were from departments of infectious disease (52% vs. 47% vs. 39%, respectively), internal medicine (33% vs. 26% vs. 27%), HIV/AIDS information and care (12% vs. 7% vs. 17%), hematology (0% vs. 3% vs. 10%), hepatogastroenterology (3% vs. 7% vs. 6%) or other areas (15% vs. 10% vs. 1%).
During the weeks the studies were carried out, 419, 416, and 380 HIV–HCV coinfected patients were included in the 2009, 2006, and 2004 surveys, respectively (Table 1). Individual patients did not undergo repeated assessments in the different surveys. They were mainly male (about 71% in the three surveys) with a mean age of 45.1±7.3 vs. 43.5±6.3 vs. 41.6±6.6years (36–50years in 80% of patients). Most patients in the three surveys were of European origin (73–82%). Non-European patients were mostly of African origin, i.e. 22% vs. 17% vs. 21% in the 2009, 2006, and 2004 surveys, respectively. In the 2009 and 2006 surveys (data not available in the 2004 survey), 35% of patients had excessive alcohol consumption: 53% vs. 53% with <30g/d, 32% vs. 28% with 30–50g/d, and 15% vs. 13% with >50g/d, respectively; 82/378 (22%) and 70/410 (17%) patients were or had been IVDUs, 72 vs. 56 patients of whom received an opiate substitution treatment.
Patients had been diagnosed with HIV infection for 12.8 vs. 13.7 vs. 12.1years (from 6 to 20years in 68%, 84%, and 77% of patients, respectively). The therapeutic management of HIV infection appeared to be very appropriate as evidenced by high rates of undetectable HIV viral load (<50copies/ml) and CD4 levels >500/ml, and a last measured HIV viral load done an average of 1.8 vs. 2.6 vs. 2.1months before the date when the survey was conducted (87%, 83%, and 91% of patients, respectively, had had an HIV viral load assessment done in the previous threemonths) (Table 1). In 2009 and 2006 (data not available in the 2004 survey), 381/419 (91%) and 377/416 (91%) of the patients received combination anti-retroviral therapy(cART) for HIV, i.e. boosted protease inhibitor based (61% vs. 66%), non-nucleoside based (23% vs. 18%), triple combination of nucleosides (3% vs. 2%), or other regimen (13% vs. 14%).
Patients had been diagnosed with HCV infection for an average of 9.5 vs. 9.6 vs. 8.5years in 2009, 2006, and 2004, respectively (from 1 to 5years in 18%, 13%, and 18%; 6–15years in 52%, 71%, and 70%; and more than 15years in 21%, 12%, and 6%) (Table 1). Patients in 2009 compared to those in 2006 and 2004 had a similar distribution of HCV genotypes (genotype 1 or 4 in 68%, 65%, and 65%, respectively). The extent of the pre-therapeutic HCV workup depended in part on the year of the survey. The liver damage assessment in particular significantly changed over time. The rate of liver biopsy alone decreased 14% vs. 38% vs. 56%, while the assessment of liver damage by means of non-invasive markers only increased (47% vs. 24%, data not available in 2004). There was no correlation between the performance of a liver biopsy and physician specialization. In the 2009 and 2006 surveys (data not available in 2004), non-invasive liver tests had been performed in 72% vs. 45% of patients using serum biomarkers in 172/330 (52%) vs. 124/185 (67%), transient elastography in 224/358 (63%) vs. 20/185 (11%), or both in 100/398 (25.1%) vs. 41/185 (22%) patients. Overall, the proportion of patients who had a liver biopsy or non-invasive markers has increased (86% vs. 82% vs. 56%). A complete workup, including HCV-RNA, HCV genotyping and a liver damage assessment by biopsy or non-invasive tests was performed in 58% vs. 63% vs. 47% in the 2009, 2006, and 2004 surveys, respectively (p<0.001).
The analysis of HCV treatment showed that 165/398 (42%) vs. 199/393 (51%) vs. 100/380 (26%) patients had been previously treated (p<0.01), whereas 21% vs. 16% vs. 17% of patients were receiving ongoing treatment in the 2009, 2006, and 2004 surveys, respectively (Table 2). The main reasons for non-treatment of HCV in 131 (42%) vs. 164 (42%) vs. 205 (54%) patients in the 2009, 2006, and 2004 surveys changed (Table 2), while the number of reasons per patient decreased (1.8 vs. 2.1 vs. 2.4). When HCV treatment was deemed questionable, the reasons given were: minimal hepatic lesions for 53% vs. 47% vs. 32% of patients, chronic excessive alcohol consumption for 35% vs. 29% vs. 31% and active drug use for 20% vs. 6% vs. 12%. The main contraindication to HCV treatment was a psychiatric disorder (83% vs. 67% vs. 73%), while all other contraindications were noted in 5–26% of patients (cardiovascular, poor general condition, neurological, immunological, hematological, etc.). Physician conviction of poor compliance with HCV treatment was centered on the reluctance of the patient (54% vs. 70% vs. 48%) and unfavorable socioeconomic conditions (43% vs. 33% vs. 31%). Patient refusal increased from 16% to 27% of patients. There was no correlation between the number of treated patients and HCV genotype distribution in any of the surveys. Among treated patients, an SVR to HCV treatment was noted in 81/165 (49%) vs. 50/167 (29%) vs. 27/92 (29%) patients; there was an absence of virological response in 40 (24%) vs. 73 (43%) vs. 40 (43%) patients; and a relapse or virological breakthrough in 44 (27%) vs. 44 (26%) vs. 25 (27%) patients, respectively. SVR rates were not significantly correlated to HCV genotypes. Genotype 1, 4, 5 or 6 vs. genotype 2 or 3 showed SVR rates of 53% and 47% vs. 41% and 59% vs. 44% and 56% in the 2009, 2006, and 2004 surveys, respectively. If the optimal duration of HCV treatment in coinfected patients is considered to be about 12months, 31% vs. 53% vs. 58% of patients had stopped their combination therapy prematurely. In the 2009 and 2006 surveys (data not available for the 2004 survey), most treated patients received a combination of pegylated interferon plus ribavirin, 94% vs. 80%. Among these, 22% vs. 20%, were also receiving an anti-depressant drug, and 34% vs. 7% were receiving erythropoietin treatment. In the 2009 and 2006 surveys, cirrhotic patients (128 and 83 patients, respectively) had a follow-up including liver ultrasound exam (mean interval of 7.1 vs. 7.5months) and upper GI endoscopy (mean interval of 13.9 vs. 10.2months), whereas only 10% vs. 8% had been referred to a liver transplant unit.
Compared to non-treated patients in all surveys (Table 3), patients who had received HCV treatment were more likely to be of European origin, had better control of HIV infection (more frequent undetectable HIV viral load, less frequent low CD4 cell count), and were more likely to have had a liver damage assessment. In a multivariate analysis in the 2009 survey (Table 4), the main characteristics that were independently associated with HCV treatment were a liver fibrosis score >F2 (on biopsy, biomarkers or transient elastography), a liver biopsy activity grade >A2, a CD4 cell count >350ml, European origin, daily alcohol consumption <30g, and male gender.
Sunday, June 20, 2010
16 Weeks Peg/Rbv vs 24 Weeks: who can be treated for 16 weeks among genotype 2/3
16 Weeks Peg/Rbv vs 24 Weeks: who can be treated for 16 weeks among genotype 2/3
After application of this criterion, the SVR rates were 91% in those randomized to 24 weeks and 82% in those randomized to 16 weeks of treatment (P = 0.0006). Most patients achieved an end-of-treatment response (data not shown); thus, the key factor behind this 9% difference in SVR rates was a higher relapse rate in patients randomized to 16 weeks of treatment (15% versus 6%, P < 0.0001).......In the original intention-to-treat analysis, the overall SVR rates did not differ significantly between treatment groups when only patients with a baseline HCV RNA level 400,000 IU/mL or less were included (82% in those treated for 24 weeks and 81% in those treated for 16 weeks).[7] The results of the current analysis supports this finding that patients achieving an RVR with a baseline serum HCV RNA level of 400,000 IU/mL or less can be treated for 16 weeks without compromising SVR rates because there was no statistically significant difference between those treated for 24 weeks and those treated for 16 weeks (95% versus 91%, P = 0.2012)......
Baseline factors that predicted relapse among genotype 2/3 patients during follow-up were for the most part the opposite of those that predicted SVR: assignment to 16 weeks of treatment (OR 2.96, 95% CI 1.76-4.95; P < 0.0001), presence of advanced fibrosis on liver biopsy (OR 2.42, 95% CI 1.43-4.12; P = 0.0011), higher HCV RNA level (OR 1.96, 95% CI 1.40-2.74; P < 0.0001), and higher body weight (OR 1.03, 95% CI 1.01-1.04; P = 0.0002). Male sex was also a significant predictor of relapse in this analysis (OR 1.79, 95% CI 1.02-3.16; P = 0.0426).......
The results show that for RVR patients with low viral load, low age, or low body weight, rates of SVR in both groups range from 89% to 95%, with differences between the two groups less than 5%. When a patient had at least two of the four positive predictors, low viral load, low age, low body weight, and noncirrhosis, then the SVR rate was 90% in the 16-week group and 93% in the 24-week group, whereas the relapse rates were 6% and 4%, respectively. The difference in SVR rate between the 16-week and 24-week groups remains low (87% versus 88%) in all treated patients (intention-to-treat patients) with RVR and at least two positive predictors.
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Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin
Hepatology June 2010
Moises Diago 1 *, Mitchell L. Shiffman 2, Jean-Pierre Bronowicki 3, Stefan Zeuzem 4, Maribel Rodriguez-Torres 5, Stephen C. Pappas 6, Andreas Tietz 7, David R. Nelson 8
1Hepatology Section, Hospital General de Valencia, Valencia, Spain
2Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA
3Department of Hepatology and Gastroenterology, INSERM U724, CHU de Nancy, Vandoeuvre-les-Nancy, France
4J.W. Goethe University Hospital, Frankfurt, Germany
5Fundacion de Investigacion de Diego, Santurce, Puerto Rico
6St Luke's Center for Liver Disease, Houston, TX
7Roche, Basel, Switzerland
8University of Florida, Gainsville, FL
email: Moises Diago (mdiagom@meditex.es)
*Correspondence to Moises Diago, Hospital General De Valencia, Av. Tres Cruces 2, 46014 Valencia, Spain
Potential conflict of interest: Dr. Shiffman advises and received grants from Biolex, Conatus, Human Genome Sciences, Romark, Valeant, Vertex, and Zymogenetics. He also advises Anadys, Bristol-Myers Squibb, and Novartis. He received grants from GlaxoSmithKline, Globeimmune, Idenix, Johnson & Johnson, and Wyeth. He is a consultant for Pfizer. He is also a consultant for, advises, is on the speakers' bureau of, and received grants from Roche. He advises, is on the speakers' bureau of, and received grants from Schering-Plough. Dr. Zeuzem is a consultant for, advises, and is on the speakers' bureau of Roche, Schering-Plough, Novartis, and Human Genome Sciences. Dr. Rodriguez-Torres is a consultant for and advises Anadys, Vertex, GlaxoSmithKline, and Pharmasset. She advises Bristol-Myers Squibb, Idera, Human Genome Sciences, Idenix, Intarcia Therapeutics, Novartis, Valeant, Sanofi-Aventis, Virochem, and Gilead. She also advises and is on the speakers' bureau of Roche. Dr. Pappas is a consultant for Orphan Therapeutics and advises Hoffmann-LaRoche. Dr. Nelson is a consultant for, advises, and received grants from Roche.
Funded by:
Roche, Basel, Switzerland
Abstract
The objective of this analysis was to compare sustained virological response (SVR) and relapse rates in patients with a rapid virological response (RVR, HCV RNA <50 IU/mL at week 4) randomized to 24 or 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 g/week plus ribavirin 800 mg/day in the multinational ACCELERATE study. The analysis was restricted to patients who received treatment for 80% or more of the planned duration. Of 1309 eligible patients, 863 individuals (65.9%) achieved an RVR and were included in this analysis (458 assigned to 16 weeks and 405 assigned to 24 weeks). The overall SVR rate was significantly higher in patients randomized to 24 weeks of treatment (91% versus 82%; P = 0.0006) and among patients infected with genotype 2 (92% versus 81%; P = 0.0010) but not genotype 3 (90% versus 84%; P = 0.1308). Relapse rates were significantly lower among all patients randomized to 24 weeks of treatment: overall (6% versus 15%, P < 0.0001); in those infected with genotype 2 (5% versus 17%, P = 0.0001), and genotype 3 (7% versus 14%, P = 0.0489). SVR rates in patients with a viral load of 400,000 IU/mL or less randomized to 24 and 16 weeks of treatment were similar, 95% and 91% (P = 0.2012). Significant pretreatment predictors of SVR included assignment to 24 weeks of treatment (P = 0.0006), absence of advanced fibrosis on liver biopsy (P = 0.0032), lower HCV RNA level (P = 0.0017), and lower body weight (P < 0.0001).
Conclusion: The standard 24-week regimen of peginterferon alfa-2a (40KD) plus ribavirin is significantly more effective than an abbreviated 16-week regimen in genotype 2/3 patients who achieve an RVR. Abbreviated regimens may be considered in patients with a low baseline viral load who achieve an RVR
Article Text
The standard of care for patients with chronic hepatitis C is the combination of pegylated interferon plus ribavirin.[1-4] When treatment-naive patients infected with hepatitis C virus (HCV) genotype 2 or 3 are treated with the standard of care for 24 weeks, sustained virological response (SVR) rates generally exceed 65% and may reach 80% or higher.[5-7] Treatment for longer durations does not increase efficacy in these individuals.[5][6] Given that a consistently high cure rate can be achieved with a 24-week combination regimen in these individuals, several studies have evaluated shorter treatment durations in patients with HCV genotype 2 or 3 infection.[7-10]
The large randomized multinational ACCELERATE trial was designed to test the hypothesis that treatment for 16 weeks in patients with HCV genotype 2 or 3 infection was noninferior to treatment for 24 weeks, as defined by a 6% noninferiority margin. The study demonstrated that 24 weeks of treatment is significantly more effective than 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 ug/week plus ribavirin (800 mg/day). Overall SVR rates in the trial were 70% and 62%, respectively (P < 0.001).[7]
Several smaller trials have selected patients for abbreviated treatment on the basis of the virological response at week 4.[8-10] The results of one of these trials with peginterferon alfa-2b (12KD) 1.0 ug/kg/week plus ribavirin (1000/1200 mg/day) suggested that individuals with a rapid virological response (RVR), defined as HCV RNA less than 50 IU/mL at week 4, achieved an SVR rate after 12 weeks of treatment that was similar to that achieved in patients receiving the standard 24-week regimen (85% versus 91%, respectively).[9] However, a larger trial that randomized patients to peginterferon alfa-2b (12KD) 1.5 ug/kg/week plus ribavirin (800-1400 mg/day) with an RVR to 14 or 24 weeks of treatment concluded that the shorter treatment duration was inferior to the longer duration, with SVR rates of 86% and 93%, respectively.[11] The difference in SVR rates between the two treatment durations in these two studies was attributable to higher relapse rates in patients assigned to the abbreviated treatment regimen.[9][11] The ACCELERATE trial also showed that SVR rates were lower in patients with an RVR who were treated for 16 or 24 weeks (79% versus 85%).[7]
The ACCELERATE trial randomized more than 1400 genotype 2 or 3 patients, 65% of whom achieved an RVR.[7] Based on an intention-to-treat analysis, SVR rates among patients randomized to longer treatment durations may be lower because of higher dropout rates compared with patients randomized to shorter treatment durations. Therefore, a conservative approach to comparing the efficacy of two identical regimens differing only in treatment duration is to restrict analyses to patients who complete the scheduled treatment duration. The large database from this trial provides an opportunity to determine whether a specific subgroup of genotype 2 or 3 patients who achieve an RVR and complete scheduled treatment, for example, those with low baseline HCV RNA levels, can be treated with an abbreviated regimen without compromising SVR rates.
Discussion
The results of this analysis confirm the findings of the intention-to-treat analysis of ACCELERATE in showing that SVR rates are higher in genotype 2/3 patients with an RVR who are treated for 24 weeks than 16 weeks. However, it should be noted that for genotype 3 patients the difference in SVR between 24 and 16 weeks was not statistically significant ( delta= 6%) in contrast to the difference in genotype 2 patients ( = 11%). In the original analysis, SVR rates in patients with an RVR treated for 24 and 16 weeks were 85% and 79%, respectively (P = 0.02).[7] The current analysis included only patients who had an RVR and who completed the planned treatment duration without relevant treatment interruptions (at least 19 doses of peginterferon alfa-2a in the 24-week treatment group and at least 13 doses in the 16-week treatment group). This approach has the advantage of compensating for the difference in withdrawal rates between the two treatment arms. More than twice as many patients withdrew from the 24-week treatment group than from the 16-week treatment group (13% versus 6%), which has the effect of reducing the difference between the two treatment durations in an intention-to-treat analysis. After application of this criterion, the SVR rates were 91% in those randomized to 24 weeks and 82% in those randomized to 16 weeks of treatment (P = 0.0006). Most patients achieved an end-of-treatment response (data not shown); thus, the key factor behind this 9% difference in SVR rates was a higher relapse rate in patients randomized to 16 weeks of treatment (15% versus 6%, P < 0.0001).
Assignment to 24 weeks of treatment was the most important predictor of SVR in the MLR analysis; conversely, assignment to the 16-week regimen was the most important predictor of relapse in the MLR analysis. Other predictors of SVR included the absence of advanced fibrosis on the pretreatment liver biopsy, a lower HCV RNA level, and lower body weight, all of which are well established as predictors of treatment success in patients with chronic hepatitis C.
In the original intention-to-treat analysis, the overall SVR rates did not differ significantly between treatment groups when only patients with a baseline HCV RNA level 400,000 IU/mL or less were included (82% in those treated for 24 weeks and 81% in those treated for 16 weeks).[7] The results of the current analysis supports this finding that patients achieving an RVR with a baseline serum HCV RNA level of 400,000 IU/mL or less can be treated for 16 weeks without compromising SVR rates because there was no statistically significant difference between those treated for 24 weeks and those treated for 16 weeks (95% versus 91%, P = 0.2012).
The authors of other studies of abbreviated regimens for genotype 2 or 3 patients have reported higher relapse rates in patients assigned to the shorter treatment duration.[9][11][12] The increase in the probability of relapse was twofold to threefold greater in patients assigned to abbreviated 12- to 14- week regimens, which is in close agreement with the 2.5-fold higher relapse rate in patients assigned to the 16-week regimen in the current analysis.
In addition to higher voluntary withdrawal rates in patients treated for longer duration, it is possible that differences in treatment exposure may have an effect on SVR rates in patients randomized to different treatment durations. For this reason we included an exposure analysis in the current analysis. Few patients had exposure levels below 80% of the planned dose of ribavirin or peginterferon alfa-2a (40KD); thus, we cannot comment on the impact of large or long-term dose reductions on the probability of achieving an SVR. Most patients had a ribavirin exposure level that was 90% to 100% of the planned amount. Among patients with 80% or greater exposure to ribavirin, the SVR rates were consistently higher in patients assigned to the longer treatment duration. Moreover, there was no trend toward a reduction in SVR rates with decreasing exposure in these individuals.
It is now clear from the results of ACCELERATE and another recently completed large randomized noninferiority study[11] that 24 weeks of treatment produces significantly higher SVR rates than abbreviated regimens and that abbreviated regimens expose patients to a significantly higher probability of virological relapse during follow-up, even in patients with an RVR. In spite of the greater efficacy of the standard treatment duration in their study, Dalgard et al.[11] argued that it would be cost-effective to assign all genotype 2 or 3 patients to abbreviated treatment and to immediately retreat those who relapse. Such a policy assumes that all patients have the same probability of relapse and that all patients will be willing to immediately re-enroll for a longer treatment duration. The results of the current analysis and that reported by Mangia et al.[13] suggest that the first assumption is incorrect; the probability of relapse varies according to several well-established predictors of treatment success. Adopting this approach would require physicians to counsel all patients to prepare themselves for the possibility of undergoing two consecutive courses of treatment, with a total treatment duration of 40 weeks. However, Mangia et al. reported that patients infected with genotype 2 or 3 who achieved an RVR but who relapsed after an abbreviated 12-week course of treatment with peginterferon alfa-2b plus ribavirin could achieve an SVR rate of 70% with a second 24-week course of the same treatment.[13]
The current analysis has shown that several subgroups of patients with an RVR have an acceptable risk:benefit ratio for contemplation of abbreviated therapy in addition to those that have a low baseline serum HCV RNA level. Given that advanced fibrosis was a stronger predictor of relapse in patients with RVR after 16 weeks of treatment (relapse rate of 27%), it is reasonable to exclude all such patients from abbreviated treatment.
Rather than reducing the treatment duration in patients who experience adverse events that must be managed by dose reductions, physicians should encourage continued treatment for the full 24-week duration to maximize the probability of SVR.
Overall, this analysis shows that for patients infected with HCV genotype 2 or 3 and who achieve an RVR at week 4, the standard 24-week treatment duration produces significantly higher SVR rates than an abbreviated 16-week regimen. Shortening the treatment duration should be considered only in patients with a low baseline HCV RNA level and without bridging fibrosis/cirrhosis who achieve an RVR. The difference in SVR rates is attributable to a significantly higher rate of virological relapse in patients treated with the abbreviated regimen.
Results
The per protocol population comprised 1309 individuals, of whom 863 patients (65.9%) achieved an RVR at week 4, completed designated treatment, and were included this analysis. Of the 863 patients included in the analysis, all were considered for the determination of SVR, with patients missing post-treatment HCV RNA values considered as nonresponders. Forty patients were excluded from the analysis of relapse because of missing HCV RNA values at end of treatment (n = 24), breakthrough (n = 5), or missing post-treatment HCV RNA values in patients with response at end of treatment (n = 11).
The baseline characteristics of patients with an RVR who completed treatment were similar, with no significant differences (all P-values > 0.2) by treatment group (Table 1). The mean overall age of patients with an RVR was 45 to 46 years, 60% to 62% were male, 87% were white, and 2% to 3% were black. Approximately 25% to 27% had a low baseline serum HCV RNA levels (
SVR rates exceeded 80% in patients with an RVR regardless of HCV genotype or the assigned treatment duration (Fig. 1A). The SVR rate was significantly lower in patients randomized to 16 than 24 weeks of treatment, overall (82% [377/458] versus 91% [367/405]; OR 0.49, 95% CI 0.32-0.74; P = 0.0006) and in those infected with genotype 2 (81% [196/243] versus 92% [194/212]; OR 0.38, 95% CI 0.21-0.69; P = 0.0010) but not genotype 3 (84% [181/215] versus 90% [173/193]; OR 0.63, 95% CI 0.35-1.15; P = 0.1308).
Virological relapse rates during follow-up were consistently and significantly higher in patients randomized to the shorter treatment duration (Fig. 1B). The relapse rates in patients randomized to 16 and 24 weeks of treatment, respectively, were 15% (67/439) and 6% (23/384) overall (OR 2.77, 95% CI 1.69-4.55; P < 0.0001); 17% (39/233) and 5% (10/204) among patients infected with HCV genotype 2 (OR 3.82, 95% CI 1.85-7.89; P = 0.0001); and 14% (28/206) and 7% (13/180) among those infected with HCV genotype 3 (OR 1.99, 95% CI 1.00-3.99; P = 0.0489).
Among genotype 2/3 patients with a low baseline viral load (HCV RNA level
Predictors of SVR and Relapse by MLR Analysis.
Baseline factors that were identified as significant and independent predictors of SVR among genotype 2/3 patients with an RVR who completed the designated treatment duration included assignment to 24 weeks of treatment (OR 2.12, 95% CI 1.38-3.24; P = 0.0006), absence of advanced fibrosis on liver biopsy (OR 2.06, 95% CI 1.27-3.33; P = 0.0032), lower HCV RNA level (OR 1.52, 95% CI 1.17-1.97; P = 0.0017), and lower body weight (OR 1.03, 95% CI 1.02-1.04; P < 0.0001).
Baseline factors that predicted relapse among genotype 2/3 patients during follow-up were for the most part the opposite of those that predicted SVR: assignment to 16 weeks of treatment (OR 2.96, 95% CI 1.76-4.95; P < 0.0001), presence of advanced fibrosis on liver biopsy (OR 2.42, 95% CI 1.43-4.12; P = 0.0011), higher HCV RNA level (OR 1.96, 95% CI 1.40-2.74; P < 0.0001), and higher body weight (OR 1.03, 95% CI 1.01-1.04; P = 0.0002). Male sex was also a significant predictor of relapse in this analysis (OR 1.79, 95% CI 1.02-3.16; P = 0.0426).
Based on the outcome of the current MLR analysis, rates of SVR and relapse in the two treatment groups were estimated for each baseline covariate shown to be an independent predictor of response (Table 2). Rates for genotype, sex, age, and alanine aminotransferase ratio are also presented for completeness, because they were significant predictors in the intention-to-treat analysis.[7] The results show that for RVR patients with low viral load, low age, or low body weight, rates of SVR in both groups range from 89% to 95%, with differences between the two groups less than 5%. When a patient had at least two of the four positive predictors, low viral load, low age, low body weight, and noncirrhosis, then the SVR rate was 90% in the 16-week group and 93% in the 24-week group, whereas the relapse rates were 6% and 4%, respectively. The difference in SVR rate between the 16-week and 24-week groups remains low (87% versus 88%) in all treated patients (intention-to-treat patients) with RVR and at least two positive predictors.
Impact of Dose Reductions on SVR.
Among patients with an RVR and who completed treatment, SVR rates were consistently higher in those who completed 24 weeks of treatment compared with 16 weeks of treatment regardless of the extent of ribavirin exposure (Fig. 2A). Only a small number of patients had ribavirin exposure that was less than 80% of the planned dose (19/863, 2%); thus, it is not possible to comment on the effect of large or prolonged dose reductions on SVR rates in individuals with an RVR. The results were generally similar when the analysis was restricted to those patients with a baseline HCV RNA level less than 400,000 IU/mL, although most patients had exposure to ribavirin that was 90% or more of the planned dose (Fig. 2B).
Figure 2b. Adherence Matters
Screen shot 2010-06-20 at 11.25.19 AM.png
Table 2. Rates of SVR and Relapse Among Subgroups of Patients
Screen shot 2010-06-20 at 11.20.50 AM.png
Figure 1. (A) SVR and (B) relapse rates according to treatment duration. Only patients confirmed to be HCV RNA-negative at the end-of-treatment were included in the calculation of relapse rates.
Screen shot 2010-06-20 at 11.20.20 AM.png
Patients and Methods
Study Design and Patients.
The inclusion and exclusion criteria, study design, and primary results of ACCELERATE are reported elsewhere.[7] Briefly, treatment-naive patients with chronic HCV genotype 2 or 3 infection were randomized to receive treatment with peginterferon alfa-2a (40KD) (PEGASYS®, Roche, Basel, Switzerland) 180 g/week plus ribavirin (COPEGUS®, Roche) 800 mg/day for either 16 or 24 weeks. Eligible patients had quantifiable HCV RNA (COBAS® AMPLICOR HCV MONITOR Test, v2.0: limit of quantitation 600 IU/mL) and elevated serum alanine aminotransferase levels. All patients were required to have undergone a liver biopsy before enrollment.
Assessment of Virological Response.
Serum HCV RNA levels were measured by qualitative polymerase chain reaction assay (COBAS® AMPLICOR HCV Test, v2.0, limit of detection 50 IU/mL) at weeks 4, 12, at the end of the scheduled treatment period (week 16 or 24), and at weeks 12 and 24 after completion of the scheduled treatment period. The primary efficacy end-point in ACCELERATE was SVR defined as undetectable serum HCV RNA at the end of follow-up (week 40 in patients randomized to 16 weeks of treatment and week 48 in those randomized to 24 weeks of treatment). Virological relapse was defined as detection of HCV RNA in serum during follow-up in a patient that was confirmed to have been HCV RNA-negative at the end of treatment. Patients without an end-of-treatment HCV RNA result or without post-treatment HCV RNA data were not included in relapse rate calculations. The impact of ribavirin exposure on SVR rates was evaluated by calculating the amount of drug received by a patient (percentage of the planned total dose). Physician-initiated dose reductions for adverse events and laboratory abnormalities and patient compliance as recorded in diaries were included in these calculations.
Analysis Populations and Statistics.
The efficacy analysis was conducted in all randomized patients with an RVR that were included in the per-protocol population who completed the scheduled treatment duration of 16 or 24 weeks. Patients were excluded from the per-protocol population when they had (1) major protocol deviations, or (2) treatment interruptions or early discontinuations resulting in less than 13 doses of peginterferon alfa-2a (40KD) or less than 13 weeks of treatment with ribavirin in patients randomized to 16 weeks, and less than 19 doses of peginterferon alfa-2a (40KD) or less than 19 weeks of treatment with ribavirin in patients randomized to 24 weeks of treatment. Use of the standard population rather than the intention-to-treat population ensures that differences in SVR rates or relapse rates are not influenced by a higher dropout rate in patients randomized to the longer treatment duration.
The baseline demographic and disease characteristics in the two treatment groups of the analysis population were compared using the chi-squared test for categorical data and t test for continuous data to verify whether the restriction to the specified analysis population had any relevant impact on the comparability of two treatment groups. SVR and relapse rates in the two treatment groups were compared with the use of the Cochran-Mantel-Haenszel test, stratified according to country of residence and HCV genotype. The common odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. The noninferiority margin specified in the study protocol for the primary analysis[7] was 6%, which was equivalent to an OR of 0.70 when assuming an SVR rate of 80% in the 24-week group. On this basis, the 16-week and 24-week regimens were considered equivalent if the lower limit of the 95% CI for the OR was at least 0.70. Because the current analysis was post hoc, no inferiority margin was assumed, the study results were known, and the subgroups lacked adequate power.
Multiple logistic regression (MLR) models were used to identify baseline factors associated with SVR and relapse in patients who achieved an RVR and who were treated for 16 or 24 weeks. Pretreatment factors considered in the analysis included assigned treatment duration at randomization plus the following baseline factors: age, sex, race (white versus nonwhite), body weight, HCV genotype (3 versus 2), serum alanine aminotransferase quotient, serum HCV RNA level, and the pretreatment liver biopsy result (no bridging fibrosis/cirrhosis versus bridging fibrosis/cirrhosis).
In the current analysis, all statistical tests are exploratory, and thus a significant result (P < 0.05) cannot be considered as formal proof of efficacy. Furthermore, the presence of nonsignificant test results cannot be considered as a formal proof of noninferiority. No adjustment of the significance level of 0.05 was considered necessary because of the exploratory nature of the analysis.
After application of this criterion, the SVR rates were 91% in those randomized to 24 weeks and 82% in those randomized to 16 weeks of treatment (P = 0.0006). Most patients achieved an end-of-treatment response (data not shown); thus, the key factor behind this 9% difference in SVR rates was a higher relapse rate in patients randomized to 16 weeks of treatment (15% versus 6%, P < 0.0001).......In the original intention-to-treat analysis, the overall SVR rates did not differ significantly between treatment groups when only patients with a baseline HCV RNA level 400,000 IU/mL or less were included (82% in those treated for 24 weeks and 81% in those treated for 16 weeks).[7] The results of the current analysis supports this finding that patients achieving an RVR with a baseline serum HCV RNA level of 400,000 IU/mL or less can be treated for 16 weeks without compromising SVR rates because there was no statistically significant difference between those treated for 24 weeks and those treated for 16 weeks (95% versus 91%, P = 0.2012)......
Baseline factors that predicted relapse among genotype 2/3 patients during follow-up were for the most part the opposite of those that predicted SVR: assignment to 16 weeks of treatment (OR 2.96, 95% CI 1.76-4.95; P < 0.0001), presence of advanced fibrosis on liver biopsy (OR 2.42, 95% CI 1.43-4.12; P = 0.0011), higher HCV RNA level (OR 1.96, 95% CI 1.40-2.74; P < 0.0001), and higher body weight (OR 1.03, 95% CI 1.01-1.04; P = 0.0002). Male sex was also a significant predictor of relapse in this analysis (OR 1.79, 95% CI 1.02-3.16; P = 0.0426).......
The results show that for RVR patients with low viral load, low age, or low body weight, rates of SVR in both groups range from 89% to 95%, with differences between the two groups less than 5%. When a patient had at least two of the four positive predictors, low viral load, low age, low body weight, and noncirrhosis, then the SVR rate was 90% in the 16-week group and 93% in the 24-week group, whereas the relapse rates were 6% and 4%, respectively. The difference in SVR rate between the 16-week and 24-week groups remains low (87% versus 88%) in all treated patients (intention-to-treat patients) with RVR and at least two positive predictors.
"
Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin
Hepatology June 2010
Moises Diago 1 *, Mitchell L. Shiffman 2, Jean-Pierre Bronowicki 3, Stefan Zeuzem 4, Maribel Rodriguez-Torres 5, Stephen C. Pappas 6, Andreas Tietz 7, David R. Nelson 8
1Hepatology Section, Hospital General de Valencia, Valencia, Spain
2Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA
3Department of Hepatology and Gastroenterology, INSERM U724, CHU de Nancy, Vandoeuvre-les-Nancy, France
4J.W. Goethe University Hospital, Frankfurt, Germany
5Fundacion de Investigacion de Diego, Santurce, Puerto Rico
6St Luke's Center for Liver Disease, Houston, TX
7Roche, Basel, Switzerland
8University of Florida, Gainsville, FL
email: Moises Diago (mdiagom@meditex.es)
*Correspondence to Moises Diago, Hospital General De Valencia, Av. Tres Cruces 2, 46014 Valencia, Spain
Potential conflict of interest: Dr. Shiffman advises and received grants from Biolex, Conatus, Human Genome Sciences, Romark, Valeant, Vertex, and Zymogenetics. He also advises Anadys, Bristol-Myers Squibb, and Novartis. He received grants from GlaxoSmithKline, Globeimmune, Idenix, Johnson & Johnson, and Wyeth. He is a consultant for Pfizer. He is also a consultant for, advises, is on the speakers' bureau of, and received grants from Roche. He advises, is on the speakers' bureau of, and received grants from Schering-Plough. Dr. Zeuzem is a consultant for, advises, and is on the speakers' bureau of Roche, Schering-Plough, Novartis, and Human Genome Sciences. Dr. Rodriguez-Torres is a consultant for and advises Anadys, Vertex, GlaxoSmithKline, and Pharmasset. She advises Bristol-Myers Squibb, Idera, Human Genome Sciences, Idenix, Intarcia Therapeutics, Novartis, Valeant, Sanofi-Aventis, Virochem, and Gilead. She also advises and is on the speakers' bureau of Roche. Dr. Pappas is a consultant for Orphan Therapeutics and advises Hoffmann-LaRoche. Dr. Nelson is a consultant for, advises, and received grants from Roche.
Funded by:
Roche, Basel, Switzerland
Abstract
The objective of this analysis was to compare sustained virological response (SVR) and relapse rates in patients with a rapid virological response (RVR, HCV RNA <50 IU/mL at week 4) randomized to 24 or 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 g/week plus ribavirin 800 mg/day in the multinational ACCELERATE study. The analysis was restricted to patients who received treatment for 80% or more of the planned duration. Of 1309 eligible patients, 863 individuals (65.9%) achieved an RVR and were included in this analysis (458 assigned to 16 weeks and 405 assigned to 24 weeks). The overall SVR rate was significantly higher in patients randomized to 24 weeks of treatment (91% versus 82%; P = 0.0006) and among patients infected with genotype 2 (92% versus 81%; P = 0.0010) but not genotype 3 (90% versus 84%; P = 0.1308). Relapse rates were significantly lower among all patients randomized to 24 weeks of treatment: overall (6% versus 15%, P < 0.0001); in those infected with genotype 2 (5% versus 17%, P = 0.0001), and genotype 3 (7% versus 14%, P = 0.0489). SVR rates in patients with a viral load of 400,000 IU/mL or less randomized to 24 and 16 weeks of treatment were similar, 95% and 91% (P = 0.2012). Significant pretreatment predictors of SVR included assignment to 24 weeks of treatment (P = 0.0006), absence of advanced fibrosis on liver biopsy (P = 0.0032), lower HCV RNA level (P = 0.0017), and lower body weight (P < 0.0001).
Conclusion: The standard 24-week regimen of peginterferon alfa-2a (40KD) plus ribavirin is significantly more effective than an abbreviated 16-week regimen in genotype 2/3 patients who achieve an RVR. Abbreviated regimens may be considered in patients with a low baseline viral load who achieve an RVR
Article Text
The standard of care for patients with chronic hepatitis C is the combination of pegylated interferon plus ribavirin.[1-4] When treatment-naive patients infected with hepatitis C virus (HCV) genotype 2 or 3 are treated with the standard of care for 24 weeks, sustained virological response (SVR) rates generally exceed 65% and may reach 80% or higher.[5-7] Treatment for longer durations does not increase efficacy in these individuals.[5][6] Given that a consistently high cure rate can be achieved with a 24-week combination regimen in these individuals, several studies have evaluated shorter treatment durations in patients with HCV genotype 2 or 3 infection.[7-10]
The large randomized multinational ACCELERATE trial was designed to test the hypothesis that treatment for 16 weeks in patients with HCV genotype 2 or 3 infection was noninferior to treatment for 24 weeks, as defined by a 6% noninferiority margin. The study demonstrated that 24 weeks of treatment is significantly more effective than 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 ug/week plus ribavirin (800 mg/day). Overall SVR rates in the trial were 70% and 62%, respectively (P < 0.001).[7]
Several smaller trials have selected patients for abbreviated treatment on the basis of the virological response at week 4.[8-10] The results of one of these trials with peginterferon alfa-2b (12KD) 1.0 ug/kg/week plus ribavirin (1000/1200 mg/day) suggested that individuals with a rapid virological response (RVR), defined as HCV RNA less than 50 IU/mL at week 4, achieved an SVR rate after 12 weeks of treatment that was similar to that achieved in patients receiving the standard 24-week regimen (85% versus 91%, respectively).[9] However, a larger trial that randomized patients to peginterferon alfa-2b (12KD) 1.5 ug/kg/week plus ribavirin (800-1400 mg/day) with an RVR to 14 or 24 weeks of treatment concluded that the shorter treatment duration was inferior to the longer duration, with SVR rates of 86% and 93%, respectively.[11] The difference in SVR rates between the two treatment durations in these two studies was attributable to higher relapse rates in patients assigned to the abbreviated treatment regimen.[9][11] The ACCELERATE trial also showed that SVR rates were lower in patients with an RVR who were treated for 16 or 24 weeks (79% versus 85%).[7]
The ACCELERATE trial randomized more than 1400 genotype 2 or 3 patients, 65% of whom achieved an RVR.[7] Based on an intention-to-treat analysis, SVR rates among patients randomized to longer treatment durations may be lower because of higher dropout rates compared with patients randomized to shorter treatment durations. Therefore, a conservative approach to comparing the efficacy of two identical regimens differing only in treatment duration is to restrict analyses to patients who complete the scheduled treatment duration. The large database from this trial provides an opportunity to determine whether a specific subgroup of genotype 2 or 3 patients who achieve an RVR and complete scheduled treatment, for example, those with low baseline HCV RNA levels, can be treated with an abbreviated regimen without compromising SVR rates.
Discussion
The results of this analysis confirm the findings of the intention-to-treat analysis of ACCELERATE in showing that SVR rates are higher in genotype 2/3 patients with an RVR who are treated for 24 weeks than 16 weeks. However, it should be noted that for genotype 3 patients the difference in SVR between 24 and 16 weeks was not statistically significant ( delta= 6%) in contrast to the difference in genotype 2 patients ( = 11%). In the original analysis, SVR rates in patients with an RVR treated for 24 and 16 weeks were 85% and 79%, respectively (P = 0.02).[7] The current analysis included only patients who had an RVR and who completed the planned treatment duration without relevant treatment interruptions (at least 19 doses of peginterferon alfa-2a in the 24-week treatment group and at least 13 doses in the 16-week treatment group). This approach has the advantage of compensating for the difference in withdrawal rates between the two treatment arms. More than twice as many patients withdrew from the 24-week treatment group than from the 16-week treatment group (13% versus 6%), which has the effect of reducing the difference between the two treatment durations in an intention-to-treat analysis. After application of this criterion, the SVR rates were 91% in those randomized to 24 weeks and 82% in those randomized to 16 weeks of treatment (P = 0.0006). Most patients achieved an end-of-treatment response (data not shown); thus, the key factor behind this 9% difference in SVR rates was a higher relapse rate in patients randomized to 16 weeks of treatment (15% versus 6%, P < 0.0001).
Assignment to 24 weeks of treatment was the most important predictor of SVR in the MLR analysis; conversely, assignment to the 16-week regimen was the most important predictor of relapse in the MLR analysis. Other predictors of SVR included the absence of advanced fibrosis on the pretreatment liver biopsy, a lower HCV RNA level, and lower body weight, all of which are well established as predictors of treatment success in patients with chronic hepatitis C.
In the original intention-to-treat analysis, the overall SVR rates did not differ significantly between treatment groups when only patients with a baseline HCV RNA level 400,000 IU/mL or less were included (82% in those treated for 24 weeks and 81% in those treated for 16 weeks).[7] The results of the current analysis supports this finding that patients achieving an RVR with a baseline serum HCV RNA level of 400,000 IU/mL or less can be treated for 16 weeks without compromising SVR rates because there was no statistically significant difference between those treated for 24 weeks and those treated for 16 weeks (95% versus 91%, P = 0.2012).
The authors of other studies of abbreviated regimens for genotype 2 or 3 patients have reported higher relapse rates in patients assigned to the shorter treatment duration.[9][11][12] The increase in the probability of relapse was twofold to threefold greater in patients assigned to abbreviated 12- to 14- week regimens, which is in close agreement with the 2.5-fold higher relapse rate in patients assigned to the 16-week regimen in the current analysis.
In addition to higher voluntary withdrawal rates in patients treated for longer duration, it is possible that differences in treatment exposure may have an effect on SVR rates in patients randomized to different treatment durations. For this reason we included an exposure analysis in the current analysis. Few patients had exposure levels below 80% of the planned dose of ribavirin or peginterferon alfa-2a (40KD); thus, we cannot comment on the impact of large or long-term dose reductions on the probability of achieving an SVR. Most patients had a ribavirin exposure level that was 90% to 100% of the planned amount. Among patients with 80% or greater exposure to ribavirin, the SVR rates were consistently higher in patients assigned to the longer treatment duration. Moreover, there was no trend toward a reduction in SVR rates with decreasing exposure in these individuals.
It is now clear from the results of ACCELERATE and another recently completed large randomized noninferiority study[11] that 24 weeks of treatment produces significantly higher SVR rates than abbreviated regimens and that abbreviated regimens expose patients to a significantly higher probability of virological relapse during follow-up, even in patients with an RVR. In spite of the greater efficacy of the standard treatment duration in their study, Dalgard et al.[11] argued that it would be cost-effective to assign all genotype 2 or 3 patients to abbreviated treatment and to immediately retreat those who relapse. Such a policy assumes that all patients have the same probability of relapse and that all patients will be willing to immediately re-enroll for a longer treatment duration. The results of the current analysis and that reported by Mangia et al.[13] suggest that the first assumption is incorrect; the probability of relapse varies according to several well-established predictors of treatment success. Adopting this approach would require physicians to counsel all patients to prepare themselves for the possibility of undergoing two consecutive courses of treatment, with a total treatment duration of 40 weeks. However, Mangia et al. reported that patients infected with genotype 2 or 3 who achieved an RVR but who relapsed after an abbreviated 12-week course of treatment with peginterferon alfa-2b plus ribavirin could achieve an SVR rate of 70% with a second 24-week course of the same treatment.[13]
The current analysis has shown that several subgroups of patients with an RVR have an acceptable risk:benefit ratio for contemplation of abbreviated therapy in addition to those that have a low baseline serum HCV RNA level. Given that advanced fibrosis was a stronger predictor of relapse in patients with RVR after 16 weeks of treatment (relapse rate of 27%), it is reasonable to exclude all such patients from abbreviated treatment.
Rather than reducing the treatment duration in patients who experience adverse events that must be managed by dose reductions, physicians should encourage continued treatment for the full 24-week duration to maximize the probability of SVR.
Overall, this analysis shows that for patients infected with HCV genotype 2 or 3 and who achieve an RVR at week 4, the standard 24-week treatment duration produces significantly higher SVR rates than an abbreviated 16-week regimen. Shortening the treatment duration should be considered only in patients with a low baseline HCV RNA level and without bridging fibrosis/cirrhosis who achieve an RVR. The difference in SVR rates is attributable to a significantly higher rate of virological relapse in patients treated with the abbreviated regimen.
Results
The per protocol population comprised 1309 individuals, of whom 863 patients (65.9%) achieved an RVR at week 4, completed designated treatment, and were included this analysis. Of the 863 patients included in the analysis, all were considered for the determination of SVR, with patients missing post-treatment HCV RNA values considered as nonresponders. Forty patients were excluded from the analysis of relapse because of missing HCV RNA values at end of treatment (n = 24), breakthrough (n = 5), or missing post-treatment HCV RNA values in patients with response at end of treatment (n = 11).
The baseline characteristics of patients with an RVR who completed treatment were similar, with no significant differences (all P-values > 0.2) by treatment group (Table 1). The mean overall age of patients with an RVR was 45 to 46 years, 60% to 62% were male, 87% were white, and 2% to 3% were black. Approximately 25% to 27% had a low baseline serum HCV RNA levels (
SVR rates exceeded 80% in patients with an RVR regardless of HCV genotype or the assigned treatment duration (Fig. 1A). The SVR rate was significantly lower in patients randomized to 16 than 24 weeks of treatment, overall (82% [377/458] versus 91% [367/405]; OR 0.49, 95% CI 0.32-0.74; P = 0.0006) and in those infected with genotype 2 (81% [196/243] versus 92% [194/212]; OR 0.38, 95% CI 0.21-0.69; P = 0.0010) but not genotype 3 (84% [181/215] versus 90% [173/193]; OR 0.63, 95% CI 0.35-1.15; P = 0.1308).
Virological relapse rates during follow-up were consistently and significantly higher in patients randomized to the shorter treatment duration (Fig. 1B). The relapse rates in patients randomized to 16 and 24 weeks of treatment, respectively, were 15% (67/439) and 6% (23/384) overall (OR 2.77, 95% CI 1.69-4.55; P < 0.0001); 17% (39/233) and 5% (10/204) among patients infected with HCV genotype 2 (OR 3.82, 95% CI 1.85-7.89; P = 0.0001); and 14% (28/206) and 7% (13/180) among those infected with HCV genotype 3 (OR 1.99, 95% CI 1.00-3.99; P = 0.0489).
Among genotype 2/3 patients with a low baseline viral load (HCV RNA level
Predictors of SVR and Relapse by MLR Analysis.
Baseline factors that were identified as significant and independent predictors of SVR among genotype 2/3 patients with an RVR who completed the designated treatment duration included assignment to 24 weeks of treatment (OR 2.12, 95% CI 1.38-3.24; P = 0.0006), absence of advanced fibrosis on liver biopsy (OR 2.06, 95% CI 1.27-3.33; P = 0.0032), lower HCV RNA level (OR 1.52, 95% CI 1.17-1.97; P = 0.0017), and lower body weight (OR 1.03, 95% CI 1.02-1.04; P < 0.0001).
Baseline factors that predicted relapse among genotype 2/3 patients during follow-up were for the most part the opposite of those that predicted SVR: assignment to 16 weeks of treatment (OR 2.96, 95% CI 1.76-4.95; P < 0.0001), presence of advanced fibrosis on liver biopsy (OR 2.42, 95% CI 1.43-4.12; P = 0.0011), higher HCV RNA level (OR 1.96, 95% CI 1.40-2.74; P < 0.0001), and higher body weight (OR 1.03, 95% CI 1.01-1.04; P = 0.0002). Male sex was also a significant predictor of relapse in this analysis (OR 1.79, 95% CI 1.02-3.16; P = 0.0426).
Based on the outcome of the current MLR analysis, rates of SVR and relapse in the two treatment groups were estimated for each baseline covariate shown to be an independent predictor of response (Table 2). Rates for genotype, sex, age, and alanine aminotransferase ratio are also presented for completeness, because they were significant predictors in the intention-to-treat analysis.[7] The results show that for RVR patients with low viral load, low age, or low body weight, rates of SVR in both groups range from 89% to 95%, with differences between the two groups less than 5%. When a patient had at least two of the four positive predictors, low viral load, low age, low body weight, and noncirrhosis, then the SVR rate was 90% in the 16-week group and 93% in the 24-week group, whereas the relapse rates were 6% and 4%, respectively. The difference in SVR rate between the 16-week and 24-week groups remains low (87% versus 88%) in all treated patients (intention-to-treat patients) with RVR and at least two positive predictors.
Impact of Dose Reductions on SVR.
Among patients with an RVR and who completed treatment, SVR rates were consistently higher in those who completed 24 weeks of treatment compared with 16 weeks of treatment regardless of the extent of ribavirin exposure (Fig. 2A). Only a small number of patients had ribavirin exposure that was less than 80% of the planned dose (19/863, 2%); thus, it is not possible to comment on the effect of large or prolonged dose reductions on SVR rates in individuals with an RVR. The results were generally similar when the analysis was restricted to those patients with a baseline HCV RNA level less than 400,000 IU/mL, although most patients had exposure to ribavirin that was 90% or more of the planned dose (Fig. 2B).
Figure 2b. Adherence Matters
Screen shot 2010-06-20 at 11.25.19 AM.png
Table 2. Rates of SVR and Relapse Among Subgroups of Patients
Screen shot 2010-06-20 at 11.20.50 AM.png
Figure 1. (A) SVR and (B) relapse rates according to treatment duration. Only patients confirmed to be HCV RNA-negative at the end-of-treatment were included in the calculation of relapse rates.
Screen shot 2010-06-20 at 11.20.20 AM.png
Patients and Methods
Study Design and Patients.
The inclusion and exclusion criteria, study design, and primary results of ACCELERATE are reported elsewhere.[7] Briefly, treatment-naive patients with chronic HCV genotype 2 or 3 infection were randomized to receive treatment with peginterferon alfa-2a (40KD) (PEGASYS®, Roche, Basel, Switzerland) 180 g/week plus ribavirin (COPEGUS®, Roche) 800 mg/day for either 16 or 24 weeks. Eligible patients had quantifiable HCV RNA (COBAS® AMPLICOR HCV MONITOR Test, v2.0: limit of quantitation 600 IU/mL) and elevated serum alanine aminotransferase levels. All patients were required to have undergone a liver biopsy before enrollment.
Assessment of Virological Response.
Serum HCV RNA levels were measured by qualitative polymerase chain reaction assay (COBAS® AMPLICOR HCV Test, v2.0, limit of detection 50 IU/mL) at weeks 4, 12, at the end of the scheduled treatment period (week 16 or 24), and at weeks 12 and 24 after completion of the scheduled treatment period. The primary efficacy end-point in ACCELERATE was SVR defined as undetectable serum HCV RNA at the end of follow-up (week 40 in patients randomized to 16 weeks of treatment and week 48 in those randomized to 24 weeks of treatment). Virological relapse was defined as detection of HCV RNA in serum during follow-up in a patient that was confirmed to have been HCV RNA-negative at the end of treatment. Patients without an end-of-treatment HCV RNA result or without post-treatment HCV RNA data were not included in relapse rate calculations. The impact of ribavirin exposure on SVR rates was evaluated by calculating the amount of drug received by a patient (percentage of the planned total dose). Physician-initiated dose reductions for adverse events and laboratory abnormalities and patient compliance as recorded in diaries were included in these calculations.
Analysis Populations and Statistics.
The efficacy analysis was conducted in all randomized patients with an RVR that were included in the per-protocol population who completed the scheduled treatment duration of 16 or 24 weeks. Patients were excluded from the per-protocol population when they had (1) major protocol deviations, or (2) treatment interruptions or early discontinuations resulting in less than 13 doses of peginterferon alfa-2a (40KD) or less than 13 weeks of treatment with ribavirin in patients randomized to 16 weeks, and less than 19 doses of peginterferon alfa-2a (40KD) or less than 19 weeks of treatment with ribavirin in patients randomized to 24 weeks of treatment. Use of the standard population rather than the intention-to-treat population ensures that differences in SVR rates or relapse rates are not influenced by a higher dropout rate in patients randomized to the longer treatment duration.
The baseline demographic and disease characteristics in the two treatment groups of the analysis population were compared using the chi-squared test for categorical data and t test for continuous data to verify whether the restriction to the specified analysis population had any relevant impact on the comparability of two treatment groups. SVR and relapse rates in the two treatment groups were compared with the use of the Cochran-Mantel-Haenszel test, stratified according to country of residence and HCV genotype. The common odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. The noninferiority margin specified in the study protocol for the primary analysis[7] was 6%, which was equivalent to an OR of 0.70 when assuming an SVR rate of 80% in the 24-week group. On this basis, the 16-week and 24-week regimens were considered equivalent if the lower limit of the 95% CI for the OR was at least 0.70. Because the current analysis was post hoc, no inferiority margin was assumed, the study results were known, and the subgroups lacked adequate power.
Multiple logistic regression (MLR) models were used to identify baseline factors associated with SVR and relapse in patients who achieved an RVR and who were treated for 16 or 24 weeks. Pretreatment factors considered in the analysis included assigned treatment duration at randomization plus the following baseline factors: age, sex, race (white versus nonwhite), body weight, HCV genotype (3 versus 2), serum alanine aminotransferase quotient, serum HCV RNA level, and the pretreatment liver biopsy result (no bridging fibrosis/cirrhosis versus bridging fibrosis/cirrhosis).
In the current analysis, all statistical tests are exploratory, and thus a significant result (P < 0.05) cannot be considered as formal proof of efficacy. Furthermore, the presence of nonsignificant test results cannot be considered as a formal proof of noninferiority. No adjustment of the significance level of 0.05 was considered necessary because of the exploratory nature of the analysis.
House Panel Calls Attention to Viral Hepatitis Threat
House Panel Calls Attention to Viral Hepatitis Threat
CQ HEALTHBEAT NEWS
June 17, 2010 – 5:43 p.m.
By John Reichard, CQ HealthBeat Editor
Ignorance and neglect are the hallmarks of the viral hepatitis epidemic – not only among the millions of people who are unaware they have the often-lethal condition, but also among policy makers who are more aware of the threat it poses.
That was the message delivered by witnesses and lawmakers at a hearing by the House Oversight and Government Reform Committee Thursday. Their aim: prod Congress and the Obama administration to respond more aggressively to the disease.
The Obama administration witness at the hearing said he gets it. But the signs of a more aggressive government response aren’t entirely reassuring, say groups that have organized to counter the disease.
Some 6 million Americans are living with chronic infection from hepatitis B and C, yet half of those with the B virus and three-quarters of those with the C virus don’t know they have it, the committee said in a notice announcing the hearing.
A major focus was to call attention to the findings of a six-month-old Institute of Medicine (IoM) report on viral hepatitis and the need to implement its recommendations.
Randall Mayer, who testified on behalf of the institute, noted that 150,000 people in the United States are expected to die from liver cancer and other liver diseases associated with the hepatitis B and C viruses.
An estimated 3.5 million to 5.3 million Americans are living with chronic infections from the viruses. Globally the toll of this “secret epidemic” is staggering: one of every 12 people globally has chronic viral hepatitis, about 54,000 of whom immigrate to the United States annually. And about a million deaths occur worldwide from the disease each year.
Greater use of the hepatitis B vaccine has driven down the incidence of that disease in the United States but 43,000 new cases still occur domestically each year. And there is no vaccine for hepatitis C.
The IoM report includes various recommendations to improve surveillance systems to detect viral hepatitis; public health officials around the United States have inadequate systems to monitor the disease. The report also directs publicity campaigns targeting at-risk populations who unknowingly spread the viruses, increase hepatitis B vaccination, develop a hepatitis C vaccine, improve screening for viral hepatitis and give intravenous drug users access to sterile needles to lessen its spread.
Howard K. Koh, assistant secretary for health at HHS, testified that the department “is taking immediate and coordinated steps to reverse” the growing medical and economic burden of viral hepatitis.
As part of its response to the IoM report, HHS has established an interagency working group to better coordinate the responses of the National Institutes of Health, the Centers for Disease Control and Prevention and other federal agencies. A subcommittee of the group is due to produce a “comprehensive strategic action plan” by Oct. 1, Koh said.
But Julie Scofield, executive director of the National Alliance of State and Territorial AIDS Directors, said in a statement that “while there has been recent increased interest in hepatitis within the administration and Congress, this interest has not yet translated into additional funding.”
The group’s statement called the hearing Thursday “the first time Congress has formally examined the federal response to viral hepatitis since December 2004. There has been little progress made in developing a comprehensive prevention and control program in the U.S. due to a lack of funding.”
The National Viral Hepatitis Roundtable, a coalition of some 175 public, private and volunteer groups involved in countering viral hepatitis, announced a new print ad campaign urging swift passage of a bill (HR 3974) to authorize prevention, education and research programs countering viral hepatitis. Sponsors include Rep. Michael M. Honda, D-Calif., and Edolphus Towns, D-N.Y., who chaired Thursday’s hearing.
A tag line of the ad campaign: “If Congress gets on the case now, the leading cause of liver cancer won’t stand a chance.”
CQ HEALTHBEAT NEWS
June 17, 2010 – 5:43 p.m.
By John Reichard, CQ HealthBeat Editor
Ignorance and neglect are the hallmarks of the viral hepatitis epidemic – not only among the millions of people who are unaware they have the often-lethal condition, but also among policy makers who are more aware of the threat it poses.
That was the message delivered by witnesses and lawmakers at a hearing by the House Oversight and Government Reform Committee Thursday. Their aim: prod Congress and the Obama administration to respond more aggressively to the disease.
The Obama administration witness at the hearing said he gets it. But the signs of a more aggressive government response aren’t entirely reassuring, say groups that have organized to counter the disease.
Some 6 million Americans are living with chronic infection from hepatitis B and C, yet half of those with the B virus and three-quarters of those with the C virus don’t know they have it, the committee said in a notice announcing the hearing.
A major focus was to call attention to the findings of a six-month-old Institute of Medicine (IoM) report on viral hepatitis and the need to implement its recommendations.
Randall Mayer, who testified on behalf of the institute, noted that 150,000 people in the United States are expected to die from liver cancer and other liver diseases associated with the hepatitis B and C viruses.
An estimated 3.5 million to 5.3 million Americans are living with chronic infections from the viruses. Globally the toll of this “secret epidemic” is staggering: one of every 12 people globally has chronic viral hepatitis, about 54,000 of whom immigrate to the United States annually. And about a million deaths occur worldwide from the disease each year.
Greater use of the hepatitis B vaccine has driven down the incidence of that disease in the United States but 43,000 new cases still occur domestically each year. And there is no vaccine for hepatitis C.
The IoM report includes various recommendations to improve surveillance systems to detect viral hepatitis; public health officials around the United States have inadequate systems to monitor the disease. The report also directs publicity campaigns targeting at-risk populations who unknowingly spread the viruses, increase hepatitis B vaccination, develop a hepatitis C vaccine, improve screening for viral hepatitis and give intravenous drug users access to sterile needles to lessen its spread.
Howard K. Koh, assistant secretary for health at HHS, testified that the department “is taking immediate and coordinated steps to reverse” the growing medical and economic burden of viral hepatitis.
As part of its response to the IoM report, HHS has established an interagency working group to better coordinate the responses of the National Institutes of Health, the Centers for Disease Control and Prevention and other federal agencies. A subcommittee of the group is due to produce a “comprehensive strategic action plan” by Oct. 1, Koh said.
But Julie Scofield, executive director of the National Alliance of State and Territorial AIDS Directors, said in a statement that “while there has been recent increased interest in hepatitis within the administration and Congress, this interest has not yet translated into additional funding.”
The group’s statement called the hearing Thursday “the first time Congress has formally examined the federal response to viral hepatitis since December 2004. There has been little progress made in developing a comprehensive prevention and control program in the U.S. due to a lack of funding.”
The National Viral Hepatitis Roundtable, a coalition of some 175 public, private and volunteer groups involved in countering viral hepatitis, announced a new print ad campaign urging swift passage of a bill (HR 3974) to authorize prevention, education and research programs countering viral hepatitis. Sponsors include Rep. Michael M. Honda, D-Calif., and Edolphus Towns, D-N.Y., who chaired Thursday’s hearing.
A tag line of the ad campaign: “If Congress gets on the case now, the leading cause of liver cancer won’t stand a chance.”
Getz Pharma to launch therapy for Hepatitis C patients
Getz Pharma to launch therapy for Hepatitis C patients
* Biotechnology-based drug for hepatitis C will be manufactured by a Pakistani company for the first time
By Irfan Aligi
KARACHI: Getz Pharma would launch the Pegylated Interferon therapy for the treatment of hepatitis C in Pakistan. The new therapy would be highly cost-effective and easy to use as the manufacturer and presenters of the new therapy have considered patients? care and comfort. It would also be the first time that a biotechnology-based essential drug would be manufactured by Getz Pharma, a Pakistani company. It is pertinent to mention that approximately every 20th person in Pakistan is infected with hepatitis C.
The initiative taken by Getz Pharma to invest in the local manufacturing of Pegylated Interferon (Unipeg) in the country would substantially reduce the cost of treatment for a person suffering from hepatitis C. The company has invested in research and development to formulate this molecule with the help of a team of scientists from the Netherlands, led by Dr Ben Rademaker, a PhD-holder.
Getz Pharma Managing Director and Chief Executive Officer Khalid Mehmood, during a press conference on Thursday, said the size of the country?s pharmacy market is about Rs 119 billion, which is growing by 12 to 13 percent. Henceforth, they have been able to export pharmacy goods to 45 countries around the world. The pharmacy sector in the country is the largest employment provider, with around five million people employed. Pakistan?s pharmacy industry meets 90 percent of the needs of pharmacy goods.
Pharmaceutical exports are at their highest as compared to other corporate sectors in the country and have achieved a 29 percent growth, which is four times of the country?s textile exports. Still, the country?s spending on health according to annual budgetary allocations is just 0.4 percent of the GDP, while Bangladesh is spending 0.8 percent, Khalid said.
Investment: He said Getz Pharma was set up in 1995 as a small company with only 45 employees, while today the number of its employees exceeded 2,500 worldwide, and 1,850 people in Pakistan. Getz Pharma invested Rs 4 billion in revamping existing facilities, in purchasing state-of-the-art production, quality control from 2005 to 2009. It has a plan to meet the 54 percent target of exporting medicines. According to the Federal Bureau of Revenue, Getz Pharma was the second largest taxpayer unit in terms of taxes and duties with an estimated Rs 636 million in 2009, he added.
Khalid said the company?s total investment in Pakistan was Rs 4 billion in the last three years, including investment in manufacturing technology of the first locally manufactured recombinant human insulin. It plans to invest an equal amount in the coming two years in new technologies that would result in local manufacturing of drugs that are currently being imported at high costs. It may be mentioned that Getz Pharma is the single largest exporter of pharmaceutical products from the country. It was estimated that the company?s exports account for approximately 40 percent of the country?s total pharmaceutical exports.
Dr Bernardus Rademaker, speaking on the occasion, said the analytical, toxicological and pharmacokinetic studies for Unipeg (Pegylated Interferon Alpha 2a) had been carried out in Europe, comparing it to the existing research molecule.
New era: He said in addition, bioactivity and potency had also been evaluated at the Centre for Applied Molecular Biology in Lahore, a premier institute of the Science and Technology Ministry. Specialised manufacturing and testing technology is required for manufacturing the Unipeg. He said Getz Pharma had acquired the technology at a substantial investment and a number of these tests were not currently available in the country?s pharmaceutical industry. Through this molecule, Getz Pharma would herald a new biotech era in the country, he added.
To a question, Dr Rademaker said since the molecule was not available in the US, it was not necessary to seek approval form the US FDA. He also said collaboration with Getz Pharma was not business-oriented, but it had been overwhelmingly planned that the hepatitis C affected population of the country should be provided with a cost-effective and latest mode of treatment.
Dr Rademaker holds a PhD in biotechnology from the State University Utrecht, Holland. He is the founder and CEO of InProPharma, a company specialising in technology platforms for the production of biologically active proteins. Prior to setting up his own company, Rephartox BV, a contract research company for the pharmaceutical industry, he was the director of Corporate Drug Development at the Rhein Biotech NV, Maastricht and the Green Cross Vaccine Company, Seoul, Korea. He is a member of the Dutch Pharmacological Society and is a registered pharmacologist. He has authored more than 50 scientific publications, and many regulatory affairs documents.
* Biotechnology-based drug for hepatitis C will be manufactured by a Pakistani company for the first time
By Irfan Aligi
KARACHI: Getz Pharma would launch the Pegylated Interferon therapy for the treatment of hepatitis C in Pakistan. The new therapy would be highly cost-effective and easy to use as the manufacturer and presenters of the new therapy have considered patients? care and comfort. It would also be the first time that a biotechnology-based essential drug would be manufactured by Getz Pharma, a Pakistani company. It is pertinent to mention that approximately every 20th person in Pakistan is infected with hepatitis C.
The initiative taken by Getz Pharma to invest in the local manufacturing of Pegylated Interferon (Unipeg) in the country would substantially reduce the cost of treatment for a person suffering from hepatitis C. The company has invested in research and development to formulate this molecule with the help of a team of scientists from the Netherlands, led by Dr Ben Rademaker, a PhD-holder.
Getz Pharma Managing Director and Chief Executive Officer Khalid Mehmood, during a press conference on Thursday, said the size of the country?s pharmacy market is about Rs 119 billion, which is growing by 12 to 13 percent. Henceforth, they have been able to export pharmacy goods to 45 countries around the world. The pharmacy sector in the country is the largest employment provider, with around five million people employed. Pakistan?s pharmacy industry meets 90 percent of the needs of pharmacy goods.
Pharmaceutical exports are at their highest as compared to other corporate sectors in the country and have achieved a 29 percent growth, which is four times of the country?s textile exports. Still, the country?s spending on health according to annual budgetary allocations is just 0.4 percent of the GDP, while Bangladesh is spending 0.8 percent, Khalid said.
Investment: He said Getz Pharma was set up in 1995 as a small company with only 45 employees, while today the number of its employees exceeded 2,500 worldwide, and 1,850 people in Pakistan. Getz Pharma invested Rs 4 billion in revamping existing facilities, in purchasing state-of-the-art production, quality control from 2005 to 2009. It has a plan to meet the 54 percent target of exporting medicines. According to the Federal Bureau of Revenue, Getz Pharma was the second largest taxpayer unit in terms of taxes and duties with an estimated Rs 636 million in 2009, he added.
Khalid said the company?s total investment in Pakistan was Rs 4 billion in the last three years, including investment in manufacturing technology of the first locally manufactured recombinant human insulin. It plans to invest an equal amount in the coming two years in new technologies that would result in local manufacturing of drugs that are currently being imported at high costs. It may be mentioned that Getz Pharma is the single largest exporter of pharmaceutical products from the country. It was estimated that the company?s exports account for approximately 40 percent of the country?s total pharmaceutical exports.
Dr Bernardus Rademaker, speaking on the occasion, said the analytical, toxicological and pharmacokinetic studies for Unipeg (Pegylated Interferon Alpha 2a) had been carried out in Europe, comparing it to the existing research molecule.
New era: He said in addition, bioactivity and potency had also been evaluated at the Centre for Applied Molecular Biology in Lahore, a premier institute of the Science and Technology Ministry. Specialised manufacturing and testing technology is required for manufacturing the Unipeg. He said Getz Pharma had acquired the technology at a substantial investment and a number of these tests were not currently available in the country?s pharmaceutical industry. Through this molecule, Getz Pharma would herald a new biotech era in the country, he added.
To a question, Dr Rademaker said since the molecule was not available in the US, it was not necessary to seek approval form the US FDA. He also said collaboration with Getz Pharma was not business-oriented, but it had been overwhelmingly planned that the hepatitis C affected population of the country should be provided with a cost-effective and latest mode of treatment.
Dr Rademaker holds a PhD in biotechnology from the State University Utrecht, Holland. He is the founder and CEO of InProPharma, a company specialising in technology platforms for the production of biologically active proteins. Prior to setting up his own company, Rephartox BV, a contract research company for the pharmaceutical industry, he was the director of Corporate Drug Development at the Rhein Biotech NV, Maastricht and the Green Cross Vaccine Company, Seoul, Korea. He is a member of the Dutch Pharmacological Society and is a registered pharmacologist. He has authored more than 50 scientific publications, and many regulatory affairs documents.
Blueberry Ameliorates Hepatic Fibrosis, Study Finds
Blueberry Ameliorates Hepatic Fibrosis, Study Finds
"In summary, in the present study, blueberries possessed a therapeutic effect on CCl4-induced hepatic fibrosis in rats through inhibiting liver inflammation and lipid peroxidation, and may be not related to the induction of phase-II enzymes through the activation of Nrf2 in rat liver during long-term of CCl4. More detailed study is needed." see link below to full text.
ScienceDaily (June 17, 2010) — Conventional drugs used in the treatment of liver diseases inevitably have side effects. An increasing number of natural substances have been studied to explore if they have protective effects on the liver. Blueberries have unique effects on human retinal, brain and tumor cells, but reports about the effects of blueberries on liver diseases are lacking.
A research article to be published on June 7, 2010 in the World Journal of Gastroenterology addresses this question. The research team led by Ming-Liang Cheng, MD, from Department of Infectious Diseases, Guiyang Medical College, Guiyang, presented some data from their research on the effectiveness of blueberries on liver fibrosis induced in laboratory animals.
Their study showed that blueberries could reduce liver indices, serum levels of hyaluronic acid and alanine aminotransferase, and increase levels of superoxide dismutase and decrease levels of malondialdehyde in liver homogenates compared with the model group. Meanwhile, the stage of hepatic fibrosis was significantly weakened. Blueberries increased the activity of glutathione-S-transferase in liver homogenates and the expression of Nrf2 and Nqo1 compared with the normal group, but there was no significant difference compared with the model group.
The authors suggest that blueberry consumption is beneficial for hepatic diseases (including fibrosis).
Journal Reference:
1. Wang YP, Cheng ML, Zhang BF, Mu M, Wu J. Effects of blueberry on hepatic fibrosis and transcription factor Nrf2 in rats. World J Gastroenterol, 2010; 16 (21): 2657-2663 DOI: http://www.wjgnet.com/1007-9327/full/v16/i21/2657.htm
"In summary, in the present study, blueberries possessed a therapeutic effect on CCl4-induced hepatic fibrosis in rats through inhibiting liver inflammation and lipid peroxidation, and may be not related to the induction of phase-II enzymes through the activation of Nrf2 in rat liver during long-term of CCl4. More detailed study is needed." see link below to full text.
ScienceDaily (June 17, 2010) — Conventional drugs used in the treatment of liver diseases inevitably have side effects. An increasing number of natural substances have been studied to explore if they have protective effects on the liver. Blueberries have unique effects on human retinal, brain and tumor cells, but reports about the effects of blueberries on liver diseases are lacking.
A research article to be published on June 7, 2010 in the World Journal of Gastroenterology addresses this question. The research team led by Ming-Liang Cheng, MD, from Department of Infectious Diseases, Guiyang Medical College, Guiyang, presented some data from their research on the effectiveness of blueberries on liver fibrosis induced in laboratory animals.
Their study showed that blueberries could reduce liver indices, serum levels of hyaluronic acid and alanine aminotransferase, and increase levels of superoxide dismutase and decrease levels of malondialdehyde in liver homogenates compared with the model group. Meanwhile, the stage of hepatic fibrosis was significantly weakened. Blueberries increased the activity of glutathione-S-transferase in liver homogenates and the expression of Nrf2 and Nqo1 compared with the normal group, but there was no significant difference compared with the model group.
The authors suggest that blueberry consumption is beneficial for hepatic diseases (including fibrosis).
Journal Reference:
1. Wang YP, Cheng ML, Zhang BF, Mu M, Wu J. Effects of blueberry on hepatic fibrosis and transcription factor Nrf2 in rats. World J Gastroenterol, 2010; 16 (21): 2657-2663 DOI: http://www.wjgnet.com/1007-9327/full/v16/i21/2657.htm
Community Testimony at Hepatitis Congress Hearing Yesterday
Community Testimony at Hepatitis Congress Hearing Yesterday
Viral Hepatitis Prevention
6/17/2010, 12:14 p.m. EDT
The Associated Press
(AP) — xfdte VIRAL-HEPATITIS sked
TESTIMONY June 17, 2010 MR. MICHAEL NINBURG EXECUTIVE DIRECTOR HEPATITIS EDUCATION PROJECT HOUSE Oversight and Government Reform VIRAL HEPATITIS PREVENTION Roll Call, Inc. 1255 22nd Street N.W. Washington, D.C. 20037 Transcript/Programming: Tel. 301-731-1728 Sales: Tel. 202-419-8500 ext 599 sales@cqrollcall.com www.cqrollcall.com Roll Call, Inc. is a private firm not affiliated with the U.S. Government. Copyright 2010 by Roll Call, Inc. Washington, D.C. U.S.A. All materials herein are protected by United States copyright law and may not be reproduced, distributed, transmitted, displayed, published or broadcast without the prior written permission of Roll Call, Inc. You may not alter or remove any trademark, copyright or other notice from copies of the content.Statement of Mr. Michael Ninburg Executive Director Hepatitis Education Project.
June 17, 2010
As a result of this inadequate government response, organizations like the Hepatitis Education Project are vaccinating more people against hepatitis A and B, and testing more people for hepatitis C than any public health district in our state. We are proud of the work we do, but the efforts of community-based organizations like ours should complement, not substitute, the work of governmental and public health agencies. I am hopeful that this hearing and the IOM report will help to outline and stimulate an appropriate governmental response to these twin epidemics and provide the rationale needed to increase funding for critical programs and services.
Two Viruses, One Family
Until very recently I was a hepatitis patient, an experience that is often fraught with uncertainty. When I was diagnosed with hepatitis C relatively little was known about the virus. Hepatitis C was only discovered in 1989, and from the early through the late 90's this new epidemic was often compared to HIV except that it attacked the liver, not the immune system. Through the mid-90's, reports about hepatitis C grew increasingly dire. People with hepatitis C were dying from their disease. Some people were lucky enough to get a liver transplant, but that was thought to just delay the inevitable.
I sought medical care for my hepatitis C in 2000. By then, the medical community had a better understanding of the natural history of the disease, but there was still much that they did not know. In 2002, I had a liver biopsy which showed that I had some liver damage, but not enough to warrant immediate treatment. I had the kind of hepatitis C that responded to treatment about 50% of the time. With newer, more effective treatments thought to be commercially available within 5 years I decided to wait for the next class of drugs and in the meantime monitor the health of my liver. Five years came and went and so did the expected due date for the next class of drugs. Now, I was looking at 2010 at the earliest. I had my second liver biopsy in 2007 and the results were not what I wanted to hear. My liver damage was progressing and if I didn't do something, it was likely that I would progress to cirrhosis relatively soon. Once I had progressed to cirrhosis, there would be other potential complications.
In January, 2009, I was very fortunate to enter a clinical trial looking at a promising experimental new drug to treat hepatitis C. The virus rapidly became undetectable in my body and I completed treatment in December, 2009. Just last month I received my final lab results and learned that I am cured. I happily use the past tense now when I say that I was a hepatitis patient.
I talk about my hepatitis story because it the story I know best. It is not, however, the story that is most important to me - that would be the story of my wife, Lily, and our little boy, Sacha. Shortly after I met Lily, I told her that I had hepatitis C and explained to her what that meant and how it was transmitted. Later I explained that there was another epidemic that was equally invisible to the general public - hepatitis B. I knew that among the groups at greatest risk were people born in countries where hepatitis B is endemic. One of those countries is China - where Lily was born. I asked Lily if she had ever been tested for hepatitis B and she said she didn't know. I suggested that it would be a good idea to find out her status. She didn't seem to think it was that important. After some cajoling - and close to another year - Lily was tested for hepatitis B. The results showed that she had chronic hepatitis B, likely contracted at birth from her mother. Fortunately it was inactive, the doctor said, but as she gets older she would need to be monitored regularly and checked for early signs of liver cancer. She took the news almost as stoically as she had when I suggested she get tested in the first place.
Confronting the Crisis - A Time for Leadership
I would like to end this testimony on a note of optimism. There are gaping holes in this country's response to viral hepatitis - that's why we're here. There are, however, examples of successful, life-saving initiatives we can look to for inspiration. Since the early 90's there has been a recommendation in the U.S. that all pregnant women get tested for hepatitis B, and all babies born to hepatitis B positive mothers be given a series of protective vaccinations beginning within 12 hours of birth. A pregnant woman with hepatitis B will transmit the virus to her newborn about 90% of the time. However, if the newborn gets this series of shots, including the hepatitis B vaccine, the child will almost always develop immunity and not develop chronic hepatitis B. As a result of this initiative, we have seen new hepatitis B infections contracted in the U.S. plummet.
Also, as a result of this initiative, my little boy was given life-saving vaccinations that spared him the potential fate of dying young from complications related to chronic hepatitis B. I am encouraged by recent events that show a growing awareness of this public health crisis. Promising developments include the IOM report on Viral Hepatitis and Liver Cancer, the introduction last year of the Viral Hepatitis and Liver Cancer Control and Prevention Act (HR 3794) and the new Interagency Workgroup on Viral Hepatitis headed by Asst. Secretary of Health Koh.
We have an opportunity and we have a responsibility to use this momentum and act now. It should be a collaborative effort - government, industry, payors, health care providers, advocates and patients - but government needs to lead. We need strong leadership within the U.S. government to coordinate a comprehensive response that uses the information we have now, seeks to collect additional information on best practices and effective interventions and implements nationwide programs that include and build upon the core elements of public health to provide information, services and referral into quality care for everyone at risk for, and infected with, hepatitis B and hepatitis C. If we wait, hundreds of thousands of Americans will die unnecessarily premature deaths. If we act now, we can save many of those lives.
As Executive Director of the Hepatitis Education Project and a Steering Committee Member of the National Viral Hepatitis Roundtable, I respectfully submit testimony for the record for the hearing "Viral Hepatitis: The Secret Epidemic" and in response to the Institute of Medicine's recent report, Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C.
Since 2001, I have had the privilege of managing the Hepatitis Education Project (HEP), a national nonprofit organization based in Seattle, Washington dedicated to improving the lives of those affected by hepatitis. HEP works with populations most affected by viral hepatitis and often least connected to the health care system. Our partners include local, state and federal agencies as well as other community-based organizations. In this testimony, I will address the urgency of the hepatitis B and hepatitis C epidemics; the role of community-based organizations in addressing this crisis; and my personal experience.
Two Viruses, One Crisis
The urgency of the public health threat posed by hepatitis B and hepatitis C to our country cannot be overstated. More than 5 million Americans are living with chronic viral hepatitis, or almost 2 percent of the U.S. population. Most of those living with hepatitis B or hepatitis C are unaware of their infection and often remain asymptomatic for decades. Those who remain undiagnosed can unwittingly transmit the viruses to others and unknowingly do things to exacerbate their own liver damage. Many will be diagnosed only when their liver is failing. Sadly, thirty percent or more will eventually develop cirrhosis of the liver and some of those will die from endstage liver disease. Others will die from liver cancer.
Much of the disease burden from viral hepatitis is preventable. Hepatitis B is preventable through a simple series of vaccinations. For those who are already living with chronic viral hepatitis, the prognosis is usually very good when diagnosis is made early. Hepatitis B and hepatitis C are treatable conditions; and hepatitis C is often curable. For people to be treated for hepatitis, however, they have to be diagnosed. This remains one of our greatest challenges.
Viral hepatitis in the U.S. must also be viewed through the lens of health disparities. Hepatitis B disproportionately affects Asian Americans and Pacific Islanders (API) at rates more than twenty times that of their non-API counterparts. A staggering 1 in 10 foreign-born APIs has chronic hepatitis B. For new hepatitis B infections, there are racial, behavioral and geographic disparities. African American men and injection drug users have the highest rates of those newly infected with hepatitis B; and southern states have a disproportionate number of those new infections.
Hepatitis C disproportionately affects African Americans and Hispanics. And the majority of new hepatitis C infections occur in injection drug users. The real ticking time-bomb, though, is the prevalence of chronic hepatitis C among baby boomers, those born between 1946 -1964. It is estimated that 2-3 million boomers are currently living with hepatitis C. Most of these men and women were infected more than 30 years ago; the overwhelming majority remains unaware of their status. For the fortunate minority who get diagnosed, many will already have advanced liver disease that is more difficult to treat and manage and leads to progressively worsening and costly health outcomes such as end- stage liver disease and liver cancer. These outcomes are preventable but not if we maintain the current programs, policies and levels of funding for prevention.
Addressing the Epidemics - the Role of Community-Based Organizations Community-based organizations like the Hepatitis Education Project do much of the work related to viral hepatitis prevention, testing, education and referral to medical care. Programs at my agency include hepatitis A and B vaccination; hepatitis C antibody testing; a national support hotline; education programs for at-risk youth, prisoners, public health workers and medical providers. HEP also operates one of the few walk-in resource centers for hepatitis patients in the country.
Unlike many other disease states, there is very little federal support for these efforts. In FY2010, for example, the Division of Viral Hepatitis (DVH) at the Centers for Disease Control and Prevention (CDC) received $19.3 million. By way of comparison, the budget for domestic HIV prevention for the same period was more than $600 million. Of the $19.3 budget CDC allocated in FY 2010, about $5 million went to states and some city health departments, or about $90,000 for each state and each of five cities. This is a woefully inadequate amount to address epidemics that affect more than 5 million people less than $1 per patient per year.
As a result of this inadequate government response, organizations like the Hepatitis Education Project are vaccinating more people against hepatitis A and B, and testing more people for hepatitis C than any public health district in our state. We are proud of the work we do, but the efforts of community-based organizations like ours should complement, not substitute, the work of governmental and public health agencies. I am hopeful that this hearing and the IOM report will help to outline and stimulate an appropriate governmental response to these twin epidemics and provide the rationale needed to increase funding for critical programs and services.
Two Viruses, One Family
Until very recently I was a hepatitis patient, an experience that is often fraught with uncertainty. When I was diagnosed with hepatitis C relatively little was known about the virus. Hepatitis C was only discovered in 1989, and from the early through the late 90's this new epidemic was often compared to HIV except that it attacked the liver, not the immune system. Through the mid-90's, reports about hepatitis C grew increasingly dire. People with hepatitis C were dying from their disease. Some people were lucky enough to get a liver transplant, but that was thought to just delay the inevitable.
I sought medical care for my hepatitis C in 2000. By then, the medical community had a better understanding of the natural history of the disease, but there was still much that they did not know. In 2002, I had a liver biopsy which showed that I had some liver damage, but not enough to warrant immediate treatment. I had the kind of hepatitis C that responded to treatment about 50% of the time. With newer, more effective treatments thought to be commercially available within 5 years I decided to wait for the next class of drugs and in the meantime monitor the health of my liver. Five years came and went and so did the expected due date for the next class of drugs. Now, I was looking at 2010 at the earliest. I had my second liver biopsy in 2007 and the results were not what I wanted to hear. My liver damage was progressing and if I didn't do something, it was likely that I would progress to cirrhosis relatively soon. Once I had progressed to cirrhosis, there would be other potential complications.
In January, 2009, I was very fortunate to enter a clinical trial looking at a promising experimental new drug to treat hepatitis C. The virus rapidly became undetectable in my body and I completed treatment in December, 2009. Just last month I received my final lab results and learned that I am cured. I happily use the past tense now when I say that I was a hepatitis patient.
I talk about my hepatitis story because it the story I know best. It is not, however, the story that is most important to me - that would be the story of my wife, Lily, and our little boy, Sacha. Shortly after I met Lily, I told her that I had hepatitis C and explained to her what that meant and how it was transmitted. Later I explained that there was another epidemic that was equally invisible to the general public - hepatitis B. I knew that among the groups at greatest risk were people born in countries where hepatitis B is endemic. One of those countries is China - where Lily was born. I asked Lily if she had ever been tested for hepatitis B and she said she didn't know. I suggested that it would be a good idea to find out her status. She didn't seem to think it was that important. After some cajoling - and close to another year - Lily was tested for hepatitis B. The results showed that she had chronic hepatitis B, likely contracted at birth from her mother. Fortunately it was inactive, the doctor said, but as she gets older she would need to be monitored regularly and checked for early signs of liver cancer. She took the news almost as stoically as she had when I suggested she get tested in the first place.
Confronting the Crisis - A Time for Leadership
I would like to end this testimony on a note of optimism. There are gaping holes in this country's response to viral hepatitis - that's why we're here. There are, however, examples of successful, life-saving initiatives we can look to for inspiration. Since the early 90's there has been a recommendation in the U.S. that all pregnant women get tested for hepatitis B, and all babies born to hepatitis B positive mothers be given a series of protective vaccinations beginning within 12 hours of birth. A pregnant woman with hepatitis B will transmit the virus to her newborn about 90% of the time. However, if the newborn gets this series of shots, including the hepatitis B vaccine, the child will almost always develop immunity and not develop chronic hepatitis B. As a result of this initiative, we have seen new hepatitis B infections contracted in the U.S. plummet.
Also, as a result of this initiative, my little boy was given life-saving vaccinations that spared him the potential fate of dying young from complications related to chronic hepatitis B. I am encouraged by recent events that show a growing awareness of this public health crisis. Promising developments include the IOM report on Viral Hepatitis and Liver Cancer, the introduction last year of the Viral Hepatitis and Liver Cancer Control and Prevention Act (HR 3794) and the new Interagency Workgroup on Viral Hepatitis headed by Asst. Secretary of Health Koh.
We have an opportunity and we have a responsibility to use this momentum and act now. It should be a collaborative effort - government, industry, payors, health care providers, advocates and patients - but government needs to lead. We need strong leadership within the U.S. government to coordinate a comprehensive response that uses the information we have now, seeks to collect additional information on best practices and effective interventions and implements nationwide programs that include and build upon the core elements of public health to provide information, services and referral into quality care for everyone at risk for, and infected with, hepatitis B and hepatitis C. If we wait, hundreds of thousands of Americans will die unnecessarily premature deaths. If we act now, we can save many of those lives.
Viral Hepatitis Prevention
6/17/2010, 12:14 p.m. EDT
The Associated Press
(AP) — xfdte VIRAL-HEPATITIS sked
TESTIMONY June 17, 2010 MR. MICHAEL NINBURG EXECUTIVE DIRECTOR HEPATITIS EDUCATION PROJECT HOUSE Oversight and Government Reform VIRAL HEPATITIS PREVENTION Roll Call, Inc. 1255 22nd Street N.W. Washington, D.C. 20037 Transcript/Programming: Tel. 301-731-1728 Sales: Tel. 202-419-8500 ext 599 sales@cqrollcall.com www.cqrollcall.com Roll Call, Inc. is a private firm not affiliated with the U.S. Government. Copyright 2010 by Roll Call, Inc. Washington, D.C. U.S.A. All materials herein are protected by United States copyright law and may not be reproduced, distributed, transmitted, displayed, published or broadcast without the prior written permission of Roll Call, Inc. You may not alter or remove any trademark, copyright or other notice from copies of the content.Statement of Mr. Michael Ninburg Executive Director Hepatitis Education Project.
June 17, 2010
As a result of this inadequate government response, organizations like the Hepatitis Education Project are vaccinating more people against hepatitis A and B, and testing more people for hepatitis C than any public health district in our state. We are proud of the work we do, but the efforts of community-based organizations like ours should complement, not substitute, the work of governmental and public health agencies. I am hopeful that this hearing and the IOM report will help to outline and stimulate an appropriate governmental response to these twin epidemics and provide the rationale needed to increase funding for critical programs and services.
Two Viruses, One Family
Until very recently I was a hepatitis patient, an experience that is often fraught with uncertainty. When I was diagnosed with hepatitis C relatively little was known about the virus. Hepatitis C was only discovered in 1989, and from the early through the late 90's this new epidemic was often compared to HIV except that it attacked the liver, not the immune system. Through the mid-90's, reports about hepatitis C grew increasingly dire. People with hepatitis C were dying from their disease. Some people were lucky enough to get a liver transplant, but that was thought to just delay the inevitable.
I sought medical care for my hepatitis C in 2000. By then, the medical community had a better understanding of the natural history of the disease, but there was still much that they did not know. In 2002, I had a liver biopsy which showed that I had some liver damage, but not enough to warrant immediate treatment. I had the kind of hepatitis C that responded to treatment about 50% of the time. With newer, more effective treatments thought to be commercially available within 5 years I decided to wait for the next class of drugs and in the meantime monitor the health of my liver. Five years came and went and so did the expected due date for the next class of drugs. Now, I was looking at 2010 at the earliest. I had my second liver biopsy in 2007 and the results were not what I wanted to hear. My liver damage was progressing and if I didn't do something, it was likely that I would progress to cirrhosis relatively soon. Once I had progressed to cirrhosis, there would be other potential complications.
In January, 2009, I was very fortunate to enter a clinical trial looking at a promising experimental new drug to treat hepatitis C. The virus rapidly became undetectable in my body and I completed treatment in December, 2009. Just last month I received my final lab results and learned that I am cured. I happily use the past tense now when I say that I was a hepatitis patient.
I talk about my hepatitis story because it the story I know best. It is not, however, the story that is most important to me - that would be the story of my wife, Lily, and our little boy, Sacha. Shortly after I met Lily, I told her that I had hepatitis C and explained to her what that meant and how it was transmitted. Later I explained that there was another epidemic that was equally invisible to the general public - hepatitis B. I knew that among the groups at greatest risk were people born in countries where hepatitis B is endemic. One of those countries is China - where Lily was born. I asked Lily if she had ever been tested for hepatitis B and she said she didn't know. I suggested that it would be a good idea to find out her status. She didn't seem to think it was that important. After some cajoling - and close to another year - Lily was tested for hepatitis B. The results showed that she had chronic hepatitis B, likely contracted at birth from her mother. Fortunately it was inactive, the doctor said, but as she gets older she would need to be monitored regularly and checked for early signs of liver cancer. She took the news almost as stoically as she had when I suggested she get tested in the first place.
Confronting the Crisis - A Time for Leadership
I would like to end this testimony on a note of optimism. There are gaping holes in this country's response to viral hepatitis - that's why we're here. There are, however, examples of successful, life-saving initiatives we can look to for inspiration. Since the early 90's there has been a recommendation in the U.S. that all pregnant women get tested for hepatitis B, and all babies born to hepatitis B positive mothers be given a series of protective vaccinations beginning within 12 hours of birth. A pregnant woman with hepatitis B will transmit the virus to her newborn about 90% of the time. However, if the newborn gets this series of shots, including the hepatitis B vaccine, the child will almost always develop immunity and not develop chronic hepatitis B. As a result of this initiative, we have seen new hepatitis B infections contracted in the U.S. plummet.
Also, as a result of this initiative, my little boy was given life-saving vaccinations that spared him the potential fate of dying young from complications related to chronic hepatitis B. I am encouraged by recent events that show a growing awareness of this public health crisis. Promising developments include the IOM report on Viral Hepatitis and Liver Cancer, the introduction last year of the Viral Hepatitis and Liver Cancer Control and Prevention Act (HR 3794) and the new Interagency Workgroup on Viral Hepatitis headed by Asst. Secretary of Health Koh.
We have an opportunity and we have a responsibility to use this momentum and act now. It should be a collaborative effort - government, industry, payors, health care providers, advocates and patients - but government needs to lead. We need strong leadership within the U.S. government to coordinate a comprehensive response that uses the information we have now, seeks to collect additional information on best practices and effective interventions and implements nationwide programs that include and build upon the core elements of public health to provide information, services and referral into quality care for everyone at risk for, and infected with, hepatitis B and hepatitis C. If we wait, hundreds of thousands of Americans will die unnecessarily premature deaths. If we act now, we can save many of those lives.
As Executive Director of the Hepatitis Education Project and a Steering Committee Member of the National Viral Hepatitis Roundtable, I respectfully submit testimony for the record for the hearing "Viral Hepatitis: The Secret Epidemic" and in response to the Institute of Medicine's recent report, Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C.
Since 2001, I have had the privilege of managing the Hepatitis Education Project (HEP), a national nonprofit organization based in Seattle, Washington dedicated to improving the lives of those affected by hepatitis. HEP works with populations most affected by viral hepatitis and often least connected to the health care system. Our partners include local, state and federal agencies as well as other community-based organizations. In this testimony, I will address the urgency of the hepatitis B and hepatitis C epidemics; the role of community-based organizations in addressing this crisis; and my personal experience.
Two Viruses, One Crisis
The urgency of the public health threat posed by hepatitis B and hepatitis C to our country cannot be overstated. More than 5 million Americans are living with chronic viral hepatitis, or almost 2 percent of the U.S. population. Most of those living with hepatitis B or hepatitis C are unaware of their infection and often remain asymptomatic for decades. Those who remain undiagnosed can unwittingly transmit the viruses to others and unknowingly do things to exacerbate their own liver damage. Many will be diagnosed only when their liver is failing. Sadly, thirty percent or more will eventually develop cirrhosis of the liver and some of those will die from endstage liver disease. Others will die from liver cancer.
Much of the disease burden from viral hepatitis is preventable. Hepatitis B is preventable through a simple series of vaccinations. For those who are already living with chronic viral hepatitis, the prognosis is usually very good when diagnosis is made early. Hepatitis B and hepatitis C are treatable conditions; and hepatitis C is often curable. For people to be treated for hepatitis, however, they have to be diagnosed. This remains one of our greatest challenges.
Viral hepatitis in the U.S. must also be viewed through the lens of health disparities. Hepatitis B disproportionately affects Asian Americans and Pacific Islanders (API) at rates more than twenty times that of their non-API counterparts. A staggering 1 in 10 foreign-born APIs has chronic hepatitis B. For new hepatitis B infections, there are racial, behavioral and geographic disparities. African American men and injection drug users have the highest rates of those newly infected with hepatitis B; and southern states have a disproportionate number of those new infections.
Hepatitis C disproportionately affects African Americans and Hispanics. And the majority of new hepatitis C infections occur in injection drug users. The real ticking time-bomb, though, is the prevalence of chronic hepatitis C among baby boomers, those born between 1946 -1964. It is estimated that 2-3 million boomers are currently living with hepatitis C. Most of these men and women were infected more than 30 years ago; the overwhelming majority remains unaware of their status. For the fortunate minority who get diagnosed, many will already have advanced liver disease that is more difficult to treat and manage and leads to progressively worsening and costly health outcomes such as end- stage liver disease and liver cancer. These outcomes are preventable but not if we maintain the current programs, policies and levels of funding for prevention.
Addressing the Epidemics - the Role of Community-Based Organizations Community-based organizations like the Hepatitis Education Project do much of the work related to viral hepatitis prevention, testing, education and referral to medical care. Programs at my agency include hepatitis A and B vaccination; hepatitis C antibody testing; a national support hotline; education programs for at-risk youth, prisoners, public health workers and medical providers. HEP also operates one of the few walk-in resource centers for hepatitis patients in the country.
Unlike many other disease states, there is very little federal support for these efforts. In FY2010, for example, the Division of Viral Hepatitis (DVH) at the Centers for Disease Control and Prevention (CDC) received $19.3 million. By way of comparison, the budget for domestic HIV prevention for the same period was more than $600 million. Of the $19.3 budget CDC allocated in FY 2010, about $5 million went to states and some city health departments, or about $90,000 for each state and each of five cities. This is a woefully inadequate amount to address epidemics that affect more than 5 million people less than $1 per patient per year.
As a result of this inadequate government response, organizations like the Hepatitis Education Project are vaccinating more people against hepatitis A and B, and testing more people for hepatitis C than any public health district in our state. We are proud of the work we do, but the efforts of community-based organizations like ours should complement, not substitute, the work of governmental and public health agencies. I am hopeful that this hearing and the IOM report will help to outline and stimulate an appropriate governmental response to these twin epidemics and provide the rationale needed to increase funding for critical programs and services.
Two Viruses, One Family
Until very recently I was a hepatitis patient, an experience that is often fraught with uncertainty. When I was diagnosed with hepatitis C relatively little was known about the virus. Hepatitis C was only discovered in 1989, and from the early through the late 90's this new epidemic was often compared to HIV except that it attacked the liver, not the immune system. Through the mid-90's, reports about hepatitis C grew increasingly dire. People with hepatitis C were dying from their disease. Some people were lucky enough to get a liver transplant, but that was thought to just delay the inevitable.
I sought medical care for my hepatitis C in 2000. By then, the medical community had a better understanding of the natural history of the disease, but there was still much that they did not know. In 2002, I had a liver biopsy which showed that I had some liver damage, but not enough to warrant immediate treatment. I had the kind of hepatitis C that responded to treatment about 50% of the time. With newer, more effective treatments thought to be commercially available within 5 years I decided to wait for the next class of drugs and in the meantime monitor the health of my liver. Five years came and went and so did the expected due date for the next class of drugs. Now, I was looking at 2010 at the earliest. I had my second liver biopsy in 2007 and the results were not what I wanted to hear. My liver damage was progressing and if I didn't do something, it was likely that I would progress to cirrhosis relatively soon. Once I had progressed to cirrhosis, there would be other potential complications.
In January, 2009, I was very fortunate to enter a clinical trial looking at a promising experimental new drug to treat hepatitis C. The virus rapidly became undetectable in my body and I completed treatment in December, 2009. Just last month I received my final lab results and learned that I am cured. I happily use the past tense now when I say that I was a hepatitis patient.
I talk about my hepatitis story because it the story I know best. It is not, however, the story that is most important to me - that would be the story of my wife, Lily, and our little boy, Sacha. Shortly after I met Lily, I told her that I had hepatitis C and explained to her what that meant and how it was transmitted. Later I explained that there was another epidemic that was equally invisible to the general public - hepatitis B. I knew that among the groups at greatest risk were people born in countries where hepatitis B is endemic. One of those countries is China - where Lily was born. I asked Lily if she had ever been tested for hepatitis B and she said she didn't know. I suggested that it would be a good idea to find out her status. She didn't seem to think it was that important. After some cajoling - and close to another year - Lily was tested for hepatitis B. The results showed that she had chronic hepatitis B, likely contracted at birth from her mother. Fortunately it was inactive, the doctor said, but as she gets older she would need to be monitored regularly and checked for early signs of liver cancer. She took the news almost as stoically as she had when I suggested she get tested in the first place.
Confronting the Crisis - A Time for Leadership
I would like to end this testimony on a note of optimism. There are gaping holes in this country's response to viral hepatitis - that's why we're here. There are, however, examples of successful, life-saving initiatives we can look to for inspiration. Since the early 90's there has been a recommendation in the U.S. that all pregnant women get tested for hepatitis B, and all babies born to hepatitis B positive mothers be given a series of protective vaccinations beginning within 12 hours of birth. A pregnant woman with hepatitis B will transmit the virus to her newborn about 90% of the time. However, if the newborn gets this series of shots, including the hepatitis B vaccine, the child will almost always develop immunity and not develop chronic hepatitis B. As a result of this initiative, we have seen new hepatitis B infections contracted in the U.S. plummet.
Also, as a result of this initiative, my little boy was given life-saving vaccinations that spared him the potential fate of dying young from complications related to chronic hepatitis B. I am encouraged by recent events that show a growing awareness of this public health crisis. Promising developments include the IOM report on Viral Hepatitis and Liver Cancer, the introduction last year of the Viral Hepatitis and Liver Cancer Control and Prevention Act (HR 3794) and the new Interagency Workgroup on Viral Hepatitis headed by Asst. Secretary of Health Koh.
We have an opportunity and we have a responsibility to use this momentum and act now. It should be a collaborative effort - government, industry, payors, health care providers, advocates and patients - but government needs to lead. We need strong leadership within the U.S. government to coordinate a comprehensive response that uses the information we have now, seeks to collect additional information on best practices and effective interventions and implements nationwide programs that include and build upon the core elements of public health to provide information, services and referral into quality care for everyone at risk for, and infected with, hepatitis B and hepatitis C. If we wait, hundreds of thousands of Americans will die unnecessarily premature deaths. If we act now, we can save many of those lives.
Benitec Limited (ASX:BLT) Granted Hepatitis C RNA Interference Patent In US
Benitec Limited (ASX:BLT) Granted Hepatitis C RNA Interference Patent In US
Melbourne, June 18, 2010 (ABN Newswire) - Benitec Limited (ASX:BLT) (PINK:BNIKF) are pleased to announce that US Patent 7727970 "Multiple promoter expression cassettes for simultaneous delivery of RNAi agents targeted to Hepatitis C virus" has been granted by the United States Patent and Trademark Office (USPTO). The granted claims cover the use of an RNA interference construct (with multiple promoters) to inhibit the level of Hepatitis C virus in animal cells, tissues and organs. Moreover, the USPTO has granted Benitec an additional 805 days patent term in recognition of the delays in examining the patent application. Additional related applications remain pending to extend the scope of protection.
Benitec has licensed the rights to use this patent for Hepatitis C exclusively to Tacere Therapeutics, Inc., who recently announced that Pfizer has exercised its option to further develop and commercialise Tacere's Hepatitis C Virus (HCV) compounds.
Benitec's Chief Scientific Officer, Dr Peter French said, "The grant of this patent is an important further recognition of our dominant global position in the transformational DNA-directed RNA interference field and provides increased depth and breadth to our patent portfolio. Benitec's ddRNAi-related patent estate (solely owned or licensed exclusively for humans from CSIRO) currently comprises over 100 patents and patent applications covering 20 jurisdictions, of which more than 30 are granted, accepted or allowed."
Link: http://www.abnnewswire.net/media/en/docs/63116-ASX-BLT-596073.pdf
About Benitec Limited
Benitec Limited (ASX:BLT) (PINK:BNIKF) is an Australian biotechnology company focused on licensing its extensive intellectual property portfolio and developing therapeutics to treat serious diseases using its proprietary ddRNAi technology. For additional information, please visit www.benitec.com.
Contact
Mel Bridges
Executive Director
Mob: +61-413-051-600
Email: mbridges@benitec.com
Peter French
Chief Executive Officer
Mob: +61-412-457-595
Email: pfrench@benitec.com
Melbourne, June 18, 2010 (ABN Newswire) - Benitec Limited (ASX:BLT) (PINK:BNIKF) are pleased to announce that US Patent 7727970 "Multiple promoter expression cassettes for simultaneous delivery of RNAi agents targeted to Hepatitis C virus" has been granted by the United States Patent and Trademark Office (USPTO). The granted claims cover the use of an RNA interference construct (with multiple promoters) to inhibit the level of Hepatitis C virus in animal cells, tissues and organs. Moreover, the USPTO has granted Benitec an additional 805 days patent term in recognition of the delays in examining the patent application. Additional related applications remain pending to extend the scope of protection.
Benitec has licensed the rights to use this patent for Hepatitis C exclusively to Tacere Therapeutics, Inc., who recently announced that Pfizer has exercised its option to further develop and commercialise Tacere's Hepatitis C Virus (HCV) compounds.
Benitec's Chief Scientific Officer, Dr Peter French said, "The grant of this patent is an important further recognition of our dominant global position in the transformational DNA-directed RNA interference field and provides increased depth and breadth to our patent portfolio. Benitec's ddRNAi-related patent estate (solely owned or licensed exclusively for humans from CSIRO) currently comprises over 100 patents and patent applications covering 20 jurisdictions, of which more than 30 are granted, accepted or allowed."
Link: http://www.abnnewswire.net/media/en/docs/63116-ASX-BLT-596073.pdf
About Benitec Limited
Benitec Limited (ASX:BLT) (PINK:BNIKF) is an Australian biotechnology company focused on licensing its extensive intellectual property portfolio and developing therapeutics to treat serious diseases using its proprietary ddRNAi technology. For additional information, please visit www.benitec.com.
Contact
Mel Bridges
Executive Director
Mob: +61-413-051-600
Email: mbridges@benitec.com
Peter French
Chief Executive Officer
Mob: +61-412-457-595
Email: pfrench@benitec.com
Lawmakers urge quick passage of bill to boost detection, treatment of hepatitis
Lawmakers urge quick passage of bill to boost detection, treatment of hepatitis
By Julian Pecquet - 06/17/10 03:01 PM ET
Lawmakers on the House Oversight panel on Thursday urged Congress to quickly pass legislation to boost the detection and treatment of viral hepatitis, the leading cause of liver cancer in the United States.
The Oversight and Government Reform Committee held the first hearing in several years on the deadly disease, which disproportionately affects blacks and Asians, and pressed for passage of a bipartisan bill that would boost funding by $600 million over the next five years.
The hearing comes on the heels of an Institute of Medicine (IOM) report that highlighted deficiencies with the federal government's response to the epidemic. The report contains two dozen expert recommendations for improvement, including enhanced screening, physician education and the creation of a coordinated system to identify people who have the disease and refer them to care.
About 5.3 million Americans are believed to have hepatitis — the disease causes 12,000 to 15,000 deaths a year — though many don’t know it.
"The current approach [...] is not working," the IOM report says.
The legislation under consideration, introduced in October by Rep. Mike Honda (D-Calif.), has 52 bipartisan co-sponsors. The "Viral Hepatitis and Liver Cancer Control and Prevention Act" is currently in the Energy and Commerce Committee.
The bill would charge the secretary of Health and Human Services with developing and implementing a plan for the prevention, control and medical management of hepatitis B and C; it would also provide federal funding for state-based screening and early intervention programs.
Honda said the bill would eventually save billions of dollars by identifying sick people early. A study by the research firm Milliman found that without federal leadership, the cost of treating hepatitis C alone could more than triple, to $85 billion a year, by 2024.
"We can do a whole lot better than what we're doing," said Oversight panel chairman Edolphus Towns (D-N.Y.). "I think it's a disgrace to have a problem of this nature and to not commit resources."
The panel heard testimony from Honda and Reps. Bill Cassidy (R-La.) and Hank Johnson (D-Ga.). Cassidy is a hepatologist who co-sponsored the bill, and Johnson last year acknowledged he was undergoing treatment for hepatitis C.
Cassidy applauded former President Bill Clinton's children’s vaccination program and said the Honda bill would "similarly save lives." But debate quickly descended into budgetary politics.
Oversight ranking member Darrell Issa (R-Calif.) said Republicans would not vote for any new directed spending unless it's part of the budget bill, which has stalled.
Meanwhile, Democrats bristled at Issa's description of the word "earmark" to describe the bill.
A coalition of more than 175 public and private organizations launched a print ad campaign on Tuesday to coincide with the hearing. The National Viral Hepatitis Roundtable ad is made to look like a movie poster and reads "Mission: Possible."
"If Congress gets on the case now," the ad says, "the leading cause of liver cancer won't stand a chance."
Patient advocates say the Honda bill will help boost funding for hepatitis prevention efforts, which currently only get 2 percent — $19.3 million — of the budget allocated to the Centers for Disease Control and Prevention's National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. Advocates hope the Honda bill will eventually allow them to get $150 million a year.
By Julian Pecquet - 06/17/10 03:01 PM ET
Lawmakers on the House Oversight panel on Thursday urged Congress to quickly pass legislation to boost the detection and treatment of viral hepatitis, the leading cause of liver cancer in the United States.
The Oversight and Government Reform Committee held the first hearing in several years on the deadly disease, which disproportionately affects blacks and Asians, and pressed for passage of a bipartisan bill that would boost funding by $600 million over the next five years.
The hearing comes on the heels of an Institute of Medicine (IOM) report that highlighted deficiencies with the federal government's response to the epidemic. The report contains two dozen expert recommendations for improvement, including enhanced screening, physician education and the creation of a coordinated system to identify people who have the disease and refer them to care.
About 5.3 million Americans are believed to have hepatitis — the disease causes 12,000 to 15,000 deaths a year — though many don’t know it.
"The current approach [...] is not working," the IOM report says.
The legislation under consideration, introduced in October by Rep. Mike Honda (D-Calif.), has 52 bipartisan co-sponsors. The "Viral Hepatitis and Liver Cancer Control and Prevention Act" is currently in the Energy and Commerce Committee.
The bill would charge the secretary of Health and Human Services with developing and implementing a plan for the prevention, control and medical management of hepatitis B and C; it would also provide federal funding for state-based screening and early intervention programs.
Honda said the bill would eventually save billions of dollars by identifying sick people early. A study by the research firm Milliman found that without federal leadership, the cost of treating hepatitis C alone could more than triple, to $85 billion a year, by 2024.
"We can do a whole lot better than what we're doing," said Oversight panel chairman Edolphus Towns (D-N.Y.). "I think it's a disgrace to have a problem of this nature and to not commit resources."
The panel heard testimony from Honda and Reps. Bill Cassidy (R-La.) and Hank Johnson (D-Ga.). Cassidy is a hepatologist who co-sponsored the bill, and Johnson last year acknowledged he was undergoing treatment for hepatitis C.
Cassidy applauded former President Bill Clinton's children’s vaccination program and said the Honda bill would "similarly save lives." But debate quickly descended into budgetary politics.
Oversight ranking member Darrell Issa (R-Calif.) said Republicans would not vote for any new directed spending unless it's part of the budget bill, which has stalled.
Meanwhile, Democrats bristled at Issa's description of the word "earmark" to describe the bill.
A coalition of more than 175 public and private organizations launched a print ad campaign on Tuesday to coincide with the hearing. The National Viral Hepatitis Roundtable ad is made to look like a movie poster and reads "Mission: Possible."
"If Congress gets on the case now," the ad says, "the leading cause of liver cancer won't stand a chance."
Patient advocates say the Honda bill will help boost funding for hepatitis prevention efforts, which currently only get 2 percent — $19.3 million — of the budget allocated to the Centers for Disease Control and Prevention's National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. Advocates hope the Honda bill will eventually allow them to get $150 million a year.
Deep sequencing analysis of baseline and on-treatment samples from HCV genotype-1
Deep sequencing analysis of baseline and on-treatment samples from HCV genotype-1 patients treated for 5 days with TMC435 monotherapy and subsequently re-treated with TMC435 in combination with PegIFNα-2a/ribavirin - poster presentation
Reported by Jules Levin
O Lenz,1 L Vijgen,1 T Verbinnen,1 H van Marck,1 I Vandenbroucke,1 M Peeters,1 G De Smedt,1 K Simmen,1 G Fanning,1 H Reesink,2 G Picchio3 1Tibotec BVBA, Mechelen, Belgium; 2Academic Medical Center, Amsterdam, The Netherlands; 3Tibotec Inc., Yardley, PA, USA
Author Conclusions
Treatment with TMC435 200 mg QD resulted in potent antiviral activity in study TMC435-C101, during five days of monotherapy, and subsequently in the same patients when combined with PegIFN/RBV in the OPERA-1 study.
Emerging viral variants were associated with a high fold change in EC50 values to TMC435 in in vitro replicon assays.
Viral variants that emerged during first exposure to TMC435 in study TMC435-C101 were no longer detectable in most cases over time, while in some they persisted at low frequencies based on ultra-dee sequencing analysis.
Persistence of viral variants in two patients at low frequency was associated with slightly reduced antiviral activity of TMC435 during the first seven days of the OPERA-1 study.
The newly identified F169L mutation reduced activity of TMC435 in vitro when combined with the Q80R and/or D168E mutation in a genotype-1b replicon.
Introduction
· TMC435 is a potent and selective macrocyclic inhibitor of the hepatitis C virus (HCV) NS3/4A protease with an in vitro 50% effective concentration (EC50) of 8 nM (6 ng/mL) in a genotype-1b replicon cell line.1 TMC435 is currently in Phase IIb development.
· In vitro resistance studies identified changes at amino acid positions 43, 80, 155, 156 and 168 within the NS3 protease domain that confer variable degrees of reduced susceptibility to TMC435.2
· In a Phase I study (TMC435-C101), six HCV genotype-1-infected patients who failed previous interferon (IFN)-based therapy received TMC435 200 mg once daily (QD) for 5 days.3 Approximately 1.5 years later, 5/6 patients were enrolled into Cohort 5 of the Phase IIa Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA)-1 study (TMC435-C201; NCT00561353) and were re-treated withTMC435 (200 mg QD) in combination with pegylated (Peg)IFNα-2a/ribavirin (RBV) for 28 days followed by PegIFNα-2a/RBV up to Week 48.4
· Median/mean trough TMC435 concentrations observed following doses of 75 mg and 200 mg QD ranged from approximately 25-50 and 350-950 fold, respectively, of the EC50 values obtained in the genotype-1b replicon cell line (6 ng/mL).3,5,6
· Here we present a detailed genotypic and phenotypic analysis of HCV isolates obtained from patients participating in the TMC435-C101 study who were re-treated in OPERA-1.
METHODS
· Plasma samples were collected during the TMC435-C101 and OPERA-1 studies.
· HCV ribonucleic acid (RNA) was extracted from plasma samples and the NS3/4A region was sequenced using standard population sequencing. In addition, selected samples were analysed using clonal single genome sequencing (20-80 clones per sample) or were subjected to massive parallel pyrosequencing (deep sequencing) using the 454 life science platform (GS-FLX, Roche Applied Science).
· For phenotypic analysis, selected mutations or patient-derived NS3 protease regions were introduced into a genotype-1b replicon backbone and the antiviral activity of TMC435 was tested and compared with the parental replicon in a standard transient replicon assay.
Figure 1. Schematic representation of genotypic and phenotypic assessments.
RESULTS
Antiviral activity and genotypic/phenotypic changes in the HCV NS3 region
· A consistent and rapid drop in plasma HCV RNA was observed in all six patients, with a maximal median reduction from baseline of 3.9 log10 IU/mL at Day 6 in study TMC435-C101. All four subjects who completed the 28-day treatment in the OPERA-1 study reached HCV RNA levels of <25 IU/mL.
· Although overall changes in HCV RNA were similar between studies, in two patients the RNA decrease from baseline was slower in OPERA-1 compared with study TMC435-C101: in patient 142 at Day 3 (-2.9 versus -3.7 log10 IU/mL) and patient 141 at Day 7 (-2.8 versus -3.5 log10 IU/mL).
· At baseline of study TMC435-C101, four patients had no detectable variations at positions identified in vitro to confer reduced susceptibility to TMC435, while in two patients (177 and 140), a Q80K and D168D/E variation was observed, respectively. Initial HCV RNA reductions in these two patients were comparable to those observed in patients without baseline variations. Change from baseline to Day 3 was 3.1 and 3.6 log10 IU/mL for these two patients in study TMC435-C101, respectively.
· Mutations at one or more of the amino acid positions 80, 155, 156 and 168 were newly detected in all subjects as early as Day 3 of study TMC435-C101.
· Population sequencing and phenotypic analysis of the HCV isolates obtained from 5/6 patients at baseline of OPERA-1 suggested that the viral variants returned to the characteristics observed prior to study TMC435-C101 in all five patients.
· Emerging mutations R155K, and Q80R/K, D168E plus F169L, were detected in two subjects in OPERA-1, respectively.
· The in vitro activity of TMC435 against the treatment emerging NS3 variants identified revealed fold changes in EC50 values (FC) >100 in all patients in study TMC435-C101 and in patient 141 in OPERA-1.
Figure 2. A) Individual changes in plasma HCV RNA from baseline in genotype-1-infected IFN-experienced patients during five days of dosing with 200 mg QD of TMC435 alone in study TMC435-C101 and in combination with PegIFNα-2a/RBV in OPERA-1. B) Mutations detected in the NS3 protease domain defined as changes from reference sequence (Con1 for genotype-1b and H77 for genotype-1a). C) Fold changes in EC50 values compared with wild-type assessed in a transient replicon assay using chimeric replicons harbouring the NS3 protease domain derived from patient samples. Day 1 = Baseline; FUP1 = follow-up 1 (2 weeks after end of dosing); FUP2 = follow-up 2 (4 weeks after end of dosing).
*Patient discontinued TMC435 due to adverse event at Day 14 (dose reduction to 100 mg at Day 10)
C201=OPERA-1
Mutations T40A, S91T/A and L153I were found in all HCV genotype-1a patients at all time points analysed; the mutation R26K was found in all HCV genotype-1b patients at all time points analysed; A156A/V was present in patient 143 at Day 4.
C201=OPERA-1
EC50, 50% effective concentration; FC, fold change; FUP, follow-up; HCV, hepatitis C virus; NR, non-responder; OPERA, Optimal Protease inhibitor Enhancement of Response to TherApy; PegIFN, pegylated interferon; QD, once daily; RBV, ribavirin; R, relapser; RNA, ribonucleic acid; wt, wild type
Presence of viral variants at baseline in studies TMC435-C101 and OPERA-1 based on ultra-deep sequencing
· No additional pre-existing NS3 mutations were detected at baseline of TMC435-C101 using ultra-deep sequencing (Q80K and D168D/E were also detected by population sequencing).
· At baseline of OPERA-1, additional mutations were observed at low frequency (<2%) in three patients: Q80L, R155G and R155K, respectively.
· Alternative codon usage was noted for wild-type and mutated amino acid, respectively.
Figure 3. The sequence of the HCV NS3 protease domain was determined for baseline samples of study TMC435-C101 and OPERA-1 using ultra-deep sequencing. Percentage of codon frequency at NS3 positions 80, 155, 156 and 168 are shown. Grey dots represent codons encoding wild-type amino acids. Coloured dots represent codons encoding mutations (defined as changes from reference sequence: Con1 for genotype-1b and H77 for genotype-1a).
C201=OPERA-1
HCV, hepatitis C virus; OPERA, Optimal Protease inhibitor Enhancement of Response to TherApy
Single genome (clonal) sequencing of NS3 protease domain and effect of isolated mutations on in vitro activity of TMC435
· In addition to single mutations, variants harbouring double and triple mutations were observed.
· In general, when introduced into the replicon, most of the single mutations detected resulted in lower fold change in EC50 values than double or triple mutations.
· Mutation F169L, which has no effect on TMC435 activity alone, further decreased susceptibility to TMC435 when combined with Q80R and/or D168E.
Figure 4. A) NS3 protease domain was amplified, cloned into standard cloning vectors and sequenced to determine linkage of mutations. Mutations at position 80, 155, 156 and 168 (169) were considered for this analysis. Frequency of clones is represented. B) Single and multiple mutations were introduced in a genotype-1b replicon backbone and EC50 values were determined using a standard transient replicon assay. Fold change in EC50 values versus the parental wild-type replicon are indicated.
Evolution of amino acid changes over time
· In patient 141, ultra-deep sequencing detected a Q80R and D168E mutation four weeks after end of dosing for study TMC435-C101, which were no longer detectable at baseline of the OPERA-1 study
- These two mutations emerged as major variants upon re-exposure to TMC435 in the OPERA-1 study.
· Different mutational patterns were observed in response to exposure to TMC435.
· Variants with different mutations at a given position were detected.
Figure 5. The sequence of the HCV NS3 domain was analysed from multiple samples using ultra-deep sequencing. Changes of codon frequency over time for NS3 at positions 80, 155, 156 and 168 are shown for patient 142 (A) and 141 (B).
C201=OPERA-1
FUP, follow-up; HCV, hepatitis C virus; AA, amino acid
References
1. Lin TI et al. Antimicrob Agents Chemother 2009;53:1377-1385.
2. Lenz O et al. Antimicrob Agents Chemother 2010;54:1878-1887.
3. Reesink HW et al. Gastroenterology 2010;138:913-921.
4. Reesink HW et al. Presented at the 60th American Association for the Study of Liver Diseases (AASLD) meeting, Boston, MA, USA, 30 October-3 November, 2009.
5. Sekar V et al. Presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna, Austria, 14-18 April, 2010.
6. Data on file. Tibotec Inc. 2010.
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Reported by Jules Levin
O Lenz,1 L Vijgen,1 T Verbinnen,1 H van Marck,1 I Vandenbroucke,1 M Peeters,1 G De Smedt,1 K Simmen,1 G Fanning,1 H Reesink,2 G Picchio3 1Tibotec BVBA, Mechelen, Belgium; 2Academic Medical Center, Amsterdam, The Netherlands; 3Tibotec Inc., Yardley, PA, USA
Author Conclusions
Treatment with TMC435 200 mg QD resulted in potent antiviral activity in study TMC435-C101, during five days of monotherapy, and subsequently in the same patients when combined with PegIFN/RBV in the OPERA-1 study.
Emerging viral variants were associated with a high fold change in EC50 values to TMC435 in in vitro replicon assays.
Viral variants that emerged during first exposure to TMC435 in study TMC435-C101 were no longer detectable in most cases over time, while in some they persisted at low frequencies based on ultra-dee sequencing analysis.
Persistence of viral variants in two patients at low frequency was associated with slightly reduced antiviral activity of TMC435 during the first seven days of the OPERA-1 study.
The newly identified F169L mutation reduced activity of TMC435 in vitro when combined with the Q80R and/or D168E mutation in a genotype-1b replicon.
Introduction
· TMC435 is a potent and selective macrocyclic inhibitor of the hepatitis C virus (HCV) NS3/4A protease with an in vitro 50% effective concentration (EC50) of 8 nM (6 ng/mL) in a genotype-1b replicon cell line.1 TMC435 is currently in Phase IIb development.
· In vitro resistance studies identified changes at amino acid positions 43, 80, 155, 156 and 168 within the NS3 protease domain that confer variable degrees of reduced susceptibility to TMC435.2
· In a Phase I study (TMC435-C101), six HCV genotype-1-infected patients who failed previous interferon (IFN)-based therapy received TMC435 200 mg once daily (QD) for 5 days.3 Approximately 1.5 years later, 5/6 patients were enrolled into Cohort 5 of the Phase IIa Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA)-1 study (TMC435-C201; NCT00561353) and were re-treated withTMC435 (200 mg QD) in combination with pegylated (Peg)IFNα-2a/ribavirin (RBV) for 28 days followed by PegIFNα-2a/RBV up to Week 48.4
· Median/mean trough TMC435 concentrations observed following doses of 75 mg and 200 mg QD ranged from approximately 25-50 and 350-950 fold, respectively, of the EC50 values obtained in the genotype-1b replicon cell line (6 ng/mL).3,5,6
· Here we present a detailed genotypic and phenotypic analysis of HCV isolates obtained from patients participating in the TMC435-C101 study who were re-treated in OPERA-1.
METHODS
· Plasma samples were collected during the TMC435-C101 and OPERA-1 studies.
· HCV ribonucleic acid (RNA) was extracted from plasma samples and the NS3/4A region was sequenced using standard population sequencing. In addition, selected samples were analysed using clonal single genome sequencing (20-80 clones per sample) or were subjected to massive parallel pyrosequencing (deep sequencing) using the 454 life science platform (GS-FLX, Roche Applied Science).
· For phenotypic analysis, selected mutations or patient-derived NS3 protease regions were introduced into a genotype-1b replicon backbone and the antiviral activity of TMC435 was tested and compared with the parental replicon in a standard transient replicon assay.
Figure 1. Schematic representation of genotypic and phenotypic assessments.
RESULTS
Antiviral activity and genotypic/phenotypic changes in the HCV NS3 region
· A consistent and rapid drop in plasma HCV RNA was observed in all six patients, with a maximal median reduction from baseline of 3.9 log10 IU/mL at Day 6 in study TMC435-C101. All four subjects who completed the 28-day treatment in the OPERA-1 study reached HCV RNA levels of <25 IU/mL.
· Although overall changes in HCV RNA were similar between studies, in two patients the RNA decrease from baseline was slower in OPERA-1 compared with study TMC435-C101: in patient 142 at Day 3 (-2.9 versus -3.7 log10 IU/mL) and patient 141 at Day 7 (-2.8 versus -3.5 log10 IU/mL).
· At baseline of study TMC435-C101, four patients had no detectable variations at positions identified in vitro to confer reduced susceptibility to TMC435, while in two patients (177 and 140), a Q80K and D168D/E variation was observed, respectively. Initial HCV RNA reductions in these two patients were comparable to those observed in patients without baseline variations. Change from baseline to Day 3 was 3.1 and 3.6 log10 IU/mL for these two patients in study TMC435-C101, respectively.
· Mutations at one or more of the amino acid positions 80, 155, 156 and 168 were newly detected in all subjects as early as Day 3 of study TMC435-C101.
· Population sequencing and phenotypic analysis of the HCV isolates obtained from 5/6 patients at baseline of OPERA-1 suggested that the viral variants returned to the characteristics observed prior to study TMC435-C101 in all five patients.
· Emerging mutations R155K, and Q80R/K, D168E plus F169L, were detected in two subjects in OPERA-1, respectively.
· The in vitro activity of TMC435 against the treatment emerging NS3 variants identified revealed fold changes in EC50 values (FC) >100 in all patients in study TMC435-C101 and in patient 141 in OPERA-1.
Figure 2. A) Individual changes in plasma HCV RNA from baseline in genotype-1-infected IFN-experienced patients during five days of dosing with 200 mg QD of TMC435 alone in study TMC435-C101 and in combination with PegIFNα-2a/RBV in OPERA-1. B) Mutations detected in the NS3 protease domain defined as changes from reference sequence (Con1 for genotype-1b and H77 for genotype-1a). C) Fold changes in EC50 values compared with wild-type assessed in a transient replicon assay using chimeric replicons harbouring the NS3 protease domain derived from patient samples. Day 1 = Baseline; FUP1 = follow-up 1 (2 weeks after end of dosing); FUP2 = follow-up 2 (4 weeks after end of dosing).
*Patient discontinued TMC435 due to adverse event at Day 14 (dose reduction to 100 mg at Day 10)
C201=OPERA-1
Mutations T40A, S91T/A and L153I were found in all HCV genotype-1a patients at all time points analysed; the mutation R26K was found in all HCV genotype-1b patients at all time points analysed; A156A/V was present in patient 143 at Day 4.
C201=OPERA-1
EC50, 50% effective concentration; FC, fold change; FUP, follow-up; HCV, hepatitis C virus; NR, non-responder; OPERA, Optimal Protease inhibitor Enhancement of Response to TherApy; PegIFN, pegylated interferon; QD, once daily; RBV, ribavirin; R, relapser; RNA, ribonucleic acid; wt, wild type
Presence of viral variants at baseline in studies TMC435-C101 and OPERA-1 based on ultra-deep sequencing
· No additional pre-existing NS3 mutations were detected at baseline of TMC435-C101 using ultra-deep sequencing (Q80K and D168D/E were also detected by population sequencing).
· At baseline of OPERA-1, additional mutations were observed at low frequency (<2%) in three patients: Q80L, R155G and R155K, respectively.
· Alternative codon usage was noted for wild-type and mutated amino acid, respectively.
Figure 3. The sequence of the HCV NS3 protease domain was determined for baseline samples of study TMC435-C101 and OPERA-1 using ultra-deep sequencing. Percentage of codon frequency at NS3 positions 80, 155, 156 and 168 are shown. Grey dots represent codons encoding wild-type amino acids. Coloured dots represent codons encoding mutations (defined as changes from reference sequence: Con1 for genotype-1b and H77 for genotype-1a).
C201=OPERA-1
HCV, hepatitis C virus; OPERA, Optimal Protease inhibitor Enhancement of Response to TherApy
Single genome (clonal) sequencing of NS3 protease domain and effect of isolated mutations on in vitro activity of TMC435
· In addition to single mutations, variants harbouring double and triple mutations were observed.
· In general, when introduced into the replicon, most of the single mutations detected resulted in lower fold change in EC50 values than double or triple mutations.
· Mutation F169L, which has no effect on TMC435 activity alone, further decreased susceptibility to TMC435 when combined with Q80R and/or D168E.
Figure 4. A) NS3 protease domain was amplified, cloned into standard cloning vectors and sequenced to determine linkage of mutations. Mutations at position 80, 155, 156 and 168 (169) were considered for this analysis. Frequency of clones is represented. B) Single and multiple mutations were introduced in a genotype-1b replicon backbone and EC50 values were determined using a standard transient replicon assay. Fold change in EC50 values versus the parental wild-type replicon are indicated.
Evolution of amino acid changes over time
· In patient 141, ultra-deep sequencing detected a Q80R and D168E mutation four weeks after end of dosing for study TMC435-C101, which were no longer detectable at baseline of the OPERA-1 study
- These two mutations emerged as major variants upon re-exposure to TMC435 in the OPERA-1 study.
· Different mutational patterns were observed in response to exposure to TMC435.
· Variants with different mutations at a given position were detected.
Figure 5. The sequence of the HCV NS3 domain was analysed from multiple samples using ultra-deep sequencing. Changes of codon frequency over time for NS3 at positions 80, 155, 156 and 168 are shown for patient 142 (A) and 141 (B).
C201=OPERA-1
FUP, follow-up; HCV, hepatitis C virus; AA, amino acid
References
1. Lin TI et al. Antimicrob Agents Chemother 2009;53:1377-1385.
2. Lenz O et al. Antimicrob Agents Chemother 2010;54:1878-1887.
3. Reesink HW et al. Gastroenterology 2010;138:913-921.
4. Reesink HW et al. Presented at the 60th American Association for the Study of Liver Diseases (AASLD) meeting, Boston, MA, USA, 30 October-3 November, 2009.
5. Sekar V et al. Presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna, Austria, 14-18 April, 2010.
6. Data on file. Tibotec Inc. 2010.
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