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Several Key Pegasys Studies at EASL 2008
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Reported by Jules Levin
43rd EASL
April 23-27, 2008
Milan, Italy
Type of response to prior pegylated interferon alfa-2b (12kd)/ribavirin predicts subsequent response to re-treatment with peginterferon alfa-2a (40kd) (pegasys)/ribavirin (copegus): results from the repeat study
Patrick Marcellin1, Bradley Freilich2, Pietro Andreone3, Adrian DiBisceglie4, Carlos Eduardo Brandao5, K. Rajender Reddy6, Antonio Craxi7,
Antonio Olveira8, GerlindeTeuber9, Diethelm Messinger10, Greg Hooper11, Matei Popescu12, Donald Jensen13
1Service d'Hepatologie and INSERM U773/CRB3, 2Liver and Pancreas Institute of Kansas City, Kansas City, MO, USA, 3Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy,
4Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA, 5Hospital Universitario Gaffree e Guinle, Rio de Janeiro, Brazil, 6Division of Gastroenterology, University of
Pennsylvania, PA, USA, 7GI and Liver Unit, University of Palermo, Palermo, Italy, 8Hospital La Paz, Madrid, Spain, 8Department of Internal Medicine, J.W. Goethe University Hospital, Frankfurt, Germany, 10IST, Mannheim,
Germany, 11Roche, Welwyn, UK, 12Roche, Basel, Switzerland, 13Center for Liver Diseases, University of Chicago Hospitals, Chicago, IL, USA
INTRODUCTION
In the REPEAT study, 16% of non-responders to pegylated interferon alfa-2b (12KD) plus ribavirin achieved a sustained virological response (SVR) after 72 weeks of re-treatment with peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS).
Patients with undetectable hepatitis C virus (HCV) RNA at week 12 of re-treatment had the highest probability of achieving an SVR with 72 weeks treatment (57% in patients randomised to 72 weeks versus 35% in patients randomised to 48 weeks).
The objective of this retrospective exploratory analysis is to investigate the magnitude of the on-treatment virological response during prior treatment with pegylated interferon alfa-2b (12KD) plus ribavirin and it's association, if any, with the week 12 response during re-treatment with peginterferon alfa-2a (40KD) plus ribavirin.
CONCLUSIONS
In the REPEAT study, the extent of the virological response to prior treatment with pegylated interferon alfa-2b (12KD) plus ribavirin was predictive of achieving undetectable or unquantifiable HCV RNA at week 12 of re-treatment with peginterferon alfa-2a (40KD) plus ribavirin.
More than 50% of patients who had a ≥2 log drop in HCV RNA but remained HCV RNA-positive at week 12 of a first course of treatment with pegylated interferon alfa-2b (12KD) achieved undetectable or unquantifiable HCV RNA at week 12 of re-treatment with peginterferon alfa-2a (40KD) plus ribavirin. Even null-responders at week 12 of previous treatment (patients with a <2 log drop), had a significant chance of clearing virus at week 12 when re-treated with peginterferon alfa-2a (40KD) plus ribavirin.
When considering re-treatment of patients with a previous nonresponse, these data will allow physicians to more accurately assess the likelihood of achieving a week 12 virological response with peginterferon alfa-2a (40KD) plus ribavirin, and hence a chance for SVR.
Patients older than 50 years infected with HCV genotype 1 and with favourable prognostic factors achieve high rates of sustained virological response (SVR) when treated with peginterferon alfa-2a (40KD) (PEGASYS) and ribavirin (COPEGUS)
K. Rajender Reddy1, Diethelm Messinger2, Matei Popescu3, Stephanos J. Hadziyannis4
1Hospital of the University of Pennsylvania, Philadelphia, USA; 2IST GmbH, Mannheim, Germany; 3Roche, Basel, Switzerland; 4Henry Dunant Hospital, Athens, Greece.
Introduction
Treatment outcomes for patients infected with chronic hepatitis C virus (HCV) depend upon viral factors such as HCV genotype and viral load. Patient factors which also play a role include age, gender, race, the presence of fibrosis/cirrhosis and drug adherence. A greater proportion of HCV patients today are of older age.
Older patients may have an array of negative prognosis factors, such as advanced fibrosis/cirrhosis, due to the longer duration of their disease, and thus do not respond to pegylated interferon therapy as well as younger patients. Furthermore, older patients often experience reductions in drug exposure on account of their lower tolerance to therapy, which impairs their rates of sustained virological response (SVR, defined as undetectable HCV RNA 24 weeks post-treatment). Early treatment would circumvent this problem by preventing negative prognostic factors from accruing. However, the question of how best to treat the increasing number of existing patients of older age still remains. To address this issue, data from HCV genotype 1 patients enrolled in two large phase III studies of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) were analysed to assess the impact of baseline and on-treatment factors on SVR in older versus younger patients.
Conclusions
High SVR rates can be achieved by subgroups of HCV genotype 1 patients >50 years, such as those with a low baseline viral load or without cirrhosis.
Ribavirin dose reductions as a result of laboratory abnormalities are more common in patients >50 years.
High exposure to peginterferon alfa-2a (40KD) and/or ribavirin during treatment must be maintained in order to achieve high SVR rates. This is particularly important for patients of older age. Additional monitoring is recommended when adjusting the dose of ribavirin in older patients; small decrements are preferable in order to maintain the highest tolerable ribavirin exposure. High SVR rates were achieved by all patients with an RVR or cEVR. Assessment of virological response at weeks 4 and 12 is thus a convenient tool to predict SVR rates for patients of any age.
In conclusion, older HCV patients are an important population and a full treatment course with pegylated interferon plus ribavirin should be considered based on their on-treatment week 4 and week 12 response.
Patients >50 years had a significantly lower overall SVR rate (39%) than patients ≤50 years (53%). The higher relapse rate in the older patients accounted for this difference (Table 2).
However, those patients >50 years with either an RVR or cEVR achieved similar SVR rates (83% and 61%, respectively) to younger patients (Figure 1).
Higher SVR rates were observed in patients >50 years who had low baseline viral loads (<400 000 IU/mL) or did not have cirrhosis (57% and 44%, respectively) compared with those with high viraemia or cirrhosis (34% and 29%, respectively).
A lower mean cumulative peginterferon alfa-2a exposure was recorded for patients of older age (6868 ug in patients >50 years vs 7230 ug in patients ≤50 years [p=0.0986]), whilst mean cumulative ribavirin exposure was significantly lower in older patients (252 g vs 304 g for younger patients [p<0.0001]).
Figure 2 shows the impact of dose modifications on SVR rates for all patients.
- A ribavirin exposure of <60% of target was experienced by a greater proportion of older patients than those ≤50 years (38% vs 22%, respectively). This was reflected in the dramatically reduced SVR rates in these patients compared with the SVR rate of those who experienced higher ribavirin exposure levels. Despite this, slightly higher SVR rates were observed in the older patient group than for younger patients at the lowest ribavirin exposure level. Of note, a ribavirin exposure of 60-<80% of target correlated with lower SVR rates in patients >50 years.
- Lower SVR rates were also associated with dose reductions in peginterferon alfa-2a to <80% target exposure, particularly in older patients: SVR rates in older patients fell to 17-18% when exposed to <80% of the target peginterferon alfa-2a
level, compared with 53% when exposure levels were ≥80%. However, as with ribavirin, slightly better responses were observed in the older compared with younger patients at the lowest peginterferon alfa-2a exposure level.
Factors predictive of SVR in patients >50 years were identified by univariate and MLR analyses.
- The MLR with baseline factors (n=131) showed that low baseline viral load (p=0.007), high ALT ratio (p=0.011) and cirrhosis (p=0.048) were significantly associated with higher SVR rates among all patients >50 years old.
- Because patients prematurely discontinuing peginterferon alfa-2a and/or ribavirin prior to the scheduled end of therapy would be expected to have lower rates of SVR and lower cumulative exposure to study drugs, the MLR including baseline and on-treatment factors was restricted to patients completing scheduled treatment (n=96). In this sub-group of patients, cumulative ribavirin exposure and cumulative peginterferon alfa-2a exposure were significant predictors of SVR as well as achievement of RVR or cEVR (Table 3).
The proportion of patients who completed their treatment was similar in both groups (76% and 73% for patients of ≤50 and >50 years, respectively). Similarly, the rate of patient withdrawal from treatment due to any adverse event did not depend on age (11% and 12%, respectively).
Conversely, more patients >50 years had ribavirin dose reductions due to laboratory abnormalities (mainly anaemia) than those of younger age (43% vs 17%).
Easy to assess on-treatment parameters correlate with degree of virological response after 12 weeks of treatment:
results from the REPEAT study
Donald Jensen1, Bradley Freilich2, Pietro Andreone3, Adrian DiBisceglie4, Carlos Eduardo Brandao5, K. Rajender Reddy6, Antonio Craxi7,
Antonio Olveira8, Gerlinde Teuber9, Diethelm Messinger10, Greg Hooper11, Matei Popescu 12, Andreas Tietz 12 and Patrick Marcellin13
1Center for Liver Diseases, University of Chicago Hospitals, Chicago, IL, USA, 2Liver and Pancreas Institute of Kansas City, Kansas City, MO, USA, 3Department of Internal Medicine, and Gastroenterology, University of
Bologna, Bologna, Italy, 4Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA, 5Hospital Universitario Gaffree e Guinle, Rio de Janeiro, Brazil, 6Division of Gastroenterology, University of Pennsylvania, Philadelphia, USA, 7GI and Liver Unit, University of Palermo, Palermo, Italy, 8Hospital La Paz, Madrid, Spain, 9Department of Internal Medicine, J.W. Goethe University Hospital, Frankfurt, Germany, 10IST, Mannheim, Germany, 11Roche, Welwyn, UK, 12Roche, Basel, Switzerland, 13Service d'Hepatologie and INSERM U773/CRB3, H™pital Beaujon, Clichy, France
INTRODUCTION
The international randomized REPEAT study showed that an extended 72-week treatment regimen of peginterferon alfa-2a (40KD) (PEGASYS) plus ribavirin (COPEGUS) significantly increases the rate of sustained virological response (SVR) in non-responders to pegylated interferon alfa-2b (12KD) plus ribavirin (16% vs 8% with the standard 48-week regimen; p=0.0006).[1] Fixed-dose induction with peginterferon alfa-2a (40KD) did not enhance SVR rates in the overall analysis.
Patients with undetectable hepatitis C virus (HCV) RNA (<50 IU/mL) at week 12 of re-treatment for 72 weeks had 57% probability of achieving an SVR with 72 weeks.
The objective of this retrospective exploratory analysis is to examine correlations between baseline and on-treatment parameters and the extent of the virological response at week 12 of treatment.
RESULTS
Baseline and week 12 virological response data were available for 850 of the 942 (90.2%) patients enrolled in the REPEAT trial, of whom 157 (18.5%) had complete viral suppression and 186 (21.9%) had a null response at week 12.
The mean cumulative dose of peginterferon and ribavirin relative to the target dose was high, with >90% for all response groups.
Predictors of complete viral suppression at week 12 are shown in Figure 2.
- Baseline predictors include infection with HCV genotype 2-6 (p<0.0001 vs genotype 1), assignment to peginterferon alfa-2a (40KD) 360 ug/week (p=0.0014 vs assignment to 180 ug/week), higher neutrophil count (p=0.0075), lower body weight (p=0.0459), younger age (p=0.0104), lower serum HCV RNA level (p<0.0001) and non-black race (p=0.0488 vs black race). On-treatment predictors include greater decreases in serum alanine aminotransferase level (p=0.0055) and platelet count (p=0.313) to week 12.
Predictors of a null response at week 12 are shown in Figure 3.
- Patients more likely to have a null response were those assigned to an initial peginterferon alfa-2a (40KD) dose of 180 ug/week (p=0.0075 vs assignment to 360 ug/week) and those with a higher body mass index (p=0.0016). On-treatment predictors of a null response include receipt of a lower cumulative dose of peginterferon alfa-2a (40 KD) (p=0.0122), and lesser decreases in body weight, haemoglobin level and platelet count to week 12 (all p<0.0001).
CONCLUSIONS
Null response was associated with a less marked decline in platelets, haemoglobin and body weight during the first 12 weeks of treatment in REPEAT, which is suggestive of a blunted systemic response to peginterferon alfa-2a (40KD).
Similar observations have been reported in a retrospective analysis of data collected during the 20-week lead-in phase of the HALT-C trial.[2]
Fixed-dose induction therapy with peginterferon alfa-2a (40KD) 360 ug/week increased the likelihood of complete viral suppression at week 12 in REPEAT.
This indicates that higher doses of peginterferon alfa-2a may be able to overcome the blunted interferon response in non-responder patients. Further studies are warranted to explore how the increased likelihood of complete viral suppression at week 12 achieved with fixed-dose induction therapy with peginterferon alfa-2a (40 KD) can be translated into higher SVR rates
Low-dose peginterferon alfa-2a (40KD) (PEGASYS) to treat hepatitis c-infected, end-stage renal disease patients undergoing haemodialysis: final study results
M Peck-Radosavljevic,1 J Boletis,2 F Besisik,3 M Lścia Ferraz,4 L Alric,5 D Samuel,6 D Messinger7 and H Cheinquer8
1University of Vienna, Vienna, Austria; 2Laiko Hospital, Athens, Greece; 3Istanbul University, Istanbul, Turkey; 4Sao Paulo Hospital, Sao Paulo, Brazil; 5Hospital Purpan, Toulouse, France;
6H™pital Paul Brousse, Villejuif, France; 7IST GmbH, Mannheim, Germany; 8Hospital da Santa Casa de Misericordia de Porto Alegre, Porto Alegre, Brazil
INTRODUCTION
There is a higher prevalence of hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD) than in the general population. These patients have reduced graft survival and patient survival. Therefore eradication of HCV increases the eligibility for kidney transplantation and improves outcomes. Conventional interferon has been reported to be poorly tolerated in patients with
ESRD on haemodialysis and ribavirin is contraindicated in patients with creatinine clearance <50 mL/min. Recently, results from a clinical trial of peginterferon alfa-2a (135 ug/week) plus ribavirin (200 mg/day) have shown that this regimen was effective among HCV-infected patients awaiting renal transplantation. However, 74% (26/35) of these patients developed severe anemia (despite low starting doses of ribavirin) and required their epoetin-alfa dose to be increased. Despite this approach several patients required a further dose reduction of ribavirin to 200 mg on every other day. Consequently monotherapy with pegylated interferon may be a more appropriate and manageable therapy for these individuals in routine clinical practice.
We conducted a multinational, randomised, open-label study, in which the efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS) 135 ug/week and 90 ug/week were evaluated in patients with ESRD.
METHODS
Non-cirrhotic, interferon-naive patients with chronic HCV infection and ESRD undergoing haemodialysis were eligible.
Patients were randomized in 8 countries to peginterferon alfa-2a 135 ug/week or 90 ug/week for 48 weeks, stratified by country and genotype (1 vs non-1).
The primary end-point was sustained virological response (SVR), defined as undetectable serum HCV RNA (<50 IU/mL) after 24-weeks of treatment-free follow-up using the Roche AMPLICOR HCV Test v2.0 (<50 IU/ml).
Pre-specified secondary efficacy end-points included the magnitude of virological response at treatment week 12, 24 and 48.
All randomized patients who received at least one dose of study medication were included in the efficacy and safety analysis. The Cochran-Mantel-Haenszel (CMH) procedure, stratified by HCV genotype (1/non-1) and country, was applied to estimate the treatment effect across the various strata. Corresponding odds-ratio (OR) and 95% confidence intervals (CI) were also determined.
RESULTS
A total of 85 patients in 8 countries were randomized to study drug of whom 81 received at least one dose of peginterferon alfa-2a 135 ug/week (n=38) or peginterferon alfa-2a 90 ug/week (n=43). Demographic and baseline characteristics were generally similar between the two groups (Table 1).
The rates of SVR among all patients, those with a baseline HCV RNA <400 000 IU/mL and the sub-set of patients infected with genotype 1 are presented in Figure 1. Overall a similar proportion of patients randomized to peginterferon alfa-2a 135 ug/week or 90 ug/week achieved an SVR 39.5% (15/38) and 34.9% (15/43) respectively (odds ratio 1.22 [95% CI 0.49-3.06]; P=0.6746).
Patients with HCV RNA <400 000 IU/mL had high rates of SVR with similar rates among patients randomized to peginterferon alfa-2a 135 ug/week (61%) or 90 ug/week (57%).
Among patients treated with peginterferon alfa-2a 135 ug/week those with an undetectable HCV RNA (<50 IU/mL) at week 12 had a high chance of SVR (61%) whereas only one patient (8%) who had detectable HCV RNA at week 12 achieved an SVR (Figure 2a).
Similar results were evident among patients treated with peginterferon alfa-2a 90 ug/week, those with an undetectable HCV RNA (<50 IU/mL) at week 12 had a high chance of SVR (88%) whereas only one patient (4%) who had detectable HCV RNA at week 12 achieved an SVR (Figure 2b).
The rates of serious adverse events and laboratory abnormalities were generally similar between the two groups (Table 2).
Overall 6 patients died during the course of the study of which 4 were the reason for withdrawal from the study. Three of the deaths were considered related to study treatment, all randomised to peginterferon alfa-2a 135 ug/week.
- A 28-year old male with a history of hypertension died of haemorrhagic stroke that was considered related to study drugs as well as to his underlying hypertension according to the investigator.
- A 49-year old female presented with fever and respiratory symptoms during haemodialysis and subsequently died of complications related to pneumonia, sepsis and multi-organ failure that was considered related to study drugs according to the investigator.
- A 59-year old male with a history of hypertension and hypertrophic cardiomyopathy died of haemorrhagic stroke that was considered related to study drugs according to the investigator as well as to his underlying medical condition.
CONCLUSIONS
Patients receiving peginterferon alfa-2a monotherapy at a dose of either 135 or 90 ug/week for 48 weeks achieved rates of SVR in the region of 35-39%.
Patients with a low baseline viral load (<400 000 IU/mL) achieved high rates of SVR with peginterferon alfa-2a 135 ug/week (61%) or 90 ug/week (57%).
The positive predictive value of an undetectable HCV RNA at week 12 on SVR were 61% and 88% in the 135 and 90 ug/week arms, respectively. The negative predictive value of a detectable HCV RNA at week 12 on SVR were 92% and 96% in the 135 and 90 ug/week arms, respectively. Thus early on-treatment markers of virological response can be used to either reinforce adherence to continued therapy among patients achieving an undetectable HCV RNA at week 12 or to consider discontinuation of treatment among patients who fail to achieve an undetectable HCV RNA at week 12.
In general treatment was well tolerated with no consistent dose-rated toxicities.
Patients with ESRD infected with HCV should be considered for treatment with peginterferon alfa-2a.
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