Douglas D. Dalke, Jeremiah Donovan, Mark Mailliard, Howard P. Monsour
Treatment options for patients having previously failed combination therapy with interferon and ribavirin for chronic hepatitis C (CHC) are limited but these patients may be candidates for retreatment with pegylated interferon based therapy. Because outcome data for retreatment with pegylated interferon plus ribavirin are lacking, we compared the effect of two different doses of peginterferon alfa-2b with ribavirin in patients with CHC having failed previous combination therapy with interferon and ribavirin.
A total of 196 patients were randomized to receive either 0.50 or 1.5 mcg/kg/week of peginterferon alfa-2b plus ribavirin 800 mg/day for 48 weeks. The primary endpoint was sustained viral response (SVR) defined as undetectable 24 week post treatment hepatitis C virus (HCV) RNA.
SVR occurred in 30% of the patients enrolled in the higher treatment group but in only 6% in the lower treatment group (P=0.04). Patients receiving the larger dose of peginterferon with ribavirin were more likely to achieve SVR. When overall SVR is stratified according to previous treatment response, relapsers (R) faired significantly better than nonresponders.
In patients with CHC who have failed to respond, or relapsed, following treatment with interferon and ribavirin, retreatment with peginterferon alfa-2b and ribavirin is a reasonable option.
Carroll B. Leevy, G. Ramaraju, Chris P. Chalmers, Lawrence M. Blatt
Treatment of HCV with PEG IFN alpha 2 and ribavirin leads to a sustained virologic response in approx. 50% of patients. Response can be predicted at week 12 by assessment of serum HCV RNA concentrations. Patients who have not had at least a 2 log10 drop in HCV RNA by week 12, have a 97-100% chance of not responding to therapy. These patients have been termed Null Responders to PEG IFN alpha 2 therapies. Preclinical studies have demonstrated strong synergistic antiviral and immunomodulatory effects of the combination of IFN alfacon-1 and IFN gamma-1b in preclinical models of HCV. Given these data, we initiated a pilot study in 32 Null Responders to pegylated IFN alpha 2 + ribavirin.
Thirty two patients were retreated with IFN alfacon-1, 15 mcg SQ daily, and IFN gamma-1b 50 mcg SQ TIW for 48 weeks. All patients had previously received PEG IFN alpha 2 and ribavirin for 12 weeks, and did not have at least a 2- log10 drop in HCV RNA (Null Responders). Following the initiation of combination therapy with IFN-alfacon-1 and IFN-gamma 1b, serum HCV RNA was assessed at week 12 and 24 weeks to determine EVR and will be assessed at weeks 48 and 72 to determine viral kinetics and sustained virologic responses. Patients were monitored for constitutional symptoms and bloods were collected for serum chemistries and hematological evaluations.
At the end of 24 weeks of therapy, 47% of these Null Responder patients had undetectable HCV RNA (RT-PCR), Assessment of the quantitative changes in HCV RNA from baseline demonstrated that these patients as a group had a significant reduction from a mean viral load at baseline. Twenty-five percent of patients required Filgrastim for reductions in ANC. Hemoglobin levels in all patients returned to normal range while patients were receiving IFN alfacon-1 and IFN-g 1b. No growth factors were used.
Retreatment of PEG IFN alpha 2 + ribavirin Null Responders with the combination of IFN-alfacon-1 and IFN-gamma 1b is well tolerated and preliminary analysis of early virologic response suggest that this treatment may be of potential benefit in these difficult to treat patients.
Further study in a larger patient population is now being initiated. The author also stated that a phase II dose study has been launched.
N. Zeng, C. K. Cohen, P. Schwartz, Rudra Rai
The combination therapy of peginterferon(PEG-IFN) and ribavirin (RBV) is the standard of care for patients with Hepatitis C infection. Preliminary data from the HALT-C trial indicates efficacy of PEG-IFN alfa2a/RBV in achieving sustained virologic responses (SVR) in patients with prior treatment. There is no available literature that examines the efficacy of PEG-IFN alfa2a in patients that were prior non-responders to PEG-IFN alfa2b.
In the past 18 months, 55 consecutive patients (M=28/F=25; Age 21-61 years) with HCV infection were treated with PEG-IFN alfa2a 180mcg QW and RBV 1000mg (<75kg) or 1200 mg (>75 mg) PO QD x 48 weeks. Patient characteristics were: Genotype 1a/ 1b: 89% (N=49); genotype 2: 3.6% (N=2); genotype 3: 7% (N=4) and genotype 4: 2% (N=1). There were 15 patients (27%) that were prior non-responders to PEG-IFN alfa2b/RBV, with detectable HCV RNA on at least 6 months of previous treatment. All 15 patients were genotype 1 with an average viral load of 3,100,000 IU/ml. In addition, 7 patients were non-responders to prior treatment with standard IFN alfa2b/RBV, and the rest (N=33) were naive to previous treatment. Virologic assessment was performed by ultrasensitive assays (Heptimax/Quest Diagnostics <5 IU/mL or Quantasure/Labcorp <5 IU/mL).
Overall virologic response rate at 24 weeks on therapy was observed in 17/33 (51%) naive patient, 3/7(43%) non-responders to standard IFN/RBV and 6/15 (40%) non-responders to PEG-IFN alfa2b /RBV. Of the PEG-IFN alfa2b/RBV non-responders (N=15) that failed re-treatment with PEG-IFN alfa2a/RBV, 33% (3/9) were African American (AA), 55% (5/9) were male, 77% (7/9) and had a null response (NR) (<1 log drop) to prior treatment. In comparison, PEG-IFN alfa2b/RBV non-responders that subsequently responded to PEG-IFN alfa2a/RBV, only 16% (1/6) were AA, 50% (3/6) were male, 67% (4/6) had NR to prior treatment. All 9 patients were genotype 1 and had comparable viral loads (p=NS). Forty eight week data below.
The results of patients who were prior non-responders to Peg-Intron with subsequent Pegasys re-treatment.
Total number 9 6
Male 8 4
Female 1 2
White 5 4
Black 4 1
Bodywieght 186.8 172.3
ALT 52.4 (60.1) 27.2 (28)
AST 48.3 (40.5) 47.2 (27.2)
Prior nonresponders to IFN/RBV viral load
Before treatment 2,804,000 2411,200
24 weeks 1,765,200 < or = 10
1 8 (88.9%) 5 (83.3%)
2 0 0
3 0 1 (16.7)
4 1 (11.1%) 0
Preliminary 24 and 48 week virologic assays using ultrasensitive HCV RNA assays suggests significant differences in viral kinetic responses to subsequent treatment with PEG-IFN alfa2a/RBV. African American and male patients demonstrated a trend towards non-response to subsequent treatment with PEG-IFN alfa 2a/RBV. Further studies are ongoing to determine SVR, but a 40% efficacy at week 24 and 33% at week 48 in achieving undetectable HCV RNA level appears promising in providing further treatment options for a select group of patients.
Stephan Kaiser, Holger Hass, Michael Gregor
Treatment with pegylated interferon alfa (PEG IFN) and ribavirin (RBV) has an efficacy in chronic hepatitis C patients with sustained response rates of about 50%. However, response in genotype 1 patients with high viral load is considerably lower with SR rates of 29-34%. Furthermore, studies with peginterferons have shown low response rates of only 6-12% in the treatment of combination therapy nonresponders. In contrast, other trials have suggested improved response rates using consensus interferon (interferon alfacon-1, CIFN) in genotype 1 / high viral load patients as well as previous combination therapy non-responders.
In this study, the efficacy of CIFN induction therapy followed by CIFN / RBV combination treatment in PEG IFN combination therapy non-responders was evaluated.
60 patients have been included. All patients had elevated ALT-values and were viremic, with 93% having genotype 1, the remaining genotype 4. Histologic confirmation of inflammation and fibrosis was obtained in all patients with grading and staging according to Ishak, where 29 patients showed cirrhosis. Patients were either treated with CIFN at a dosage of 9 ug QD for 16 weeks or with CIFN 27 ug QD for 4 weeks, followed by 12 weeks of CIFN 18 ug QD. Thereafter, treatment was continued in all groups with CIFN 9 ug QD with RBV (at 10-15 mg/kg/d) for another 34-56 weeks, depending when the PCR result became negative ensuring a negative PCR result for at least 48 weeks under therapy. No growth factors were used.
The results show that after the initial 24 weeks of CIFN / RBV therapy, a negative PCR was observed in 46% in the CIFN 9 ug / RBV group (n=25), and in 52% of the CIFN 27/18 ug / RBV group (n=25). End-of-treatment rates were 42% and 48%, respectively. For the patients already in follow-up the sustained viral response rates were 23% and 27%. Due to side effects CIFN had to be reduced in 4 patients and discontinued in 2 patients. The SVR rates will be reported when all patients complete the 24 week follow-up period.
CIFN daily dosing/induction therapy together with subsequent RBV combination therapy thus shows sustained viral response rates in about one quarter of previous peginterferon combination therapy non-responders. If these response rates can be reproduced in a larger multicenter trial being conducted at present, an effective treatment will be in place for this difficult-to-treat patient group.
Charles D. Howell, Lennox S. Jeffers, Sylvia Hu, Juan Carlos Lopez-Talavera
Interferon, alone or combined with RBV, is less effective for CHC genotype 1 infection in Black Americans than White Americans. Racial differences in tolerability and adherence to therapy have not been studied.
To evaluate the safety and tolerability of peginterferon alfa-2a (40KD)/RBV and the impact of adherence on sustained virological response (SVR) in Black patients with genotype 1 infection.
Treatment-naive Blacks with HCV genotype 1 and elevated ALT levels were enrolled and treated with peginterferon alfa-2a (40KD) 180 mcg/wk plus RBV 1000 or 1200 mg/day for 48 wks, with 24 wks of treatment-free follow-up.
· A total of 78 Black patients participated in the study.
§ Sixty-two of 78 (80%) patients completed 48 weeks of treatment; and 60 of 78 (77%) returned after week 72
§ Using an intention-to-treat (ITT) analysis, 20 patients (26%, 95 CI 16-35) achieved SVR.
§ The incidence of most AEs was generally higher among whites than blacks across all body systems. Several AEs, including injection site erythema, vomiting, alopecia, and dry skin, were experienced more frequently by white patients than by black patients. One black patient died as a result of an acute anterior myocardial infarction about 180 days after the last dose of the study drug.
· Hematologic Parameters
§ Changes in laboratory parameters observed in this study were consistent with the known effects of Pegasys and Copegus. Decreases in hemotologic parameters were observed in both racial groups during treatment.
§ Blacks had lower mean baseline ANCs and nadirs than the whites. There was a sharp decrease in mean ANCs during the first week of therapy for black patients.
§ While 40% (31/78) of black patients experienced grade 3 or 4 neutropenia, only 19% (5/28) of white patients had a similar decline in ANC. No patient with neutropenia developed a serious infection. In blacks, as well as whites, the ANC returned to baseline values shortly after completion of treatment.
§ The trend in lymphocyte counts during treatment was similar to that in neutrophils.
§ Race-related differences were not observed for anemia and thrombocytopenia. Regarding these parameters, low percentages of black (5%) patients experienced a decrease in hemoglobin levels to <8.5 g/dL. No patient had treatment discontinued for anemia.
§ A reduction in platelet counts to less than 50x109/L occurred in 2 black patients with no related serious complications.
§ The growth factors erythropoietin and G-CSF were each administrated to only 3 (4%) of black patients.
· Serious Adverse Events
§ Of the two serious infections that occurred in black patients during the study, neither was considered to be related to Pegasys/Copegus treatment. One infection occurred well after treatment was completed (During week 70). Neither serious infection was associated with severe neutropenia or lymphocytopenia (defined as a neutrophil or lymphocyte count <0.5 x 109/L.
· Dose Modifications
§ The percentage of patients who had their dose of Pebays withheld or reduced because of an adverse event or laboratory abnormality was 46% (36 of 78) among blacks and 29% (8 of 28) among whites. For all except 4 black patients who completed treatment, the cumulative dose of Pegasys was >80% of the intended dose, and reductions were transient. Two of the 4 patients had an SVR. The dose of Copegus was modified as the result of an AE or laboratory abnormality for 40% (31 of 78) of blacks compared to 46% (13 of 28) for whites. Likewise, dose modifications for Copegus were transient in most cases.
§ The most common reason for modifications of the Pegasys for the Pegasys dosage was Neutropenia (37%; 29 of 78), while anemia was most frequent reason for modification of Copegus dose (24%; 19 of 78).
§ Overall 18 of 78 (23%) black patients withdrew from the study prior to week 72. Of those, 8 failed to return for follow-up. 4 withdrew consent, 1 was discontinued due to protocol violation, and 1 was discontinued due to insufficient therapeutic response. The percentage of patients who were discontinued prematurely for AEs or laboratory abnormalities by the investigator was 5% (4 of 78) among blacks and 18% (5 of 28) among whites. Two of the 4 black patients discontinued because of neutropenia. Other reasons for discontinuation were insufficient therapeutic response, failure/refusal to return, and protocol violation.
· Exposure and treatment outcome
§ Most of the patients who received, <60% of the planned doses for each drug were those who were terminated early from treatment.
· Therapy with Pegasys plus Copegus was effective in inducing an SVR in 26% of black patients. This is the highest response to combination therapy yet reported in the black population.
· No new safety concerns regarding Pegasys plus Copegus therapy emerged among black HCV genotype 1 patients. In fact, for several adverse events, black patients reported fewer episodes than white patients.
· Our data support the conclusions drawn pivotal studies of combination treatment that SVR is more likely in patients with HCV genotype 1 who complete 48 weeks of treatment and receive the full doses of both Pegasys and Copegus.