Treatment of Hepatitis C in Hemodialysis Patients with Pegylated Interferon α-2a as Monotherapy

Abstract

Background. The high prevalence of hepatitis C virus (HCV) infection in hemodialysis patients is of great concern because they have a higher rate of mortality than HCV-negative hemodialysis patients. The aim of the study was to evaluate the efficacy and safety of pegylated interferon α-2a monotherapy in hemodialysis patients with chronic HCV infection. Methods. Fourteen dialysis patients with chronic HCV infection were scheduled to receive 135 μg pegylated interferon α-2a subcutaneously, once a week, after dialysis session for a period of 48 weeks. Efficacy and safety were assessed by end of treatment viral response, sustained viral response, biochemical response, and adverse events. Serum HCV RNA levels were assessed using reverse transcriptase polymerase chain reaction (RT-PCR), while HCV genotype was analyzed by RT-PCR followed by hybridization of amplified products. Results. Of the 14 patients enrolled in the study, 9 completed treatment. Eight patients (57%) had undetectable levels of HCV RNA at the end of treatment, while one patient remained positive. Two (14.3%) patients were discontinued because of insufficient therapeutic response. Three patients (21.34%) did not finish treatment because serious adverse events occurred: one patient with bronchopneumonia and one with pericarditis were discontinued from treatment, while one patient died due to cerebral hemorrhage. Sustained viral response was present in 36% of the patients (5/8 patients) at the end of the follow up period. Biochemical response with normalization of serum ALT levels during treatment was observed in all treated patients (83 ± 20.1 U/L at baseline vs. 23.4 ± 4.6 U/L at week 48). The most common adverse events were flu-like syndrome, myalgia, arthralgia, and pancytopenia. Most of the adverse events were manageable. The serious adverse events were believed to be unrelated to the therapy, but rather to the co-morbidities of the hemodialysis patients. Conclusions. Pegylated interferon α-2a treatment was effective in a considerable proportion of the treated hemodialysis patients with hepatitis C, and it was reasonably safe to use.

Keywords:

• adverse events
• hemodialysis
• hepatitis C
• pegylated interferon α-2a
• renal failure chronic

INTRODUCTION

Hepatitis C virus (HCV) infection continues to be a major disease burden in the world, with a prevalence of about 170 million people worldwide (3%).[1] It is the main cause of liver disease leading to liver cirrhosis and liver carcinoma, and is the most frequent indication for liver transplantation.[2]

In patients on chronic hemodialysis, the prevalence of HCV infection is of great concern because HCV-positive patients have a higher rate of mortality.[3],[4] The reported prevalence of HCV infection ranged from 8% to 20% in dialysis patients of developed countries, and much higher in less developed countries.[5–8] In the United States, 8.4% of hemodialysis patients were HCV positive in 2000.[9] The presence of HCV antibodies among hemodialysis patients was 57% in Saudi Arabia in 2001, 80% in Egypt in 2000, and 65.8% in Bulgaria in 1998.[10] The prevalence among the patients in our hemodialysis unit was 64% in 2005.[11]

The clinical course of hepatitis C in hemodialysis patients is usually silent and asymptomatic with normal or only slightly elevated serum aminotransferase levels.[10],[12] The only therapeutic agent that has been proven to be effective was interferon α. Two separate meta-analyses have found that interferon α can be effective in 33–37% of HCV-infected dialysis patients, and even those who were infected with genotype 1 had a substantial sustained viral response (SVR) of 26%.[13],[14] Pegylated technology has improved the pharmacokinetic and pharmaco-dynamic profiles of interferon through sustained absorption, slower rate of clearance, and longer half-life. The sustained high concentration of pegylated interferon in plasma maintains an antiviral effect on HCV and makes the once weekly administration possible.[15–17] Recent studies recommended treatment of HCV infection in hemodialysis patients with pegylated interferon as monotherapy, which resulted with a higher rate of response than treatment with conventional interferon.[18] However, the experience with pegylated interferon in these patients is limited. The aim of our study was to evaluate the efficacy and safety of pegylated interferon α-2a used as monotherapy in hemodialysis patients with chronic hepatitis C virus infection.

METHODS

Patients

Fourteen hemodialysis patients (11 men and 3 women, mean age 43.3 ± 9.7 years) with chronic hepatitis C virus infection were enrolled in the study. Their sera were positive for HCV RNA and anti HCV antibodies (HCV Ab). HCV RNA had remained positive for more than six months after the detection of the antibodies to HCV.

Inclusion Criteria

Hemodialysis patients were eligible for the study if they met the following criteria: age of 18 years or older; serum positive for HCV RNA; serum HCV RNA viral load higher than 600 IU/mL; compensated liver disease, which is defined as the absence of ascites, variceal bleeding, and encephalopathy in the medical history; hemoglobin levels ≥ 10 g/dL; white blood cell count ≥ 2500/mm³ and absolute neutrophil count ≥ 1500/mm³; platelet count ≥ 90,000/mm³; thyroid-stimulating hormone within normal limits; and willingness to practice contraception.

Exclusion Criteria

Criteria for exclusion were hypersensitivity to interferon α, other cause for chronic liver disease than chronic hepatitis C, evidence for decompensated liver disease, history of organ transplantation or immunosuppression, autoimmune disease, systemic administration of steroids, malignant disease, poorly controlled diabetes mellitus, severe cardiac and pulmonary disease, poorly controlled hypertension, psychiatric disorder (depression or psychosis), seizure disorders, abuse of alcohol (>50 g/day), use of intravenous or inhaled drugs, and HIV co-infection.

The patients were on maintenance hemodialysis program with dialysis sessions of four hours, three times per week, on low-flux synthetic membranes and bicarbonate bath. Data regarding sex, age, duration of dialysis, duration of HCV infection, HCV genotype, and viral load are summarized in Table 1.

Table 1 Data of the dialysis patients with chronic HCV infection treated with pegylated interferon α-2a

Case	Sex	Age (years)	Duration of dialysis (years)	Duration of HCV infection (years)	HCV genotype	Quantity of HCV RNA (IU/ml)
1	M	32	10	8	1a	>850,000
2	M	54	5	3	1a	>405 000
3	F	43	9	4	1a	>783 000
4	M	34	16	8	1a	>850,000
5	F	42	16	8	1a	>405 000
6	M	60	16	8	1a	>850,000
7	M	54	5	4	1a	>850,000
8	M	51	4	2	1a	>508 000
9	M	40	3	2	1a	>119 000
10	M	31	9	4	1a	>850,000
11	M	53	5	2	1a	>850,000
12	M	43	11	4	1a	>850,000
13	F	45	5	2	1a	>850,000
14	M	40	3	2	4a	>850,000

Study Design

Over a period of four years, fourteen patients who met the criteria were treated with pegylated interferon α-2a. They received the drug subcutaneously, once per week, after the dialysis session for a period of 48 weeks. The treatment was initiated with the dose of 135 μg, with the possibility of dose-adjustment according to the clinical and laboratory parameters. The dose could be reduced by 50% if the absolute neutrophil count decreased below 750/mm³ and discontinued if it fell below 500/mm³. The dose of pegylated interferon could also be reduced by 50% if the platelet count decreased below 70,000/mm³ and could be discontinued if the platelets fell below 50,000/mm³.

Safety was assessed by the occurrence of adverse events, changes in vital signs, and the results of laboratory tests. They were recorded at the beginning of treatment (baseline), at weeks 1, 2, 4, 6, and 8, and then every four weeks for the rest of the 48 week study period. The patients were followed regularly by nephrologists and specialists for infectious diseases. The study was approved at a consensus conference on prevention, diagnosis, rational therapy, and monitoring of patients with hepatitis B and hepatitis C, organized by the ministry of health on December 23, 2003.

Assessment of Efficacy

The primary end point of treatment was sustained viral response (SVR), defined as absence of detectable levels of HCV RNA (<50 IU/mL) in the serum at week 72 (i.e., 24 weeks after the end of treatment). Secondary end points were as follows:

1. early viral response (EVR), defined as undetectable levels of HCV RNA at week 12;

2. end of treatment viral response (ETVR), defined as undetectable levels of HCV RNA at week 48; and

3. biochemical response (BR), defined as normalization of serum alanine aminotransferase levels during treatment.[17]

Efficacy was assessed by monitoring serum HCV RNA levels, examined at the following time points: two weeks prior to start of treatment, during the treatment period at weeks 12, 24, and 48, and 24 weeks after treatment completion (i.e., at week 72 of the study). HCV RNA levels were determined using reverse transcriptase polymerase chain reaction (AMPLICOR Hepatitis C Virus Test, version 2.0, Roche). HCV genotype was analyzed by reverse transcriptase PCR followed by hybridization of amplified products.

RESULTS

Nine of the fourteen patients enrolled in the study completed the treatment. Two patients (14.3%) did not complete treatment because they experienced serious adverse events. One patient developed pericarditis at week 2 and was discontinued from treatment. The other patient caught pneumonia at week 20, needed hospital treatment, and was taken off interferon therapy. One patient (7.14%) died due to cerebral hemorrhage at week 26. Treatment was discontinued in two patients (14.3%) because of insufficient therapeutic response (lack of EVR at week 12).

Early viral response was present in 10 (71.4%) patients, including the patients with pneumonia and cerebral hemorrhage. At the end of treatment (48 weeks), 8 patients (57.1%) had undetectable levels of HCV RNA. At the end of the follow up period (72 weeks), 5 patients (35.7%) had sustained viral response and 3 (21.4%) patients relapsed. The efficacy of treatment is presented in Table 2.

Table 2 Viral response at week 12, 24, 48, and 72 of the patients in the study

	HCV RNA positive	HCV RNA negative	Treatment discontinued	Total numberof patients
Baseline	14	—	—	14
Week 12	3	10	1	14
Week 24	3	9	2	14
Week 48	3	8	3	14
Week 72	6	5	3	14

The mean (± SE) serum alanine aminotransferase (ALT) levels, as a measure of biochemical response and one of our secondary end points of treatment, at baseline was 83 ± 20.1 U/L. After 48 weeks of treatment, serum ALT level was 23.4 ± 4.6 U/L (see Figure 1).

Figure 1. Serum alanine aminotransferase (ALT) levels in treated dialysis patients, during 48 weeks of treatment with pegylated interferon α-2a.

Adverse Events

All patients experienced flu-like symptoms. Most of the treated patients had myalgia (11 patients, 78.6%) and arthralgia (12 patients, 85.7%). A reduction of hemoglobin occurred in 11 patients. The lowest hemoglobin level of 9.71 ± 0.3 g/dL was observed at week 24. The dose of epoetin had to be increased to correct the hemoglobin levels (see Figure 2).

Figure 2. Hemoglobin levels (g/dL) and epoetin dose (U/kg/week) in dialysis patients during treatment with pegylated interferon α-2a.

Moderate neutropenia and thrombocytopenia were reported in 6 (42.9%) and 3 (21.4%) patients, respectively, and were not related to any clinical events. During treatment, in most of the patients, the absolute neutrophil and platelet count decreased to some extent, but the count of less than 750/mm³ and 50,000/mm³, respectively, was not recorded. The mean (± SE) neutrophil count was 3400 ± 305/mm³ at base line. It decreased to 2700 ± 187/mm³ at week 8, and then stabilized around the baseline value (3700 ± 668/mm³). The mean (± SE) platelet count was 175,600 ± 17,777/mm³ at baseline, 125,200 ± 9,783/mm³ at week 40, and 146,900 ± 24,532/mm³ at the end of treatment. None of the patients had clinically significant bleeding associated with thrombocytopenia, and in none of them was treatment discontinued because of neutropenia or thrombocytopenia.

We also noted some less frequent adverse events. Three patients had pharyngitis, and another three experienced muscle weakness. Rare events, occurring in one patient each, included injection site reaction, insomnia, vomiting, alopecia, rush, dry skin, and back pain.

Serious adverse events occurred in three patients (21%). Two male patients, one with pneumonia and another with pericarditis, were hospitalized and discontinued from treatment. The neutropil count was 5,100 /mm³ at start and 5,600 /mm³ the day before hospitalization of the patient with pneumonia, after 20 weeks of treatment. The second patient was diagnosed with pericarditis only two weeks after the onset of treatment. The third, a female patient, suddenly died from cerebral hemorrhage at week 26 of treatment. Her platelet count was 186,000 /mm³ on admission and 147,000 /mm³ on the day before she died.

DISCUSSION

Many trials with the use of standard interferon treatment of chronic hepatitis C in hemodialysis patients reported sustained response rates of 20–60%. They were significantly higher than the response rates of the patients with normal renal function (20%).[19–22] These results suggested that hemodialysis patients responded better to interferon therapy than those without renal disease. One explanation could be the reduced clearance and hence higher interferon concentrations in hemodialysis patients. Also, the hemodialysis procedure could not remove interferon, a large molecule with molecular weight >16 000 kD.[14],[23] Adverse events with interferon as monotherapy seemed to be higher in hemodialysis patients compared to those with normal renal function.[13],[14] Adverse events mainly included flu-like symptoms and pancytopenia due to medullary suppression. They were among the principal reasons for dose reduction or treatment discontinuation.[24–26] Diminishing hemoglobin levels, which could occur during treatment, might be maintained by increasing the erythropoietin dose.[24]

The first published experience with pegylated interferon α-2a for the treatment of chronic HCV infection in hemodialysis patients was conducted on two patients with chronic hepatitis C and one with acute hepatitis C infection.[25] The dose of 180 μg pegylated interferon α-2a was set for the initiation of treatment. SVR was observed in both patients with chronic infection. The encouraging data underlined the necessity of further studies and the need for defined guidelines in this field. Rivera et al.[26] treated 27 hemodialysis patients with chronic HCV infection. Twenty of them were treated with interferon α-2a and 7 with pegylated interferon α-2a. SVR was achieved in 11 (40.7%) patients. Treatment was effective in a high proportion of hemodialysis patients, with response rates higher than for the general population. However, authors reported restrictions of treatment due to the high incidence of side effects.

Low sustained response rate of 22% in 16 hemodialysis patients with chronic HCV infection was reported by Russo et al.[19] in their randomized trial on the use of pegylated interferon α-2b as monotherapy. The study was terminated before achieving target enrollment because of the need for study modifications and the large number of serious adverse events (hypertension and infection).

Recently, Sporea et al.[22] reported treatment of 10 hemodialysis patients with pegylated interferon α-2a. Sustained viral response was observed in 30% (i.e., in 3 out of the 6 patients who finished the 48 weeks of treatment). Two patients were excluded from the study because of lack of compliance, one patient was discontinued from treatment due to sepsis after surgery, and one patient died of cerebral hemorrhage caused by arterial hypertension after 16 weeks of therapy. The treatment was initiated with a dose of 180 μg per week, but in two patients the dose was reduced to 135 μg due to thrombocytopenia and hemorrhagic complications (epistaxis, metrorrhagia). Authors reported also some moderate adverse events but did not stop treatment in any of the patients.

Limited experience on the use of pegylated interferon in hemodialysis patients with chronic HCV infection, as well as the extent of this problem in our country, prompted us to conduct the current study. Patients were treated according to the Pegasys Treatment Algorithm.[27] We could observe end of treatment viral response in 57.1% of the treated patients, and biochemical response in all of them. Sustained viral response was present in 5 patients, representing 36% of the patients who started treatment and 62.5% of the patients who completed the follow up period (5/8). These results were comparable to the ones obtained in a few other studies involving hemodialysis patients with chronic HCV infection and treated with the same formulation of modified interferon α-2a.[22],[25],[26] During treatment, the patients had predictable and manageable decreases of hemoglobin level, neutrophil, and platelet count. Pegylated interferon α-2a was well tolerated, and laboratory abnormalities were moderate. None of the patients required dose modifications or discontinuation of treatment due to laboratory abnormalities. In our opinion, it was reasonably safe to use pegylated interferon α-2a in hemodialysis patients even if moderate adverse events were common. We believe that the serious adverse events that occurred were not related to the therapy, but to the co-morbidities of the patients. The achievement of undetectable HCV RNA in the sera of hemodialysis patients could mean that further progression of liver disease might be prevented.

Effective therapy for chronic HCV infection in hemodialysis patients is an important goal because of the high prevalence of HCV among the dialysis population and the poor prospects for the development of an effective vaccine.

Despite the encouraging results, the real issue is whether the hemodialysis patients in whom sustained viral response is achieved are likely to be reinfected months or years later due to nosocomial transmission of HCV in the dialysis unit. Strategies for the prevention of nosocomial transmission, such as the isolation of HCV-positive patients on separate machines and/or in separate wards and strict observation of general hygienic precautions, should be reinforced.