Elderly patients are at greater risk of cytopenia during antiviral therapy for hepatitis C

Department of Medicine, McGill University Health Centre, Montreal, Quebec Correspondence: Dr Marc Deschênes, McGill University Health Centre, Liver Transplant Program, 687 avemie des Pins, Room 2.28, Montreal, Quebec H3A 1A1.Telephone 514-843-1616, fax 514-843-1421, e-mail marc.deschenes@muhc.mcgill.ca Received for publication June 16, 2005. Accepted January 16, 2006 CG Nudo, P Wong, N Hilzenrat, M Deschênes. Elderly patients are at greater risk of cytopenia during antiviral therapy for hepatitis C. Can J Gastroenterol 2006;20(9):589-592.


METHODS
The charts of patients treated for chronic HCV at Royal Victoria Hospital (Montreal, Quebec) and Jewish General Hospital (Montreal, Quebec) were reviewed.Patients were defined as elderly if they were 60 years or older.The elderly group was compared with control patients, younger than 60 years of age, who were attending and treated at the clinics.An attempt was made to match patients based on sex, treating physician, prescribed treatment and prescribed treatment duration.Patients with HIV coinfection were not included in the analysis.The data recorded included end of treatment response (ETR), sustained virological response (SVR), adverse events, dose modification and withdrawal of therapy.All patients begun therapy from October 1996 to September 2002.The choice of drug therapy (IFN monotherapy, IFN and RBV, or PEG-IFN and RBV) was based on the therapy that was available at the time of treatment initiation and the choice of the treating physician.The treating physician decided the prescribed treatment duration.
ETR was defined as a negative qualitative HCV RNA test using the polymerase chain reaction (PCR) at the end of therapy (HCV PCR, Roche Kit [USA]).SVR was defined as a negative HCV RNA test using PCR after 24 weeks of completion of therapy.Clinically significant anemia, thrombocytopenia and neutropenia were considered to have occurred if patients developed grade 2 or greater cytopenia as defined by the Common Toxicity Criteria of the National Cancer Institute (USA) (15).Treating physicians treated laboratory abnormalities and adverse events by reducing drug doses according to manufacturer's instructions or by discontinuing therapy.

Statistical analysis
Statistical analysis was performed using GraphPad Quickcals Software (GraphPad Software Inc, USA).The Fisher's exact test was used to compare the incidence of ETR, SVR, laboratory abnormality events, adverse events, incidence of dose modification and incidence of withdrawal of therapy between the two groups.Student's t test was used to compare the mean laboratory values before and after therapy between the two groups.P≤0.05 was considered statistically significant.

RESULTS
Table 1 lists the patient's baseline characteristics.There was no significant difference in baseline characteristics between the two groups except for age and lower hemoglobin and platelet levels in the elderly group.A higher proportion of young patients had stage 2 fibrosis or equivalent (16)(17)(18).There was no difference in the proportion of elderly patients with stage 3 and 4 fibrosis compared with the young group (73.3% versus 53.7%, P=0.14).There was no difference in treatment drugs and viral genotype between the elderly and young group.
Of all patients attending the HCV clinics, 20% of the elderly patients and 33% of young patients were treated.Five physicians were involved in the treatment of the patients in the HCV clinics.There was no difference in distribution of patients among physicians.The first physician treated five young and five elderly patients, the second physician treated six young and four elderly, the third physician treated seven young and six elderly, the fourth physician treated 18 young and 13 elderly and the fifth physician treated five young and two elderly.Of these 30 elderly patients, 10% received IFN monotherapy, 70% received a combination of IFN/RBV therapy and 20% received a combination of PEG-IFN/RBV therapy.
The 30 elderly patients were compared with 41 young control patients.There was no significant difference in ETR (46.7% versus 65.8%, P=0.11) and SVR (33.3% versus 51.2%, P=0.13) between the two groups.
The rate of early termination of therapy in the elderly group was 53.3% and it was 34.1% in the young group (P=0.17).Adverse events were the most common reason for discontinuing  RBV Ribavirin therapy (Table 2).The rate of dose reduction of therapy in the elderly group was 43.3% compared with 29.3% in the young group.The elderly had a significantly higher rate of dose reduction of therapy, 40% versus 6% (P=0.031),due to laboratory abnormalities (anemia, thrombocytopenia and neutropenia).None of the physicians used growth factors to treat cytopenias.All patients reported common adverse events (Table 3), although the younger group reported an overall higher rate of events than the elderly group (4.46 events per patient versus 2.9 events per patient, P<0.001).A significantly higher number of younger patients reported depression, myalgias and irritability.There were no adverse cardiovascular events reported.
Both treatment groups had significant and similar drops in blood counts with therapy.The mean drops in blood counts were 31.6 g/L and 31 g/L for hemoglobin, 2.0×10 9 /L and 1.6×10 9 /L for neutrophils, and 47×10 9 /L and 36×10 9 /L for platelets, for the group younger than 60 years and the group 60 years or older, respectively (Table 4).Although no young patients developed grade 2 or higher thrombocytopenia, 10% of the elderly patients developed grade 2 (50×10 9 /L to 74×10 9 /L) and grade 3 (10×10 9 /L to 49×10 9 /L) thrombocytopenia with therapy.
The elderly group had a significantly higher overall rate of laboratory abnormalities than the younger group (0.93 events per patient versus 0.488 events per patient, P=0.01).

DISCUSSION
In the present comparison of young (younger than 60 years) and elderly (60 years or older) patients treated with IFN-based therapy for HCV, we found that elderly patients with chronic HCV can be treated successfully.The elderly patients tolerated therapy well and reported fewer side effects than the younger patients.However, they were at greater risk for developing cytopenias while on treatment.
The elderly patients had a trend toward a higher rate of premature discontinuation of therapy, which was not statistically significant (53.3% versus 34.1%, P=0.17) (Table 2).These rates are higher than previously reported rates of premature treatment termination.Earlier trials using standard IFN and RBV therapy have reported a 20% discontinuation rate (4,5).Fried et al (19) reported 10% discontinuation for PEG-IFN and RBV therapy and 11% discontinuation for standard IFN and RBV.In another study (2), 14% and 13% had discontinuation of therapy for PEG-IFN and standard IFN, respectively.These lower rates of discontinuation are likely to be a reflection of strict selection of patients who are more likely to have adhered to therapy.The results of the present study are thus more generalizable to real patient populations.All of these studies demonstrated that the most common reason for termination of therapy was adverse events, as was demonstrated in the present study.
The elderly group also had a trend toward a higher incidence of dose reduction of therapy due to all causes, which was not statistically significant (43.3% versus 29.9%).The elderly did have a significantly higher rate of dose reductions due to laboratory abnormalities (40% versus 6%, P=0.031).The rates are comparable with previously published rates.Previous studies (19) have demonstrated that dose reductions were required in 32% of patients treated with PEG-IFN and 27% in those treated with standard IFN, with laboratory abnormalities being the most common reason for dose reduction.In another study (2), dose modifications were required at a frequency of 42% for adverse events and 27% for laboratory abnormalities with PEG-IFN therapy.The rate was 34% for adverse events and 21% for laboratory abnormalities with standard IFN (2).
Both the younger and elderly group had significant and similar drops in blood counts with therapy.However, patients    The younger patients reported a higher incidence of adverse events (4.46 per patient versus 2.9 per patient).Despite this, treating physicians more often prematurely discontinued therapy in elderly patients for adverse events, 30% of elderly patients versus 12.2% of younger patients.This may be explained by the fact that the elderly patients may have had more severe adverse events or that the treating physician was more reluctant to continue therapy in an elderly patient with symptoms than in a younger patient.Despite a trend toward a higher incidence of premature treatment termination in the elderly group (53.3% versus 34.1%), they did not have a significantly lower rate of ETR and SVR.It is feasible that a lower rate of discontinuation of therapy in elderly patients may translate into a higher rate of ETR and SVR in this group.McHutchison et al (20) have already described that patients who receive more than 80% of the IFN regimen, more than 80% of RBV and more than 80% of the expected duration of therapy have a higher rate of SVR.The present study is the first to specifically look at chronic HCV treatment response in the elderly.The rates of ETR and SVR in the control group studied are similar to previously published response rates (2,19).We expected the treatment response in the elderly group to be significantly lower than that of the control group.This was based on the assumption that the elderly patients likely had HCV for a longer period of time and it is well established that the duration of the disease is a prognostic factor for response to therapy.This is evident in the fact that the elderly patients had a trend toward a higher rate of grade 3 and 4 fibrosis compared with the younger patients (73.3% versus 53.7%, P=0.14).Despite this and a documented higher rate of treatment termination, laboratory abnormalities and dose modifications in the elderly group, we found no significant difference in ETR and SVR when compared with the control group.This finding may be due to the fact that we had a small number of patients and did not have enough power to detect a difference.
Our data have demonstrated that elderly patients can be successfully treated with IFN-based therapy for HCV.They are more at risk for developing cytopenias while on treatment, thus, close monitoring of blood counts is necessary.Judicious dose modification and use of growth factors may improve treatment success.Larger studies are needed to confirm these findings and determine whether SVR differs in the elderly.
Risk of cytopenia during antiviral therapyCan J Gastroenterol Vol 20 No 9 September 2006 591

TABLE 4
The higher rate of grade 2 or greater cytopenias may be explained by the lower level of baseline hemoglobin, neutrophils and platelets in the elderly group.Our data show that such patients are at greater risk for cytopenias and, thus, require close monitoring and appropriate adjustment of therapy when cytopenias do occur.