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Hepatitis C and Hepatocellular Carcinoma: Grist for the Mill EDITORIAL
"in the United States HCC surveillance is not applied as widely as it is in many European and Far Eastern countries"
"Most gastroenterologists offer some form of surveillance to their patients,16 but few other caregivers do.17 In 1 study, only 60% of patients presenting with HCC received any form of surveillance.18 Seventeen percent of patients with HCC were known to be cirrhotic and did not receive surveillance, and 18% were not even known to be cirrhotic. When surveillance is offered, it is most frequently with periodic testing of alpha-fetoprotein,17 whereas the recommendation is not to use alpha-fetoprotein, but to rely on ultrasound.19"
"these results from the HALT-C study have shown clearly that maintenance hepatitis C treatment does not reduce the incidence of HCC. HCC can occur at an appreciable frequency in patients with advanced fibrosis but who do not have cirrhosis. The risk factors for HCC can be identified and an algorithm has been developed that identifies patients at risk for HCC more accurately who can then be targeted for surveillance. However, the intensity of surveillance in the United States has to increase to a level that exists elsewhere in the world before HCC surveillance will result in mortality reduction."
Gastroenterology Jan 2009
Morris ShermanCorresponding Author Informationemail address
University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
Refers to article:
Editorial Accompanies ArticleLinking Article with CGH Incidence of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease , 19 September 2008
Anna S. Lok, Leonard B. Seeff, Timothy R. Morgan, Adrian M. di Bisceglie, Richard K. Sterling, Teresa M. Curto, Gregory T. Everson, Karen L. Lindsay, William M. Lee, Herbert L. Bonkovsky, Jules L. Dienstag, Marc G. Ghany, Chihiro Morishima, Zachary D. Goodman, HALT-C Trial Group
Gastroenterology
January 2009 (Vol. 136, Issue 1, Pages 138-148)
The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) study is a prospective, randomized, investigator-initiated study to determine whether maintenance therapy with low-dose pegylated interferon alpha in patients with chronic hepatitis C who had failed to clear virus following a standard course of treatment would slow the progression of disease.1 Progression of disease was determined on biopsy and by the development of the end-stage complications of progressive hepatitis C, namely development of hepatocellular carcinoma (HCC), liver failure, and the need for liver transplant. Previous reports from the HALT-C study have indicated that this treatment regimen did not halt progression of liver disease.1 In a report in this issue of Gastroenterology, Lok et al2 provide evidence that the incidence of hepatocellular carcinoma is also not different in those who were on maintenance therapy versus untreated controls. These results are in contradistinction to an earlier report on 2-year maintenance therapy in nonresponders.3 However, the sample size in this study was small and may have led to type 1 error.3
HCC is a common complication of cirrhosis in patients with chronic hepatitis C. The reported incidence of HCC varies between <1% and >10% in some series.4, 5, 6 The quality of the studies looking at this issue varies, with a paucity of prospective studies, and none that compare the incidence of HCC in patients with hepatitis C cirrhosis with an uninfected control group. Some factors that identify patients with hepatitis C at risk for HCC have been identified, including older age, cirrhosis, and a low platelet count. Thus far, however, there has been no attempt to use these factors to predict HCC occurrence within a defined time period, such as 3–5 years. Risk of HCC in hepatitis C cirrhosis is not fixed, but increases with time as disease progresses. Despite this, quoted incidence figures in cirrhosis assume that all patients have equal risk. This is relevant when the issue of surveillance for HCC is considered. It would be very helpful to have some means of more accurately identifying those hepatitis C cirrhotics with a higher risk of developing cancer within a short period of time. For example, if the 5-year risk of HCC were 5%, then patients might warrant surveillance; if the 5-year risk was only 0.5%, surveillance might not be recommended.
There are several issues that are raised by this report from the HALT-C study. These are related to the incidence of HCC and the assessment of HCC risk, the efficacy of surveillance, and HCC staging.
The incidence of HCC in noncirrhotic patients in the HALT-C study was unexpectedly high. In the cirrhotic group, the incidence of HCC was 7.0%. In the patients who were noncirrhotic, the incidence of HCC was 4.1%. In North America, until this report, HCC developing in a noncirrhotic hepatitis C patient was considered uncommon. Although the patients were not cirrhotic, they did have advanced fibrosis as a precondition for inclusion in the study.
These results can be interpreted in 2 ways. One explanation, as the authors note, is that the severity of fibrosis on the initial biopsy was undercalled, because of sampling error, and these patients actually had cirrhosis. Some patients clearly progressed to cirrhosis over the course of the study, but it is unlikely that 47% of initial biopsies were underinterpreted. Others developed thrombocytopenia, suggesting that they had portal hypertension, and thus were indeed cirrhotic, even if not identified on biopsy. Alternatively, these results indicate that the cancer risk starts to increase before cirrhosis develops. There were some patients who developed HCC who did not have cirrhosis by any clinical, biochemical, or hematologic criteria. Whatever the true explanation, it is irrelevant to the clinical situation. Clinicians are faced with biopsies in patients with hepatitis C that show advanced fibrosis but not cirrhosis. These HALT-C study results mean that a patient with hepatitis C who has bridging fibrosis must now be considered to be at risk for HCC. Whether these biopsies are underinterpreted because of sampling or not, the clinician has to decide whether the patient warrants HCC surveillance. This is a difficult question to answer and is discussed in more detail.
The objective of HCC surveillance is to decrease mortality from that disease. There are no randomized, controlled trials of HCC surveillance in hepatitis C that address this endpoint. Therefore, to identify patients who might benefit from surveillance, we have to rely on modeling studies to determine the efficacy and cost efficacy of HCC surveillance. There are a handful of such studies7, 8, 9; as expected, each has utilized different disease models and has included different assumptions. There does seem to be some agreement, however, that at an annual HCC incidence of about 1.5% surveillance becomes both effective in terms of life-years saved, and cost effective (ie, the cost of surveillance was <$50,000 per life-year saved). By this criterion, even patients with cirrhosis in this study would not quite qualify for surveillance, because the overall annual incidence was only about 1.4%, and in the noncirrhotic group the incidence was only 0.8%. Some of the modeling studies are old; others rely heavily on retrospective data for transition probabilities. Some do not include modern approaches to the management of HCC (eg, liver transplantation). These models are probably no longer trustworthy, given new data, and should be revisited. The HALT-C study, among others, now provides prospective data that can be inserted into any disease model. In addition, there has been significant progress in the management of small HCC, which none of the earlier analyses capture. However, until we have new models we should continue to provide surveillance for our patients with cirrhosis, but whether patients with bridging fibrosis should also undergo surveillance cannot be answered at present, because we do not know whether the incidence is less or more than 1.5%.
The second important outcome of this analysis was the development of a predictive model for HCC using Cox proportional hazard techniques. The Cox proportional hazards technique assumes that the effect of a risk factor remains proportional to the outcome over the time period analyzed. In other words, if age, platelet count, or other factors influence outcome, the magnitude of this influence does not change over time. The analysis is a mathematical calculation that determines whether the variables examined in the model are associated with the outcome, and whether they are associated independently of other variables, as well as the magnitude of that association. By calculating a numerical value representing the strength of the association for each of the variables associated with development of HCC, a score can be calculated for each patient. In this analysis, Lok et al2 divided the range of possible scores into 3 risk strata; low, medium, and high. The incidence of HCC predicted by the Cox proportional hazard model was calculated for patients in each stratum and compared with the actual incidence (Table 1). For patients with the lowest risk scores, the expected incidence of HCC was <1%, and the observed incidence between 0.0% and 0.4% at 3 and 5 years. For patients in the highest risk group, the calculated incidence should have been >5%, and the observed 3- and 5-year incidences were 6.1% and 17.8%, respectively. We are not given the annual incidence figures in the risk strata, so we cannot know whether any of these groups fall within the 1.5% incidence rate at which surveillance becomes cost effective. However, it is likely that the high-risk group does fall within that category and should undergo surveillance. The intermediate risk group has a 3-year HCC incidence of 1.5% and a 5-year incidence of 4.8%. This group probably does not get in under the 1.5% wire. That is not to say that physicians looking after these patients should not offer surveillance, only that as public policy (or from a third-party payer point of view) it may not be worthwhile. The decision to offer surveillance or not for individual patients is always a decision between the patient and the physician.
The HALT-C data on HCC risk and the stratification into risk groups requires validation in another cohort. In addition, we need to know how accurate these predictions are, that is, the sensitivity, specificity, and positive predictive values of the scores as well as the area under the receiver operating characteristic curve. This is a method to determine how good a diagnostic test really is at predicting the presence of a diagnosis. Sensitivity is plotted against 1/specificity, producing a curve above a diagonal line (Figure 1). The greater the area under the curve, the better the test. A useful test should have an AUC of ≥0.8.
In addition to independent validation and accurate description of the performance characteristics of the model, it is important to know whether the model is applicable over time, as disease progresses and as cancer risk likely increases. Does someone who is initially in a low-risk category progress to higher risk categories over time, and does this actually reflect an increased risk? If this can be confirmed, we would have an excellent tool to determine who should and who should not undergo HCC surveillance.
Until recently, there has been no way of accurately predicting patients at risk for HCC except in broad strokes, cirrhotics, patients with hepatitis B, and so on. However, the HALT-C data and data presented elsewhere looking at HCC risk in chronic hepatitis B will improve our predictive ability. Chen et al10 have developed a nomogram of HCC risk in chronic hepatitis B using data from the REVEAL study. Data such as HBV DNA concentration, HBV genotype, and age were analyzed in a similar fashion as described herein to construct a nomogram that very much resembles the cholesterol/heart attack risk nomogram developed from the Framingham study. This nomogram can be used as patients progress through the stages of their disease, but the effect of hepatitis B therapy on the cancer risk has not been factored in.
One factor in common between the hepatitis B risk nomogram and that developed by Lok et al is the contribution of smoking to cancer risk. Perhaps it is time that hepatologists and gastroenterologists jumped on the antismoking bandwagon together with pulmonologists and cardiologists, and encouraged our patients to stop smoking to reduce cancer risk.
Subjects in the HALT-C study underwent regular surveillance using ultrasonography. The surveillance interval was between 6 and 12 months. At the time the study was designed, the optimal surveillance interval was not known. More recently, data have emerged suggesting that a 6-month surveillance interval is associated with a better survival than a 12-month interval.11 No doubt as a result of surveillance, 75% of HCC patients in the HALT-C study were diagnosed as early stage disease, Model for End-Stage Liver Disease (MELD) Tumor–Node–Metastasis (TNM) T1 or T2. The MELD TNM staging is fairly commonly used to stage HCC in the United States, but was developed primarily to help assess patients with HCC for liver transplantation.12 It is not a true staging system, because it was developed to compare survival in patients with HCC and those without HCC on the transplant waiting list. It should not be used in patients who are not undergoing liver transplantation. There are several other HCC staging systems available, but the most widely accepted is the Barcelona Cancer of the Liver Clinic (BCLC) staging system,13 which combines tumor characteristics with liver function and performance status. The MELD TNM ignores liver function and performance status, appropriately; the liver would be removed at transplantation. Poor liver function is not a restriction on this modality of treatment. However, in the nontransplant setting, liver function is a major determinant of what treatment might be provided. MELD TNM should only be used for the specific purpose for which it was designed.
Regular surveillance identified 75% of HCCs at T1 or T2. We are not told what proportion were T1 or T2, which is an important distinction. The objective of HCC surveillance should be to find lesions <2 cm (T1) because the likelihood of a cure with treatment is greatest for these lesions. For example, studies have documented that complete ablation using radiofrequency is possible in almost 100% of lesions <2 cm,14, 15 but as the lesion approaches 3 cm in size, the complete ablation rate decreases. Because tumor size is a surrogate for vascular invasion and because vascular invasion is a poor prognostic sign, the smaller the HCC at diagnosis the better.
Unfortunately, in the United States HCC surveillance is not applied as widely as it is in many European and Far Eastern countries. Most gastroenterologists offer some form of surveillance to their patients,16 but few other caregivers do.17 In 1 study, only 60% of patients presenting with HCC received any form of surveillance.18 Seventeen percent of patients with HCC were known to be cirrhotic and did not receive surveillance, and 18% were not even known to be cirrhotic. When surveillance is offered, it is most frequently with periodic testing of alpha-fetoprotein,17 whereas the recommendation is not to use alpha-fetoprotein, but to rely on ultrasound.19
Finally, despite universal surveillance in the HALT-C study, only 54% of patients with HCC underwent attempt at cure with resection, transplantation, or radiofrequency ablation. In another study,18 only 35% of patients thought to be suitable for liver transplantation actually received a new liver. That the rate of liver transplantation in the HALT-C cohort is so high is no doubt a reflection of the academic nature of the centers involved in the study. However, liver transplantation is not the answer for the majority of patients with HCC, not even in the United States. There are simply not enough donor livers to go round.
In the HALT-C study, an additional small group of patients underwent chemoembolization. This is not a curative therapy. We are not given sufficient detail to know why these patients presented with such advanced disease despite surveillance. Ideally, surveillance should identify the majority of HCCs at a stage when curative treatment is possible. The hepatology group in Toronto has been providing surveillance for a large cohort of patients at risk for HCC for several years now. In our experience, it is rare not to be able to offer an attempt at curative therapy (resection, local ablation, or transplantation) for these HCC found on surveillance. In Europe and Japan 50%–60% of patients undergoing surveillance present with single lesions, usually <2 cm.20
In summary, these results from the HALT-C study have shown clearly that maintenance hepatitis C treatment does not reduce the incidence of HCC. HCC can occur at an appreciable frequency in patients with advanced fibrosis but who do not have cirrhosis. The risk factors for HCC can be identified and an algorithm has been developed that identifies patients at risk for HCC more accurately who can then be targeted for surveillance. However, the intensity of surveillance in the United States has to increase to a level that exists elsewhere in the world before HCC surveillance will result in mortality reduction.
References
1. Di Bisceglie AM, Shiffman ML, Everson GT, et al. Prolonged therapy of advanced chronic hepatitis C with peginterferon: the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) Trial. N Engl J Med. In press.
2. Lok AS, Seeff LB, Morgan TR, et al. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease. Gastroenterology. 2009;136:138–148. Abstract | Full Text | Full-Text PDF (878 KB) | CrossRef
3. Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology. 1999;117:1164–1172. Abstract | Full Text | Full-Text PDF (161 KB) | MEDLINE | CrossRef
4. Simonetti RG, Camma C, Fiorello F, et al. Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis (A case-control study). Ann Intern Med. 1992;116:97–102. MEDLINE
5. Benvegnu L, Gios M, Boccato S, et al. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut. 2004;53:744–749. MEDLINE | CrossRef
6. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463–472. Abstract | Full Text | Full-Text PDF (319 KB) | MEDLINE | CrossRef
7. Sarasin FP, Giostra E, Hadengue A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis. Am J Med. 1996;101:422–434. Abstract | Full-Text PDF (1594 KB) | MEDLINE | CrossRef
8. Arguedas MR, Chen VK, Eloubeidi MA, et al. Screening for hepatocellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis. Am J Gastroenterol. 2003;98:679–690. MEDLINE | CrossRef
9. Thompson Coon J, Rogers G, Hewson P, et al. Surveillance of cirrhosis for hepatocellular carcinoma: a cost-utility analysis. Br J Cancer. 2008;98:1166–1175. CrossRef
10. Chen CJ, Yang HI, Iloeje UH, et al. A risk function nomogram for predicting HCC in patients with chronic hepatitis b: the Reveal-HBV study. J Hepatol. 2007;46(Suppl 1):S180. Full-Text PDF (137 KB) | CrossRef
11. Kim DY, Han KH, Sang HA, et al. Semiannual surveillance for hepatocellular carcinoma improved patient survival compared to annual surveillance (Korean experience). Hepatology. 2004;6(Suppl 1):368.
12. Marsh JW, Dvorchik I, Bonham CA, et al. Is the pathologic TNM staging system for patients with hepatoma predictive of outcome?. Cancer. 2000;88:538–543.
13. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–338. MEDLINE | CrossRef
14. Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology. 2004;40:1352–1360. MEDLINE | CrossRef
15. Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice?. Hepatology. 2008;47:82–89. CrossRef
16. Chalasani N, Said A, Ness R, et al. Screening for hepatocellular carcinoma in patients with cirrhosis in the United States: results of a national survey. Am J Gastroenterol. 1999;94:2224–2229. MEDLINE | CrossRef
17. 17Davila JA, Weston A, Smalley W, et al. Utilization of screening for hepatocellular carcinoma in the United States. J Clin Gastroenterol. 2007;41:777–782. CrossRef
18. Stravitz RT, Heuman DM, Chand N, et al. Surveillance for hepatocellular carcinoma in patients with cirrhosis improves outcome. Am J Med. 2008;121:119–126. Abstract | Full Text | Full-Text PDF (380 KB) | CrossRef
19. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–1236. MEDLINE | CrossRef
20. Tanaka H, Nouso K, Kobashi H, et al. Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival. Liver Int. 2006;26:543–551. MEDLINE
Saturday, June 20, 2009
Retreating chronic hepatitis C with daily interferon
Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results
Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results
Hepatology June 6 2009
Bruce R. Bacon 1 *, Mitchell L. Shiffman 2, Flavia Mendes 3, Reem Ghalib 4, Tarek Hassanein 5, Giuseppe Morelli 6, Shobha Joshi 7, Kenneth Rothstein 8, Paul Kwo 9, Norman Gitlin 10
1Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO
2Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA
3Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL
4Liver Institute at Methodist Hospital, Dallas, TX
5Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, CA
6Division of Gastroenterology and Hepatology, University of Florida, Gainesville, FL
7Division of Gastroenterology and Hepatology, Tulane University Hospital and Clinic, New Orleans, LA
8Albert Einstein Center for Liver Disease, Philadelphia, PA
9Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN
10Division of Gastroenterology and Hepatology, Emory Crawford Long Hospital, Atlanta, GA
Up to 50% of patients with chronic hepatitis C fail to respond to initial therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). With unsuccessful viral eradication, these patients remain at risk for developing progression of their liver disease. Retreatment with PEG-IFN/RBV yields sustained virologic response (SVR) rates that are under 10%. A wholly synthetic interferon, interferon alfacon-1 or consensus interferon (CIFN) given with RBV, was evaluated in patients who failed initial PEG-IFN/RBV therapy. The intent-to-treat analysis included 487 patients; 245 received CIFN 9 ug/day and RBV, and 242 received CIFN 15 ug/day and RBV. Within this group of patients, 59.3% had documented advanced fibrosis at baseline liver biopsy (stage F3 or F4). SVR rates were 6.9% (17/245 patients) in the 9 ug group and 10.7% (26/242) in the 15 ug group. In the intent-to-treat analysis, SVR rates were higher among patients with a >2-log10 decrease in hepatitis C virus RNA during prior PEG-IFN/RBV therapy: 11% (4/38) in the 9 ug group and 23% (7/31) in the 15 ug group. Among patients with lower baseline fibrosis scores (F0-F3), SVR rates were 7.8% (15/192) in the 9 ug group and 13.1% (23/175) in the 15 ug group. In this same group of patients (F0-F3), if a >2-log10 decrease in hepatitis C virus RNA with previous PEG-IFN/RBV treatment was achieved, SVR rates improved to 10.7% and 31.6% in the 9 ug and 15 ug groups, respectively. CIFN/RBV combination retreatment was safe and well tolerated. Conclusion: Retreatment of PEG-IFN and RBV nonresponders with CIFN and RBV is safe and efficacious and can be considered a retreatment strategy for patients failing previous therapy with PEG-IFN/RBV, especially in interferon-sensitive patients with lower baseline fibrosis scores.
Article Text
Since 2001, the standard of care for patients with chronic hepatitis C has been the combination of pegylated interferon (PEG-IFN) and ribavirin (RBV).[1][2] This combination has produced sustained virologic response (SVR) rates of 50%-60% in patients infected with hepatitis C virus (HCV) genotype 1 who adhere to their therapeutic regimens and 40% in intention-to-treat populations.[1][2] However, because only about 65% of patients become HCV RNA-undetectable when treated with this regimen, more than one-third of all patients are classified as nonresponders. Some of these patients have relatively mild liver disease but may have symptoms of HCV viremia, while other patients have advanced fibrosis and are at risk for developing complications of chronic liver disease, including decompensated cirrhosis and hepatocellular carcinoma, and may require liver transplantation.[3-5]
The optimal approach to PEG-IFN/RBV nonresponders has not been well defined. Some clinicians have used the watchful waiting approach[6] and are anticipating new antiviral therapies with either protease inhibitors or polymerase inhibitors. However, it remains to be determined just how effective these new agents will be when combined with PEG-IFN and RBV in the retreatment of PEG-IFN/RBV nonresponders.[7]
Alternative therapies have included retreatment with the alternative brand of PEG-IFN not used in the initial therapy, although most results with this approach have been disappointing. Other approaches have included prolonged treatment with PEG-IFN, maintenance therapy, or the use of higher dosages of either PEG-IFN and/or RBV.[8-12] The strategy studied in the current investigation included high doses of daily consensus interferon (CIFN) (Infergen; interferon alfacon-1) 9 or 15 g/day given with RBV.
Abbreviations
AE, adverse event; bDNA, branched DNA; CIFN, consensus interferon; DIRECT, Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy; Hb, hemoglobin; HCV, hepatitis C virus; ITT, intention to treat; PEG-IFN, pegylated interferon; RBV, ribavirin; REPEAT, REtreatment with PEgasys in PATients Not Responding to Peg-Intron Therapy; SVR, sustained virologic response; TMA, transcription-mediated amplification.
Patients and Methods
This study, referred to as the DIRECT (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy) trial, was designed by the sponsor and by several of the academic investigators. The data were managed by the sponsor and the academic investigators. The sponsor performed the statistical analysis. The academic investigators were responsible for the development of the final manuscript and had unrestricted access to the data. An author involved with the design or execution of this study either wrote or edited every section of the manuscript. Both an academic author (B. R. B.) and an industry representative (Michael Beckloff, Three Rivers Pharmaceuticals, Cranberry Township, PA) attest to the completeness and accuracy of the data.
Study Design.
This was a phase 3, randomized, open-label, multicenter, U.S.-based registration trial conducted to investigate the efficacy, tolerability, and safety of daily CIFN at dosages of 9 and 15 g/day (interferon alfacon-1, Infergen; Three Rivers Pharmaceuticals, LLC, Cranberry Township, PA) administered with daily RBV (Ribasphere, Three Rivers Pharmaceuticals, LLC) compared with no treatment in patients who did not respond to prior therapy with either PEG-IFN alfa-2a or alfa-2b and RBV. The trial was divided into 2 sections: DIRECT-001 and DIRECT-002 (Fig. 1).
Patients were randomized at a 1:1:1 ratio into three study groups: CIFN 9 ug/day (group 1), 15 ug/day (group 2) plus oral RBV 1,000-1,200 mg/day (based on body weight), or a control, no-treatment group (group 3). The no-treatment group was mandated by the U.S. Food and Drug Administration in order to provide a comparison of safety for the two treatment groups. It was not anticipated that any of the patients randomized to the control group would have a spontaneous response. After 24 weeks of observation, all patients in the control group of DIRECT-001 were offered randomization into DIRECT-002 to receive CIFN 9 or 15 g/day plus RBV.
At week 24, patients who had undetectable plasma HCV RNA by branched DNA (bDNA) assay, confirmed by transcription-mediated amplification (TMA) assay, or who had a 2-log10 decrease from baseline in HCV RNA were assigned to continue therapy to week 48. Patients with a <2-log10 decrease from baseline in plasma HCV RNA (bDNA assay) were considered nonresponders and were withdrawn from treatment. At week 48, patients with undetectable plasma HCV RNA (by bDNA and TMA assays) were assigned to return for regular visits in the follow-up period (weeks 52, 60, 68, and 72) until 24 weeks after their last dose of study drug (week 72). Patients with detectable plasma HCV RNA (bDNA or TMA assay) at any time between weeks 48 and 72 were classified as relapsers.
All patients who discontinued therapy early at any time were instructed to return for a single follow-up visit 30 days after their last dose of study drug to complete early termination/discontinuation assessments. Patients who had undetectable plasma HCV RNA by bDNA and TMA assays at the time of stopping therapy or at the early termination/discontinuation visit were to return for follow-up plasma HCV RNA assessments through week 72, as long as their plasma HCV RNA levels remained undetectable by both bDNA and TMA assays. Patients who discontinued for nonresponse at weeks 12 or 24 did not undergo a follow-up HCV RNA measurement.
Patients in the no-treatment group in DIRECT-001 were given the option to enroll in DIRECT-002 under the following conditions: if they achieved a <2-log10 decrease in plasma HCV RNA at week 24 compared with baseline or if they had detectable plasma HCV RNA by bDNA or by TMA at week 48. These patients were then treated according to the same protocol followed in DIRECT-001. The results of DIRECT-001 and DIRECT-002 were pooled for the purpose of this analysis.
Patients.
Men and women were eligible for enrollment if they were chronically infected with HCV of any genotype. Chronic infection was identified based on a history of being positive for serum anti-HCV and/or HCV RNA. A liver biopsy performed within 3 years of screening must have demonstrated evidence of chronic HCV infection. Hepatic fibrosis was interpreted by local pathologists based upon the Metavir scoring system. Patients with advanced liver disease, including bridging fibrosis (F3) and cirrhosis (F4), were eligible for the study as long as they had normal liver function as evidenced by serum albumin >3.5 mg/dL, platelet count >75,000/mm3, and no prior episode of hepatic decompensation (variceal hemorrhage, hepatic encephalopathy, ascites, or hepatocellular carcinoma).
Prior nonresponse and adherence after initial therapy with PEG-IFN alfa-2a (180 ug/week) or PEG-IFN alfa-2b (1.5 ug/kg/week) plus RBV was determined via careful chart review completed by the study site principal investigator and confirmed by an external study monitor. Nonresponders had to have had a <2-log10 decrease in HCV RNA between weeks 12 and 24 or detectable HCV RNA at weeks 24 or 48. Patients were required to have had completed a minimum of 90 days between discontinuation of their prior regimen and the start of the current study medication. All patients had to have received at least 80% of the cumulative standard dosages of PEG-IFN and RBV for at least 38 weeks (80% of the planned treatment duration). Patients were excluded if this previous treatment was prematurely discontinued, dosing was interrupted, or if the dose of PEG-IFN was reduced because of noncompliance, safety, or tolerability issues (including hematologic or psychiatric side effects).
Patients were also excluded if they were pregnant or lactating women or male partners of pregnant women, or if they were not suitable candidates for enrollment or unlikely to comply with the requirements of the study in the opinion of the investigator or sponsor.
Treatment and Assessments.
Screening took place between 8 weeks and 1 day before the first day of treatment. After providing informed consent, patients were screened for inclusion criteria, underwent a physical examination, provided a baseline medical history, and had blood drawn for laboratory testing. After screening, eligible patients were randomized in a 1:1:1 ratio to receive CIFN 9 or 15 ug/day plus RBV 1,000 mg/day (body weight <75 kg) or 1,200 mg/day (body weight >75 kg) or no treatment (Fig. 1). RBV was provided as capsules containing 200 mg of active drug. An independent data monitoring committee conducted regular interim safety assessments throughout the study.
Plasma HCV RNA levels were determined first using the bDNA quantitative assay, which has a sensitivity of detection of 615 IU/mL and a reportable range of 615 to 6,920,000 IU/mL. The Bayer TMA assay, with a sensitivity of detection of 5 IU/mL, was used whenever HCV RNA levels were undetectable via bDNA assay.
Patients developing anemia, defined as hemoglobin (Hb) <10 g/dL, were managed by reducing the dose of RBV to 600 mg/day. The use of growth factors was not permitted. If the Hb increased to >10 g/dL, the RBV dose could be increased in 200-mg/day increments as tolerated according to the discretion of the site principal investigator. RBV dose was not increased after being reduced to 600 mg/day for patients with a history of cardiovascular disease whose Hb decreased by 2 g/dL or more during any 4-week period. RBV was permanently discontinued in patients whose Hb dropped below 8.5 g/dL. In those patients with a history of cardiac or cerebrovascular disease, Hb remaining below 12 g/dL after 4 weeks on a reduced dose required permanent discontinuation of RBV. Neutropenia was managed by CIFN dose reduction; in patients whose absolute neutrophil count fell to <0.75 x 109/L, starting doses of 15 ug were lowered to 9 ug and then to 6 ug, and starting doses of 9 ug were lowered to 6 ug.
Efficacy Variables.
The primary efficacy variable was the proportion of patients with SVR, defined as undetectable plasma HCV RNA by both bDNA and TMA assays at 24 weeks after the last dose of study drug. In addition, SVR was further explored for the effect of race, genotype, sex, age, baseline HCV RNA, presence/absence of cirrhosis, body weight, and previous response to PEG-IFN/RBV.
Safety and Tolerability.
All adverse events (AEs) and serious AEs were recorded for patients who received at least 1 dose of study medication (active-treatment groups) or who completed baseline assessments (no-treatment group). AEs were recorded until either 30 days after the last dose of study medication (active-treatment groups) or until the last study visit (no-treatment group). AEs were graded from 1 to 5 (1, mild; 2, moderate; 3, severe; 4, life-threatening or disabling; 5, death) based on the Common Toxicity Criteria for Adverse Events v3.0. An AE was considered a serious AE if it resulted in death, was life-threatening, required inpatient hospitalization, or resulted in persistent or significant disability or incapacity.
Statistical Methods.
At least 170 patients were needed in each of the three study groups (for a total of 510 patients) to provide an approximately 91% power to detect a difference in SVR between each of the active treatment groups and the no-treatment group. This analysis was performed using a two-sided Fisher's exact test at alpha= 0.05 significance level, with adjustment for multiple comparisons, and assumed an SVR rate of 10% for either of the active treatment groups and 1.2% for the no-treatment group. The study was not powered to detect differences between the 9 ug and the 15 ug arms.
Data were summarized and analyzed for two patient populations: the intention-to-treat (ITT) population and patients who did not receive any dose modifications. The ITT group consisted of all patients who were randomized to receive CIFN in DIRECT-001, as well as all patients from the no-treatment group in DIRECT-001 who went on to receive at least 1 dose of CIFN in DIRECT-002. Data from the ITT population were used in all efficacy and safety analyses.
Descriptive statistics were determined for continuous variables (patient counts, mean, standard deviation, median, minimum, and maximum) and categorical variables (number and percentage of patients for each category). Percentages were calculated using the number of patients without missing data as the denominator unless otherwise indicated. Calculations of virologic response (both sustained and at specific visits) used the number of ITT patients as the denominator. All statistical testing was conducted at the 0.05 level of significance using SAS software, version 8.2.
Results
Patients and Disposition.
Five hundred fifteen patients were randomized at 44 sites in the United States and Puerto Rico to receive CIFN 9 g/day plus RBV 1,000 or 1,200 mg/day (n = 171), CIFN 15 g/day plus RBV (n = 172), or no treatment (n = 172). Of the 172 patients in the no-treatment group in DIRECT-001, 144 continued on to DIRECT-002. Of these, 74 received CIFN 9 ug/day plus RBV 1,000 or 1,200 mg/day, and 70 received CIFN 15 g/day plus RBV 1,000 or 1,200 mg/day. The final ITT population included 487 patients (245 who received CIFN 9 ug/day and 242 who received CIFN 15 ug/day).
Baseline demographic and clinical characteristics of the two CIFN treatment groups are presented in Table 1. The majority of patients were male (70%) and Caucasian (64%). Of the enrolled patients, 59.3% had advanced liver disease on biopsy, including bridging fibrosis (F3; 35%) or cirrhosis (F4; 25%). In addition, 52% of patients had hepatic steatosis. The average time between biopsy sampling and study day 1 was 1.6 years. Patients included in the DIRECT trial were required to be off PEG-IFN/RBV therapy for at least 3 months prior to starting CIFN therapy. The median washout period between previous treatment and day 1 of CIFN therapy was 448 days (15 months) and 506 days (16.8 months) for the 9 ug and 15 ug groups, respectively. Sixty-eight percent of the patients had high baseline HCV RNA levels of >850,000 IU/mL. The majority of patients (79%) failed to achieve an early virologic response (at least a 2-log10 drop in HCV RNA from the pretreatment baseline) to previous PEG-IFN therapy.
Antiviral Efficacy.
By ITT analysis, pooled end-of-treatment response via TMA assay in the pooled 9 ug arm was 14.7% (36/245), with a subsequent SVR of 6.9% (17/245). In the 15 ug arm, pooled end-of-treatment response via TMA assay was 18.5% (45/242), with an SVR rate of 10.7% (26/242). Relapse rates pooled for both arms were 52% (19/36) and 42% (19/45) for the 9 ug and 15 ug groups, respectively. Post hoc analysis revealed steatosis and time to viral negativity had the most impact on relapse rates.[13] As expected, in DIRECT 001, patients in the no-treatment arm achieved a 0% SVR. In patients who did not have dose modifications, overall SVR rates were 7% in the CIFN 9 ug group and 17% in the 15 ug group (Fig. 2A,B). The SVR rates were not significantly different between the 001 and 002 arms (P = 0.818). Although the study was not powered to detect differences between the 9 ug and 15 ug groups, a post hoc analysis revealed no difference in SVR rates between the two (P = 0.141, 95% CI -8.8%-1.2%).
Patients who achieved a complete early virologic response (defined as viral negativity at week 12 via TMA assay) were more likely to demonstrate an SVR than the general study population. In the 9 ug group, 81.3% (13/16) of patients with complete early virologic response achieved SVR, whereas in the 15 ug group, 63.6% (14/22) of patients with complete early virologic response demonstrated SVR. In patients deemed slow responders (>2-log drop at week 12, viral-negative at week 24), SVR rates were 11.7% (2/17) and 35.4% (11/31) in the 9 ug and 15 ug groups, respectively. Two patients in the 9 ug arm and one patient in the 15 ug arm achieved SVR despite being viral-positive at week 24.
Patients achieving the greatest log reduction in terms of viral response to initial PEG-IFN/RBV therapy had the best likelihood of responding to retreatment with CIFN and RBV (Fig. 3A,B). Among F0-F2 patients with >2-log10 decreases in HCV RNA during their prior PEG-IFN/RBV therapy, SVR rates were 13.3% (2/15) and 30.0% (3/10) in the 9 ug and 15 ug groups, respectively. A similar trend was seen in the 15 ug arm in patients with bridging fibrosis (F3). SVR for the F0-F2 group of patients was 8.7% (9/104) in the 9ug group and 14.9% (14/94) in the 15 ug group. With patients displaying bridging fibrosis only on biopsy, overall SVR was 6.8% (6/88) and 11.1% (9/81) in the 9 and 15 ug groups, respectively. Complete SVR for noncirrhotics (F0-F3) was 7.8% (15/192) in the 9 ug group versus 13.1% (23/175) in the 15 ug group, whereas cirrhotics achieved SVR rates of 3.8% (2/53) and 4.5% (3/67) in the 9 ug and 15 ug groups, respectively. In the cirrhotic cohort, patients required at least a 1-log drop on prior therapy to benefit from retreatment with CIFN and RBV. African American patients achieved lower SVR rates than Caucasians (4.2% versus 11%, respectively). In this population, pooled analysis between the two dosage arms revealed that 35.4% of the patients had failed at least two or more prior treatment regimens, with 52.7% having obtained a <1-log drop on prior PEG-IFN/RBV therapy. In addition to this, 60.2% had dose reductions while on CIFN/RBV therapy. Finally, non-genotype 1 patients (genotype 2/3) achieved an overall SVR rate of 23.1% (3/13) and 88.8% (8/9) in the 9 ug and 15 ug groups, respectively. Further univariate predictors of response are discussed in Table 2.
Safety and Tolerability.
A total of 83.6% of patients in the 9 ug group and 71.7% of patients in the 15 ug group received at least 80% of their cumulative CIFN dose. The most common reason for early termination was treatment failure. Discontinuation due to not achieving a >2-log drop at week 24 was similar between the pooled dosage arms of 001 and 002 (32.3% versus 28.4%, P value not significant). Other reasons for treatment discontinuation are listed in Table 3.
Table 4 summarizes the most common AEs experienced by patients in the pooled 001 and 002 arms of the DIRECT trial. Most AEs were grade 2 or 3 and were more commonly related to administration of both CIFN and RBV than either drug alone. Most patients experienced at least one AE in the study. Individual AEs resulting from treatment with CIFN were typical of those reported with IFN-based therapy. All AEs were more common in the CIFN 9 and 15 ug groups than in the no-treatment group. RBV-induced hemolytic anemia occurred in 6.4% of patients. In general, most AEs were either not drug-related based on the opinion of the study site principal investigator or were thought to be related to the combination of study drugs rather than to either CIFN or RBV alone. The most common AEs leading to dose modifications in both CIFN treatment groups included neutropenia, fatigue, leukopenia, depression, nausea, myalgia, lymphopenia, and anemia. Overall, discontinuations for AEs occurred in 14% of the 9 ug group and 21% of the 15 ug group in the pooled ITT analysis.
from Jules: selected AEs in Table 4, (download pdf to see all tables): neutropenia 36% and 44% in 9 and 15 ug/day; nausea 45% i 9 & 15 ug/day; fatigue 75% and 77% in 9 and 15 ug/day; flu-like symptoms 40% & 42% in 9 and 15 ug/day;
Discussion
Retreatment of PEG-IFN/RBV nonresponders with daily CIFN/RBV resulted in an SVR rate of 6.9% with 9 ug/day CIFN and 10.7% with 15 ug/day CIFN. Patients whose doses were not reduced achieved SVR rates of 7% in the 9 ug group and 17% in the 15 ug group. These findings are consistent with a previous clinical trial demonstrating encouraging SVR rates with this higher dose of CIFN, 15 g/day.[14] The best response rate, 31.6%, was observed in noncirrhotic patients (F0-F3) who had a partial virologic response with a >2-log10 decline in HCV RNA during their previous course of PEG-IFN treatment.
These results were achieved even though the patients in the DIRECT trial had numerous poor prognostic factors for a successful response. Approximately 95% had HCV genotype 1, about 20% were African American, 68% had a high baseline HCV RNA level of >850,000 IU/mL, and almost 90% had a baseline HCV RNA level of >400,000 IU/mL. Approximately 80% had a <2-log10 decline in HCV RNA during prior treatment. Sixty percent of patients had advanced liver disease, including cirrhosis (25%) and bridging fibrosis (35%), and 52% had steatosis on biopsy. All of these factors have been shown to significantly reduce rates of SVR.
Overall, the alternative strategies for improving SVR in PEG-IFN/RBV nonresponders have not met with success. Two trials of maintenance IFN therapy were evaluated in PEG-IFN/RBV nonresponders with advanced fibrosis or cirrhosis to determine if this strategy can reduce progression to cirrhosis, complications of cirrhosis, hepatocellular carcinoma, the need for liver transplantation, and death.[8][15] The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial demonstrated that maintenance PEG-IFN alfa-2a therapy at a dose of 90 g/week over 3.5 years provided no overall benefit compared with no treatment.[8] Similar results were observed in the Colchicine versus PEG-Intron Long Term study, which compared PEG-IFN alfa-2b 0.5 g/kg/week to colchicine over 3.5 years.[15]
In the recently completed REtreatment with PEgasys in PATients Not Responding to Peg-Intron Therapy (REPEAT) trial, nonresponders and relapsers to previous PEG-IFN alfa-2b and RBV were retreated with either a standard dose of PEG-IFN alfa-2a 180 g/week or a higher dose of 360 g/week for 12 weeks, after which the dose was reduced to the standard dose.[16] Patients who became HCV RNA undetectable by week 24 were treated for either 48 or 72 weeks. In a protocol-defined primary analysis, SVR rates after retreatment with PEG-IFN alfa-2a and RBV were only 7% to 9% with 48 weeks of treatment but increased to 14% to 16% in those patients treated for 72 weeks. This increase in SVR resulted from a decline in relapse with the prolonged course of treatment. The use of the higher induction dose of PEG-IFN alfa-2a, 360 g/week, did not impact SVR rates. The SVR results of this study, using 72 weeks of PEG-IFN alfa-2a are comparable with those achieved with 48 weeks of treatment with CIFN/RBV in the DIRECT trial. Several differences exist between the REPEAT and DIRECT trials that confound direct comparison of the results. It is not known what proportion of patients in the REPEAT trial were treatment-compliant, and the number of relapse patients included in the trial is not clear.[17] Furthermore, the patients enrolled in the DIRECT trial had more advanced liver disease than those in REPEAT (60% versus 27% with stage F3-F4) and contained a higher percentage of African American patients (20% versus 10%).
Recent studies of CIFN and RBV have demonstrated a favorable response in the retreatment of PEG-IFN/RBV nonresponders.[14][18][19] Two open-label trials demonstrated SVR rates ranging from 10% to 37%, with varying CIFN regimens.[17][19] In a third study, 137 consecutive patients who did not become HCV RNA-undetectable during treatment with PEG-IFN alfa-2b with RBV were switched to CIFN 15 ug/day for 12 weeks, followed by CIFN three times weekly for an additional 36 weeks with weight-based doses of RBV.[14] SVR rates were noted in 37% of patients who remained on their full doses of therapy. The SVR rate was 27% in African Americans and 41% in Caucasian patients.
Several other new and promising therapies are under development for the treatment of chronic hepatitis C. These include RBV-like molecules, polymerase and protease inhibitors, and novel IFN formulations.[7][20] Two protease inhibitors, Boceprevir and Telaprevir, are the furthest along in development. Phase III studies are in the midst of enrollment, and these agents may gain U.S. Food and Drug Administration approval in 2 to 3 years. In addition, it has already been demonstrated that both protease and polymerase inhibitors will require the use of both IFN and RBV to achieve an SVR in treatment-naÏve or treatment-experienced patients.
In conclusion, the current study shows the benefit CIFN holds for difficult-to-treat patients with chronic hepatitis C who have failed to respond to previous treatment with PEG-IFN and RBV. The present study demonstrated that some patients with chronic hepatitis C who have failed to respond to treatment with PEG-IFN and RBV can be successfully retreated with daily CIFN and RBV. The greatest SVR rate during retreatment in the present study was observed in F0-F3 patients who had a partial virologic response during their prior course of treatment. Therefore, once-daily CIFN in combination with RBV can be considered for select patients with chronic HCV who have failed to respond to prior treatment with PEG-IFN and RBV.
Retreating chronic hepatitis C with daily interferon alfacon-1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results
Hepatology June 6 2009
Bruce R. Bacon 1 *, Mitchell L. Shiffman 2, Flavia Mendes 3, Reem Ghalib 4, Tarek Hassanein 5, Giuseppe Morelli 6, Shobha Joshi 7, Kenneth Rothstein 8, Paul Kwo 9, Norman Gitlin 10
1Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO
2Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA
3Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL
4Liver Institute at Methodist Hospital, Dallas, TX
5Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, CA
6Division of Gastroenterology and Hepatology, University of Florida, Gainesville, FL
7Division of Gastroenterology and Hepatology, Tulane University Hospital and Clinic, New Orleans, LA
8Albert Einstein Center for Liver Disease, Philadelphia, PA
9Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN
10Division of Gastroenterology and Hepatology, Emory Crawford Long Hospital, Atlanta, GA
Up to 50% of patients with chronic hepatitis C fail to respond to initial therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). With unsuccessful viral eradication, these patients remain at risk for developing progression of their liver disease. Retreatment with PEG-IFN/RBV yields sustained virologic response (SVR) rates that are under 10%. A wholly synthetic interferon, interferon alfacon-1 or consensus interferon (CIFN) given with RBV, was evaluated in patients who failed initial PEG-IFN/RBV therapy. The intent-to-treat analysis included 487 patients; 245 received CIFN 9 ug/day and RBV, and 242 received CIFN 15 ug/day and RBV. Within this group of patients, 59.3% had documented advanced fibrosis at baseline liver biopsy (stage F3 or F4). SVR rates were 6.9% (17/245 patients) in the 9 ug group and 10.7% (26/242) in the 15 ug group. In the intent-to-treat analysis, SVR rates were higher among patients with a >2-log10 decrease in hepatitis C virus RNA during prior PEG-IFN/RBV therapy: 11% (4/38) in the 9 ug group and 23% (7/31) in the 15 ug group. Among patients with lower baseline fibrosis scores (F0-F3), SVR rates were 7.8% (15/192) in the 9 ug group and 13.1% (23/175) in the 15 ug group. In this same group of patients (F0-F3), if a >2-log10 decrease in hepatitis C virus RNA with previous PEG-IFN/RBV treatment was achieved, SVR rates improved to 10.7% and 31.6% in the 9 ug and 15 ug groups, respectively. CIFN/RBV combination retreatment was safe and well tolerated. Conclusion: Retreatment of PEG-IFN and RBV nonresponders with CIFN and RBV is safe and efficacious and can be considered a retreatment strategy for patients failing previous therapy with PEG-IFN/RBV, especially in interferon-sensitive patients with lower baseline fibrosis scores.
Article Text
Since 2001, the standard of care for patients with chronic hepatitis C has been the combination of pegylated interferon (PEG-IFN) and ribavirin (RBV).[1][2] This combination has produced sustained virologic response (SVR) rates of 50%-60% in patients infected with hepatitis C virus (HCV) genotype 1 who adhere to their therapeutic regimens and 40% in intention-to-treat populations.[1][2] However, because only about 65% of patients become HCV RNA-undetectable when treated with this regimen, more than one-third of all patients are classified as nonresponders. Some of these patients have relatively mild liver disease but may have symptoms of HCV viremia, while other patients have advanced fibrosis and are at risk for developing complications of chronic liver disease, including decompensated cirrhosis and hepatocellular carcinoma, and may require liver transplantation.[3-5]
The optimal approach to PEG-IFN/RBV nonresponders has not been well defined. Some clinicians have used the watchful waiting approach[6] and are anticipating new antiviral therapies with either protease inhibitors or polymerase inhibitors. However, it remains to be determined just how effective these new agents will be when combined with PEG-IFN and RBV in the retreatment of PEG-IFN/RBV nonresponders.[7]
Alternative therapies have included retreatment with the alternative brand of PEG-IFN not used in the initial therapy, although most results with this approach have been disappointing. Other approaches have included prolonged treatment with PEG-IFN, maintenance therapy, or the use of higher dosages of either PEG-IFN and/or RBV.[8-12] The strategy studied in the current investigation included high doses of daily consensus interferon (CIFN) (Infergen; interferon alfacon-1) 9 or 15 g/day given with RBV.
Abbreviations
AE, adverse event; bDNA, branched DNA; CIFN, consensus interferon; DIRECT, Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy; Hb, hemoglobin; HCV, hepatitis C virus; ITT, intention to treat; PEG-IFN, pegylated interferon; RBV, ribavirin; REPEAT, REtreatment with PEgasys in PATients Not Responding to Peg-Intron Therapy; SVR, sustained virologic response; TMA, transcription-mediated amplification.
Patients and Methods
This study, referred to as the DIRECT (Daily-Dose Consensus Interferon and Ribavirin: Efficacy of Combined Therapy) trial, was designed by the sponsor and by several of the academic investigators. The data were managed by the sponsor and the academic investigators. The sponsor performed the statistical analysis. The academic investigators were responsible for the development of the final manuscript and had unrestricted access to the data. An author involved with the design or execution of this study either wrote or edited every section of the manuscript. Both an academic author (B. R. B.) and an industry representative (Michael Beckloff, Three Rivers Pharmaceuticals, Cranberry Township, PA) attest to the completeness and accuracy of the data.
Study Design.
This was a phase 3, randomized, open-label, multicenter, U.S.-based registration trial conducted to investigate the efficacy, tolerability, and safety of daily CIFN at dosages of 9 and 15 g/day (interferon alfacon-1, Infergen; Three Rivers Pharmaceuticals, LLC, Cranberry Township, PA) administered with daily RBV (Ribasphere, Three Rivers Pharmaceuticals, LLC) compared with no treatment in patients who did not respond to prior therapy with either PEG-IFN alfa-2a or alfa-2b and RBV. The trial was divided into 2 sections: DIRECT-001 and DIRECT-002 (Fig. 1).
Patients were randomized at a 1:1:1 ratio into three study groups: CIFN 9 ug/day (group 1), 15 ug/day (group 2) plus oral RBV 1,000-1,200 mg/day (based on body weight), or a control, no-treatment group (group 3). The no-treatment group was mandated by the U.S. Food and Drug Administration in order to provide a comparison of safety for the two treatment groups. It was not anticipated that any of the patients randomized to the control group would have a spontaneous response. After 24 weeks of observation, all patients in the control group of DIRECT-001 were offered randomization into DIRECT-002 to receive CIFN 9 or 15 g/day plus RBV.
At week 24, patients who had undetectable plasma HCV RNA by branched DNA (bDNA) assay, confirmed by transcription-mediated amplification (TMA) assay, or who had a 2-log10 decrease from baseline in HCV RNA were assigned to continue therapy to week 48. Patients with a <2-log10 decrease from baseline in plasma HCV RNA (bDNA assay) were considered nonresponders and were withdrawn from treatment. At week 48, patients with undetectable plasma HCV RNA (by bDNA and TMA assays) were assigned to return for regular visits in the follow-up period (weeks 52, 60, 68, and 72) until 24 weeks after their last dose of study drug (week 72). Patients with detectable plasma HCV RNA (bDNA or TMA assay) at any time between weeks 48 and 72 were classified as relapsers.
All patients who discontinued therapy early at any time were instructed to return for a single follow-up visit 30 days after their last dose of study drug to complete early termination/discontinuation assessments. Patients who had undetectable plasma HCV RNA by bDNA and TMA assays at the time of stopping therapy or at the early termination/discontinuation visit were to return for follow-up plasma HCV RNA assessments through week 72, as long as their plasma HCV RNA levels remained undetectable by both bDNA and TMA assays. Patients who discontinued for nonresponse at weeks 12 or 24 did not undergo a follow-up HCV RNA measurement.
Patients in the no-treatment group in DIRECT-001 were given the option to enroll in DIRECT-002 under the following conditions: if they achieved a <2-log10 decrease in plasma HCV RNA at week 24 compared with baseline or if they had detectable plasma HCV RNA by bDNA or by TMA at week 48. These patients were then treated according to the same protocol followed in DIRECT-001. The results of DIRECT-001 and DIRECT-002 were pooled for the purpose of this analysis.
Patients.
Men and women were eligible for enrollment if they were chronically infected with HCV of any genotype. Chronic infection was identified based on a history of being positive for serum anti-HCV and/or HCV RNA. A liver biopsy performed within 3 years of screening must have demonstrated evidence of chronic HCV infection. Hepatic fibrosis was interpreted by local pathologists based upon the Metavir scoring system. Patients with advanced liver disease, including bridging fibrosis (F3) and cirrhosis (F4), were eligible for the study as long as they had normal liver function as evidenced by serum albumin >3.5 mg/dL, platelet count >75,000/mm3, and no prior episode of hepatic decompensation (variceal hemorrhage, hepatic encephalopathy, ascites, or hepatocellular carcinoma).
Prior nonresponse and adherence after initial therapy with PEG-IFN alfa-2a (180 ug/week) or PEG-IFN alfa-2b (1.5 ug/kg/week) plus RBV was determined via careful chart review completed by the study site principal investigator and confirmed by an external study monitor. Nonresponders had to have had a <2-log10 decrease in HCV RNA between weeks 12 and 24 or detectable HCV RNA at weeks 24 or 48. Patients were required to have had completed a minimum of 90 days between discontinuation of their prior regimen and the start of the current study medication. All patients had to have received at least 80% of the cumulative standard dosages of PEG-IFN and RBV for at least 38 weeks (80% of the planned treatment duration). Patients were excluded if this previous treatment was prematurely discontinued, dosing was interrupted, or if the dose of PEG-IFN was reduced because of noncompliance, safety, or tolerability issues (including hematologic or psychiatric side effects).
Patients were also excluded if they were pregnant or lactating women or male partners of pregnant women, or if they were not suitable candidates for enrollment or unlikely to comply with the requirements of the study in the opinion of the investigator or sponsor.
Treatment and Assessments.
Screening took place between 8 weeks and 1 day before the first day of treatment. After providing informed consent, patients were screened for inclusion criteria, underwent a physical examination, provided a baseline medical history, and had blood drawn for laboratory testing. After screening, eligible patients were randomized in a 1:1:1 ratio to receive CIFN 9 or 15 ug/day plus RBV 1,000 mg/day (body weight <75 kg) or 1,200 mg/day (body weight >75 kg) or no treatment (Fig. 1). RBV was provided as capsules containing 200 mg of active drug. An independent data monitoring committee conducted regular interim safety assessments throughout the study.
Plasma HCV RNA levels were determined first using the bDNA quantitative assay, which has a sensitivity of detection of 615 IU/mL and a reportable range of 615 to 6,920,000 IU/mL. The Bayer TMA assay, with a sensitivity of detection of 5 IU/mL, was used whenever HCV RNA levels were undetectable via bDNA assay.
Patients developing anemia, defined as hemoglobin (Hb) <10 g/dL, were managed by reducing the dose of RBV to 600 mg/day. The use of growth factors was not permitted. If the Hb increased to >10 g/dL, the RBV dose could be increased in 200-mg/day increments as tolerated according to the discretion of the site principal investigator. RBV dose was not increased after being reduced to 600 mg/day for patients with a history of cardiovascular disease whose Hb decreased by 2 g/dL or more during any 4-week period. RBV was permanently discontinued in patients whose Hb dropped below 8.5 g/dL. In those patients with a history of cardiac or cerebrovascular disease, Hb remaining below 12 g/dL after 4 weeks on a reduced dose required permanent discontinuation of RBV. Neutropenia was managed by CIFN dose reduction; in patients whose absolute neutrophil count fell to <0.75 x 109/L, starting doses of 15 ug were lowered to 9 ug and then to 6 ug, and starting doses of 9 ug were lowered to 6 ug.
Efficacy Variables.
The primary efficacy variable was the proportion of patients with SVR, defined as undetectable plasma HCV RNA by both bDNA and TMA assays at 24 weeks after the last dose of study drug. In addition, SVR was further explored for the effect of race, genotype, sex, age, baseline HCV RNA, presence/absence of cirrhosis, body weight, and previous response to PEG-IFN/RBV.
Safety and Tolerability.
All adverse events (AEs) and serious AEs were recorded for patients who received at least 1 dose of study medication (active-treatment groups) or who completed baseline assessments (no-treatment group). AEs were recorded until either 30 days after the last dose of study medication (active-treatment groups) or until the last study visit (no-treatment group). AEs were graded from 1 to 5 (1, mild; 2, moderate; 3, severe; 4, life-threatening or disabling; 5, death) based on the Common Toxicity Criteria for Adverse Events v3.0. An AE was considered a serious AE if it resulted in death, was life-threatening, required inpatient hospitalization, or resulted in persistent or significant disability or incapacity.
Statistical Methods.
At least 170 patients were needed in each of the three study groups (for a total of 510 patients) to provide an approximately 91% power to detect a difference in SVR between each of the active treatment groups and the no-treatment group. This analysis was performed using a two-sided Fisher's exact test at alpha= 0.05 significance level, with adjustment for multiple comparisons, and assumed an SVR rate of 10% for either of the active treatment groups and 1.2% for the no-treatment group. The study was not powered to detect differences between the 9 ug and the 15 ug arms.
Data were summarized and analyzed for two patient populations: the intention-to-treat (ITT) population and patients who did not receive any dose modifications. The ITT group consisted of all patients who were randomized to receive CIFN in DIRECT-001, as well as all patients from the no-treatment group in DIRECT-001 who went on to receive at least 1 dose of CIFN in DIRECT-002. Data from the ITT population were used in all efficacy and safety analyses.
Descriptive statistics were determined for continuous variables (patient counts, mean, standard deviation, median, minimum, and maximum) and categorical variables (number and percentage of patients for each category). Percentages were calculated using the number of patients without missing data as the denominator unless otherwise indicated. Calculations of virologic response (both sustained and at specific visits) used the number of ITT patients as the denominator. All statistical testing was conducted at the 0.05 level of significance using SAS software, version 8.2.
Results
Patients and Disposition.
Five hundred fifteen patients were randomized at 44 sites in the United States and Puerto Rico to receive CIFN 9 g/day plus RBV 1,000 or 1,200 mg/day (n = 171), CIFN 15 g/day plus RBV (n = 172), or no treatment (n = 172). Of the 172 patients in the no-treatment group in DIRECT-001, 144 continued on to DIRECT-002. Of these, 74 received CIFN 9 ug/day plus RBV 1,000 or 1,200 mg/day, and 70 received CIFN 15 g/day plus RBV 1,000 or 1,200 mg/day. The final ITT population included 487 patients (245 who received CIFN 9 ug/day and 242 who received CIFN 15 ug/day).
Baseline demographic and clinical characteristics of the two CIFN treatment groups are presented in Table 1. The majority of patients were male (70%) and Caucasian (64%). Of the enrolled patients, 59.3% had advanced liver disease on biopsy, including bridging fibrosis (F3; 35%) or cirrhosis (F4; 25%). In addition, 52% of patients had hepatic steatosis. The average time between biopsy sampling and study day 1 was 1.6 years. Patients included in the DIRECT trial were required to be off PEG-IFN/RBV therapy for at least 3 months prior to starting CIFN therapy. The median washout period between previous treatment and day 1 of CIFN therapy was 448 days (15 months) and 506 days (16.8 months) for the 9 ug and 15 ug groups, respectively. Sixty-eight percent of the patients had high baseline HCV RNA levels of >850,000 IU/mL. The majority of patients (79%) failed to achieve an early virologic response (at least a 2-log10 drop in HCV RNA from the pretreatment baseline) to previous PEG-IFN therapy.
Antiviral Efficacy.
By ITT analysis, pooled end-of-treatment response via TMA assay in the pooled 9 ug arm was 14.7% (36/245), with a subsequent SVR of 6.9% (17/245). In the 15 ug arm, pooled end-of-treatment response via TMA assay was 18.5% (45/242), with an SVR rate of 10.7% (26/242). Relapse rates pooled for both arms were 52% (19/36) and 42% (19/45) for the 9 ug and 15 ug groups, respectively. Post hoc analysis revealed steatosis and time to viral negativity had the most impact on relapse rates.[13] As expected, in DIRECT 001, patients in the no-treatment arm achieved a 0% SVR. In patients who did not have dose modifications, overall SVR rates were 7% in the CIFN 9 ug group and 17% in the 15 ug group (Fig. 2A,B). The SVR rates were not significantly different between the 001 and 002 arms (P = 0.818). Although the study was not powered to detect differences between the 9 ug and 15 ug groups, a post hoc analysis revealed no difference in SVR rates between the two (P = 0.141, 95% CI -8.8%-1.2%).
Patients who achieved a complete early virologic response (defined as viral negativity at week 12 via TMA assay) were more likely to demonstrate an SVR than the general study population. In the 9 ug group, 81.3% (13/16) of patients with complete early virologic response achieved SVR, whereas in the 15 ug group, 63.6% (14/22) of patients with complete early virologic response demonstrated SVR. In patients deemed slow responders (>2-log drop at week 12, viral-negative at week 24), SVR rates were 11.7% (2/17) and 35.4% (11/31) in the 9 ug and 15 ug groups, respectively. Two patients in the 9 ug arm and one patient in the 15 ug arm achieved SVR despite being viral-positive at week 24.
Patients achieving the greatest log reduction in terms of viral response to initial PEG-IFN/RBV therapy had the best likelihood of responding to retreatment with CIFN and RBV (Fig. 3A,B). Among F0-F2 patients with >2-log10 decreases in HCV RNA during their prior PEG-IFN/RBV therapy, SVR rates were 13.3% (2/15) and 30.0% (3/10) in the 9 ug and 15 ug groups, respectively. A similar trend was seen in the 15 ug arm in patients with bridging fibrosis (F3). SVR for the F0-F2 group of patients was 8.7% (9/104) in the 9ug group and 14.9% (14/94) in the 15 ug group. With patients displaying bridging fibrosis only on biopsy, overall SVR was 6.8% (6/88) and 11.1% (9/81) in the 9 and 15 ug groups, respectively. Complete SVR for noncirrhotics (F0-F3) was 7.8% (15/192) in the 9 ug group versus 13.1% (23/175) in the 15 ug group, whereas cirrhotics achieved SVR rates of 3.8% (2/53) and 4.5% (3/67) in the 9 ug and 15 ug groups, respectively. In the cirrhotic cohort, patients required at least a 1-log drop on prior therapy to benefit from retreatment with CIFN and RBV. African American patients achieved lower SVR rates than Caucasians (4.2% versus 11%, respectively). In this population, pooled analysis between the two dosage arms revealed that 35.4% of the patients had failed at least two or more prior treatment regimens, with 52.7% having obtained a <1-log drop on prior PEG-IFN/RBV therapy. In addition to this, 60.2% had dose reductions while on CIFN/RBV therapy. Finally, non-genotype 1 patients (genotype 2/3) achieved an overall SVR rate of 23.1% (3/13) and 88.8% (8/9) in the 9 ug and 15 ug groups, respectively. Further univariate predictors of response are discussed in Table 2.
Safety and Tolerability.
A total of 83.6% of patients in the 9 ug group and 71.7% of patients in the 15 ug group received at least 80% of their cumulative CIFN dose. The most common reason for early termination was treatment failure. Discontinuation due to not achieving a >2-log drop at week 24 was similar between the pooled dosage arms of 001 and 002 (32.3% versus 28.4%, P value not significant). Other reasons for treatment discontinuation are listed in Table 3.
Table 4 summarizes the most common AEs experienced by patients in the pooled 001 and 002 arms of the DIRECT trial. Most AEs were grade 2 or 3 and were more commonly related to administration of both CIFN and RBV than either drug alone. Most patients experienced at least one AE in the study. Individual AEs resulting from treatment with CIFN were typical of those reported with IFN-based therapy. All AEs were more common in the CIFN 9 and 15 ug groups than in the no-treatment group. RBV-induced hemolytic anemia occurred in 6.4% of patients. In general, most AEs were either not drug-related based on the opinion of the study site principal investigator or were thought to be related to the combination of study drugs rather than to either CIFN or RBV alone. The most common AEs leading to dose modifications in both CIFN treatment groups included neutropenia, fatigue, leukopenia, depression, nausea, myalgia, lymphopenia, and anemia. Overall, discontinuations for AEs occurred in 14% of the 9 ug group and 21% of the 15 ug group in the pooled ITT analysis.
from Jules: selected AEs in Table 4, (download pdf to see all tables): neutropenia 36% and 44% in 9 and 15 ug/day; nausea 45% i 9 & 15 ug/day; fatigue 75% and 77% in 9 and 15 ug/day; flu-like symptoms 40% & 42% in 9 and 15 ug/day;
Discussion
Retreatment of PEG-IFN/RBV nonresponders with daily CIFN/RBV resulted in an SVR rate of 6.9% with 9 ug/day CIFN and 10.7% with 15 ug/day CIFN. Patients whose doses were not reduced achieved SVR rates of 7% in the 9 ug group and 17% in the 15 ug group. These findings are consistent with a previous clinical trial demonstrating encouraging SVR rates with this higher dose of CIFN, 15 g/day.[14] The best response rate, 31.6%, was observed in noncirrhotic patients (F0-F3) who had a partial virologic response with a >2-log10 decline in HCV RNA during their previous course of PEG-IFN treatment.
These results were achieved even though the patients in the DIRECT trial had numerous poor prognostic factors for a successful response. Approximately 95% had HCV genotype 1, about 20% were African American, 68% had a high baseline HCV RNA level of >850,000 IU/mL, and almost 90% had a baseline HCV RNA level of >400,000 IU/mL. Approximately 80% had a <2-log10 decline in HCV RNA during prior treatment. Sixty percent of patients had advanced liver disease, including cirrhosis (25%) and bridging fibrosis (35%), and 52% had steatosis on biopsy. All of these factors have been shown to significantly reduce rates of SVR.
Overall, the alternative strategies for improving SVR in PEG-IFN/RBV nonresponders have not met with success. Two trials of maintenance IFN therapy were evaluated in PEG-IFN/RBV nonresponders with advanced fibrosis or cirrhosis to determine if this strategy can reduce progression to cirrhosis, complications of cirrhosis, hepatocellular carcinoma, the need for liver transplantation, and death.[8][15] The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis trial demonstrated that maintenance PEG-IFN alfa-2a therapy at a dose of 90 g/week over 3.5 years provided no overall benefit compared with no treatment.[8] Similar results were observed in the Colchicine versus PEG-Intron Long Term study, which compared PEG-IFN alfa-2b 0.5 g/kg/week to colchicine over 3.5 years.[15]
In the recently completed REtreatment with PEgasys in PATients Not Responding to Peg-Intron Therapy (REPEAT) trial, nonresponders and relapsers to previous PEG-IFN alfa-2b and RBV were retreated with either a standard dose of PEG-IFN alfa-2a 180 g/week or a higher dose of 360 g/week for 12 weeks, after which the dose was reduced to the standard dose.[16] Patients who became HCV RNA undetectable by week 24 were treated for either 48 or 72 weeks. In a protocol-defined primary analysis, SVR rates after retreatment with PEG-IFN alfa-2a and RBV were only 7% to 9% with 48 weeks of treatment but increased to 14% to 16% in those patients treated for 72 weeks. This increase in SVR resulted from a decline in relapse with the prolonged course of treatment. The use of the higher induction dose of PEG-IFN alfa-2a, 360 g/week, did not impact SVR rates. The SVR results of this study, using 72 weeks of PEG-IFN alfa-2a are comparable with those achieved with 48 weeks of treatment with CIFN/RBV in the DIRECT trial. Several differences exist between the REPEAT and DIRECT trials that confound direct comparison of the results. It is not known what proportion of patients in the REPEAT trial were treatment-compliant, and the number of relapse patients included in the trial is not clear.[17] Furthermore, the patients enrolled in the DIRECT trial had more advanced liver disease than those in REPEAT (60% versus 27% with stage F3-F4) and contained a higher percentage of African American patients (20% versus 10%).
Recent studies of CIFN and RBV have demonstrated a favorable response in the retreatment of PEG-IFN/RBV nonresponders.[14][18][19] Two open-label trials demonstrated SVR rates ranging from 10% to 37%, with varying CIFN regimens.[17][19] In a third study, 137 consecutive patients who did not become HCV RNA-undetectable during treatment with PEG-IFN alfa-2b with RBV were switched to CIFN 15 ug/day for 12 weeks, followed by CIFN three times weekly for an additional 36 weeks with weight-based doses of RBV.[14] SVR rates were noted in 37% of patients who remained on their full doses of therapy. The SVR rate was 27% in African Americans and 41% in Caucasian patients.
Several other new and promising therapies are under development for the treatment of chronic hepatitis C. These include RBV-like molecules, polymerase and protease inhibitors, and novel IFN formulations.[7][20] Two protease inhibitors, Boceprevir and Telaprevir, are the furthest along in development. Phase III studies are in the midst of enrollment, and these agents may gain U.S. Food and Drug Administration approval in 2 to 3 years. In addition, it has already been demonstrated that both protease and polymerase inhibitors will require the use of both IFN and RBV to achieve an SVR in treatment-naÏve or treatment-experienced patients.
In conclusion, the current study shows the benefit CIFN holds for difficult-to-treat patients with chronic hepatitis C who have failed to respond to previous treatment with PEG-IFN and RBV. The present study demonstrated that some patients with chronic hepatitis C who have failed to respond to treatment with PEG-IFN and RBV can be successfully retreated with daily CIFN and RBV. The greatest SVR rate during retreatment in the present study was observed in F0-F3 patients who had a partial virologic response during their prior course of treatment. Therefore, once-daily CIFN in combination with RBV can be considered for select patients with chronic HCV who have failed to respond to prior treatment with PEG-IFN and RBV.
Monday, June 15, 2009
Correction it is at 1425 Madison ave
Corrction my Liver Support Group is at 1425 Madison ave not 1485 Madison ave
Liver Support Group
I will be attending my home group again this Wed. the 17th at 6PM and it is open to all, hope to see you there. It will be held at 1485 Madison ave off of East 98st New York City in room 11-84 on the 11th floor. Need directions email me.
Scott Weinstein
Scott Weinstein
To have an open loving heart
There is one power though that is demonstrated in such
a motivated life and it is this: to have an open loving heart,
and to allow that love to flow from that heart.
For 'a loving heart is the beginning of knowledge.'
A heart such as that will open the whole mind and will make
the intellect alert, for it has been written that 'the heart
sees further than the head.' It knows no boundaries and it
refuses to be hemmed in.
When the head says 'no', the heart says 'yes'. A life ruled
by the heart is a free spirit that follows the pathway of faith
and resists the power of fear.
The heart is a powerful warrior when at times the head can
be a slinking coward.
Develop the heart as well as the head and you will know
victory like you have never known before.
But before you speak, keep silent unless you have something
to say.
Spend your time in reading and learning first and foremost
and then and only then, as you equip yourself, your time
will come when you will speak.
But whatever you do, do what you say and say what you do.
Unknown
a motivated life and it is this: to have an open loving heart,
and to allow that love to flow from that heart.
For 'a loving heart is the beginning of knowledge.'
A heart such as that will open the whole mind and will make
the intellect alert, for it has been written that 'the heart
sees further than the head.' It knows no boundaries and it
refuses to be hemmed in.
When the head says 'no', the heart says 'yes'. A life ruled
by the heart is a free spirit that follows the pathway of faith
and resists the power of fear.
The heart is a powerful warrior when at times the head can
be a slinking coward.
Develop the heart as well as the head and you will know
victory like you have never known before.
But before you speak, keep silent unless you have something
to say.
Spend your time in reading and learning first and foremost
and then and only then, as you equip yourself, your time
will come when you will speak.
But whatever you do, do what you say and say what you do.
Unknown
Telaprevir Improves HCV Clearance in Resistant Patients
Telaprevir Improves HCV Clearance in Resistant Patients
By Todd Neale, Staff Writer, MedPage Today
Published: June 03, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
CHICAGO, June 3 -- The investigational protease inhibitor telaprevir, added to standard hepatitis C (HCV) treatment, produced a sustained virologic response in about half of patients who had previously failed with conventional therapy, a phase IIb trial showed.
Action Points
■Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Patients who received telaprevir, peginterferon, and ribavirin had higher response rates than those who received peginterferon and ribavirin alone, the current standard treatment, according to Adrian Di Bisceglie, M.D., of Saint Louis University.
The group of patients who received telaprevir and peginterferon, but not ribavirin had less of a benefit than those who received all three drugs, he reported at Digestive Disease Week here.
Because there is no existing standard of care for patients who fail to respond to standard treatment for HCV, he said, "I personally believe this . . . represents a new paradigm for how we will treat nonresponders in the future."
About three million people in the U.S. are infected with HCV, and about half will be able to clear the virus with peginterferon and ribavirin, according to Dr. Di Bisceglie.
Conducted at 53 centers, the PROVE3 (Protease Inhibition for Viral Evaluation) study follows the PROVE1 and PROVE2 studies, which evaluated the effect of telaprevir in treatment-naive patients. (See EASL: Telaprevir Shows Promise of Shortened Hepatitis C Therapy and AASLD: Telaprevir Yields Good Response in Combo Therapy for HCV)
PROVE3 involved 453 patients with HCV genotype 1, the most common in the U.S. All had failed prior courses of treatment, either by having no virologic response, by relapsing after completing successful treatment, or by having the virus re-emerge before the end of treatment.
The patients were randomized to four treatment arms with varying duration of treatment with telaprevir, peginterferon, and ribavirin:
•12 weeks of all three drugs followed by 12 weeks of standard treatment
•24 weeks of all three drugs followed by 24 weeks of standard treatment
•24 weeks of telaprevir and peginterferon, but no ribavirin
•24 weeks of placebo plus standard treatment followed by 24 weeks of standard treatment (control)
The median age of the patients was 51 and about two-thirds were male. All four groups were well-matched according to baseline characteristics.
The primary endpoint was sustained virologic response 24 weeks after the end of each treatment regimen.
All three telaprevir groups were superior to placebo in the percentage of patients who had a sustained virologic response at follow-up:
•51% in patients who received 12 weeks of telaprevir (P<0.001)
•52% in those who received telaprevir for 24 weeks along with standard treatment (P<0.001)
•23% in those who did not receive ribavirin (P=0.035)
•14% in the controls
Similar benefits were seen at four weeks, indicating a rapid virologic response, and immediately at the end of treatment.
Some patients relapsed between the end of treatment and the follow-up, 24 weeks later. The relapse rates were 30% and 13% in the two groups that received telaprevir plus standard treatment and 53% in both the group that did not receive ribavirin and the controls.
Notably, almost 40% of patients who had not responded to treatment at all before the study showed a sustained virologic response at follow-up in the two groups that received all three drugs (P<0.001 for both). That compared with only 9% of the controls.
Response rates of 69% and 76% were seen among prior relapsers (P<0.001 for both), with the higher rate occurring in those who received 48 weeks of standard treatment in addition to 24 weeks of telaprevir.
There was no difference in response rates between patients with and without cirrhosis.
"It appears that telaprevir is able to overcome this and other traditional poor response factors," Dr. Di Bisceglie said.
The most common adverse events in groups receiving telaprevir were fatigue, nausea, headache, rash, itching, anemia, and gastrointestinal side effects, only some of which were severe enough to result in discontinuation.
The dosing regimen involving 24 weeks of all three drugs, followed by 24 weeks of peginterferon and ribavirin, is currently being evaluated in a phase III trial dubbed REALIZE.
Dr. Di Bisceglie said FDA approval for telaprevir is about two years away. Telaprevir and a similar drug, boceprevir, appear to be the closest to approval.
Patients with significant liver disease should receive treatment with peginterferon and ribavirin right away, he said, but patients who have previously failed a course of treatment might think about waiting for these drugs to hit the market.
"These drugs are coming and not that far away, and it may be better to be waiting with our nonresponders for better treatment," he said.
The study was supported by Tibotec and Vertex Pharmaceuticals, co-developers of telaprevir.
Dr. Di Bisceglie reported no conflicts of interest.
Primary source: Digestive Disease Week
Source reference:
Di Bisceglie A, et al "SVR results of PROVE3, a phase 2b clinical trial assessing safety and efficacy of telaprevir in hepatitis C genotype-1-infected patients with prior non-response, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy" DDW 2009; Abstract 751d.
By Todd Neale, Staff Writer, MedPage Today
Published: June 03, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news
CHICAGO, June 3 -- The investigational protease inhibitor telaprevir, added to standard hepatitis C (HCV) treatment, produced a sustained virologic response in about half of patients who had previously failed with conventional therapy, a phase IIb trial showed.
Action Points
■Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Patients who received telaprevir, peginterferon, and ribavirin had higher response rates than those who received peginterferon and ribavirin alone, the current standard treatment, according to Adrian Di Bisceglie, M.D., of Saint Louis University.
The group of patients who received telaprevir and peginterferon, but not ribavirin had less of a benefit than those who received all three drugs, he reported at Digestive Disease Week here.
Because there is no existing standard of care for patients who fail to respond to standard treatment for HCV, he said, "I personally believe this . . . represents a new paradigm for how we will treat nonresponders in the future."
About three million people in the U.S. are infected with HCV, and about half will be able to clear the virus with peginterferon and ribavirin, according to Dr. Di Bisceglie.
Conducted at 53 centers, the PROVE3 (Protease Inhibition for Viral Evaluation) study follows the PROVE1 and PROVE2 studies, which evaluated the effect of telaprevir in treatment-naive patients. (See EASL: Telaprevir Shows Promise of Shortened Hepatitis C Therapy and AASLD: Telaprevir Yields Good Response in Combo Therapy for HCV)
PROVE3 involved 453 patients with HCV genotype 1, the most common in the U.S. All had failed prior courses of treatment, either by having no virologic response, by relapsing after completing successful treatment, or by having the virus re-emerge before the end of treatment.
The patients were randomized to four treatment arms with varying duration of treatment with telaprevir, peginterferon, and ribavirin:
•12 weeks of all three drugs followed by 12 weeks of standard treatment
•24 weeks of all three drugs followed by 24 weeks of standard treatment
•24 weeks of telaprevir and peginterferon, but no ribavirin
•24 weeks of placebo plus standard treatment followed by 24 weeks of standard treatment (control)
The median age of the patients was 51 and about two-thirds were male. All four groups were well-matched according to baseline characteristics.
The primary endpoint was sustained virologic response 24 weeks after the end of each treatment regimen.
All three telaprevir groups were superior to placebo in the percentage of patients who had a sustained virologic response at follow-up:
•51% in patients who received 12 weeks of telaprevir (P<0.001)
•52% in those who received telaprevir for 24 weeks along with standard treatment (P<0.001)
•23% in those who did not receive ribavirin (P=0.035)
•14% in the controls
Similar benefits were seen at four weeks, indicating a rapid virologic response, and immediately at the end of treatment.
Some patients relapsed between the end of treatment and the follow-up, 24 weeks later. The relapse rates were 30% and 13% in the two groups that received telaprevir plus standard treatment and 53% in both the group that did not receive ribavirin and the controls.
Notably, almost 40% of patients who had not responded to treatment at all before the study showed a sustained virologic response at follow-up in the two groups that received all three drugs (P<0.001 for both). That compared with only 9% of the controls.
Response rates of 69% and 76% were seen among prior relapsers (P<0.001 for both), with the higher rate occurring in those who received 48 weeks of standard treatment in addition to 24 weeks of telaprevir.
There was no difference in response rates between patients with and without cirrhosis.
"It appears that telaprevir is able to overcome this and other traditional poor response factors," Dr. Di Bisceglie said.
The most common adverse events in groups receiving telaprevir were fatigue, nausea, headache, rash, itching, anemia, and gastrointestinal side effects, only some of which were severe enough to result in discontinuation.
The dosing regimen involving 24 weeks of all three drugs, followed by 24 weeks of peginterferon and ribavirin, is currently being evaluated in a phase III trial dubbed REALIZE.
Dr. Di Bisceglie said FDA approval for telaprevir is about two years away. Telaprevir and a similar drug, boceprevir, appear to be the closest to approval.
Patients with significant liver disease should receive treatment with peginterferon and ribavirin right away, he said, but patients who have previously failed a course of treatment might think about waiting for these drugs to hit the market.
"These drugs are coming and not that far away, and it may be better to be waiting with our nonresponders for better treatment," he said.
The study was supported by Tibotec and Vertex Pharmaceuticals, co-developers of telaprevir.
Dr. Di Bisceglie reported no conflicts of interest.
Primary source: Digestive Disease Week
Source reference:
Di Bisceglie A, et al "SVR results of PROVE3, a phase 2b clinical trial assessing safety and efficacy of telaprevir in hepatitis C genotype-1-infected patients with prior non-response, viral breakthrough or relapse to peginterferon-alfa-2a/b and ribavirin therapy" DDW 2009; Abstract 751d.
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