Immediate virological response predicts the success of short-term peg-interferon monotherapy for chronic hepatitis C

Abstract

AIM: To investigate the efficacy of short-term peg-interferon (PEG-IFN) monotherapy for chronic hepatitis C patients who achieved an immediate virological response.

METHODS: Defining an “immediate virological response (IVR)” as the loss of serum hepatitis C virus (HCV) RNA 7 d after the first administration of PEG-IFN α, we conducted a 12-wk course of PEG-IFN α2a monotherapy without the addition of ribavirin for 38 patients who had low pretreatment HCV RNA load and exhibited IVR. The patients included 21 men and 17 women, whose ages ranged from 22 to 77 years (mean ± SD: 52.0 ± 17.8 years). There were 4 patients with HCV genotype 1b, 23 patients with genotype 2a and 4 patients with genotype 2b. HCV genotype was not determined for the remaining 7 patients. Patients were categorized into a sustained virological response (SVR) group, if serum HCV RNA remained negative for 24 wk after the end of treatment, or into a relapse group.

RESULTS: Based on the intention-to-treat analysis, 35 patients (92.1%) achieved SVR. One patient (2.6%) relapsed with serum HCV RNA 12 wk after the end of treatment. Two patients (5.3%) withdrew from the study during the 24-wk follow-up period. With regard to the HCV RNA genotype, the SVR rates were 100% (4/4) for genotype 1b, 95.7% (22/23) for genotype 2a and 100% (4/4) for genotype 2b. The SVR rate in 7 patients, whose HCV RNA genotypes were not determined, was 71.4% (5/7).

CONCLUSION: Short-term PEG-IFN α2a monotherapy is highly effective for chronic hepatitis C patients who have low pretreatment HCV RNA load and exhibit IVR.

Key Words: Chronic hepatitis C; Immediate virological response; Interferon therapy

INTRODUCTION

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. About 170 million patients are chronically infected with HCV worldwide. Interferon (IFN) therapy is important for suppressing the progression of chronic liver disease derived from HCV infection. Currently, combination therapy with peg-interferon α (PEG-IFN α) and ribavirin (RBV) is the first-line therapy used to eliminate HCV in patients with chronic hepatitis C. The duration of treatment is determined based on the viral genotype, with treatment administered for 48 wk in patients with genotype 1 and 24 wk in patients with genotypes 2 or 3[1,2]. However, long-term administration of IFN and RBV increases the cost of treatment and the risk of severe adverse events.

The efficacy of IFN therapy depends on the HCV genotype, pretreatment viral load and early viral kinetics[3-7]. Thus, IFN therapy must be individualized and optimized according to the virological and clinical status of each patient. Several studies have shown that the duration of IFN therapy could be shortened in patients who achieve serum HCV RNA negativity during the early stages of treatment[7-9]. Therefore, it is essential that we reduce the treatment duration for patients who exhibit a quick virological response to IFN therapy. In the present study, we focused on the initial response to PEG-IFN α administration and studied the efficacy of short-term PEG-IFN α2a monotherapy for patients who had low pretreatment HCV RNA load.

MATERIALS AND METHODS

Definition of IVR and protocol for PEG-IFN α2a therapy

We defined an “immediate virological response (IVR)” as the loss of serum HCV RNA 7 d after the first administration of PEG-IFN α. Patients with low pretreatment HCV RNA load (< 1.0 × 10⁵ IU/mL) were monitored for HCV RNA in the serum 7 d after the first administration of PEG-IFN α2a. We scheduled a 12-wk treatment course of PEG-IFN α2a without the addition of RBV for patients who achieved IVR. The patients received subcutaneous injection of 180 μg of PEG-IFN α2a (Pegasys, Roche) once per week. According to the circumstance of each patient, the dose was reduced to 90 μg or the treatment course was terminated.

Patients

We administered PEG-IFN α2a without the addition of RBV to a total of 59 patients with low HCV RNA load from December 2004 to November 2007. They were monitored for serum HCV RNA 7 d after the first administration of PEG-IFN α2a. Among these, 38 patients who achieved IVR were enrolled in this study. The age, gender, HCV genotype, serum HCV RNA level, ALT level, hemoglobin (Hb), and the neutrophil and platelet (PLT) counts before treatment are shown in Table 1. The patients included 21 men and 17 women, whose ages ranged from 22 to 77 years (mean ± SD: 52.0 ± 17.8 years). There were 4 patients with genotype 1b, 23 patients with genotype 2a and 4 patients with genotype 2b. HCV genotype was not determined for the remaining 7 patients. Among the 38 patients enrolled in this study, 37 received IFN therapy for the first time for HCV infection. Pt. 16 is the same patient as Pt. 3, who received the same treatment course for HCV genotype 2a infection at 26 years of age. After the initial successful treatment, the patient was infected with genotype 2b HCV and re-treated at 28 years of age. Pt. 25 had been treated for hepatocellular carcinoma prior to this IFN treatment course.

Table 1 Patient characteristics.

Pt. No.	Age (yr)	Gender	Genotype	Viral load (IU/mL)	ALT (IU/L)	Hb (g/dL)	Neutrophil (/mm3)	PLT (× 103/mm3)	Naive/ re-treatment
1	51	M	2a	2.4 × 104	83	10.5	2729	254	Naive
2	56	M	1b	7.6 × 103	14	14.0	2565	268	Naive
3	26	F	2a	2.7 × 104	157	15.6	5217	284	Naive
4	67	M	2a	< 5.0 × 103	63	15.2	3940	159	Naive
5	48	F	2a	1.1 × 104	121	12.1	1851	146	Naive
6	48	F	2a	7.0 × 104	48	12.7	3084	244	Naive
7	70	M	2a	5.3 × 104	119	13.7	2002	157	Naive
8	64	M	ND	< 5.0 × 103	65	14.5	2200	148	Naive
9	22	M	ND	< 5.0 × 103	51	15.3	5003	308	Naive
10	40	F	2a	1.1 × 104	198	14.2	2424	190	Naive
11	68	F	2a	9.3 × 103	31	11.8	3567	212	Naive
12	60	M	2a	< 5.0 × 103	18	14.9	1520	265	Naive
13	68	F	2a	1.8 × 104	112	13.4	3338	190	Naive
14	76	M	2a	1.8 × 104	39	13.6	2540	272	Naive
15	25	F	2a	8.6 × 104	181	12.2	2649	260	Naive
16	28	F	2b	1.9 × 104	19	14.4	3522	324	Re-treatment
17	23	M	ND	< 5.0 × 103	456	15.0	3483	257	Naive
18	57	F	2b	5.9 × 103	97	14.2	2080	306	Naive
19	48	M	2a	6.4 × 104	41	15.1	1688	235	Naive
20	56	M	2b	5.1 × 104	124	15.1	3810	82	Naive
21	34	F	2a	2.8 × 104	72	13.4	4004	98	Naive
22	32	F	2a	1.7 × 104	41	12.5	1853	259	Naive
23	74	M	ND	< 5.0 × 103	37	10.6	1784	92	Naive
24	45	M	2a	1.0 × 104	41	16.3	4606	147	Naive
25	76	F	2a	< 5.0 × 103	54	10.9	2948	192	Naive
26	53	F	1b	5.0 × 103	13	11.9	3438	204	Naive
27	27	F	ND	< 5.0 × 103	46	15.1	2205	169	Naive
28	71	F	ND	5.0 × 103	40	14.1	2022	98	Naive
29	70	M	2a	5.1 × 104	81	14.5	2894	125	Naive
30	60	M	1b	5.7 × 103	40	15.1	1502	297	Naive
31	57	M	2a	2.8 × 104	61	15.5	3154	137	Naive
32	77	M	2a	< 5.0 × 103	68	10.3	1430	125	Naive
33	69	F	1b	1.6 × 104	21	12.8	2772	186	Naive
34	37	F	2a	< 5.0 × 103	42	13.1	2343	314	Naive
35	23	M	ND	< 5.0 × 103	46	14.6	2772	238	Naive
36	36	M	2a	1.3 × 104	26	14.5	5126	242	Naive
37	57	F	2b	4.7 × 104	50	14.9	1628	130	Naive
38	71	M	2a	3.5 × 104	102	14.4	3852	109	Naive
mean ± SD	52.0 ± 17.8				76.8 ± 77.6	13.7 ± 1.5	2838.20 ± 972.50	212.9 ± 79.1

ND: Not determined; ALT: Alanine transaminase; Hb: Hemoglobin; PLT: Platelet.

Determination of serum HCV RNA load and the HCV genotype

Pretreatment serum HCV RNA levels were determined by RT-PCR using an Amplicor HCV monitor v2.0 series kit (Roche Diagnostics Co.), which had a detection limit of 5.0 × 10³ IU/mL. When the serum HCV RNA level was below the detection limit, qualitative analysis of the HCV RNA was performed by RT-PCR using a COBAS Amplicor HCV test kit v2.0 (Roche Diagnostics Co.), which had a detection limit of 50 IU/mL. Qualitative analysis of HCV RNA was performed 7 d after the first administration for the evaluation of IVR, and at 24 wk after the end of treatment for the evaluation of the SVR. HCV genotype was determined using an HCV Genotyping SMITEST kit (Roche Diagnostics Co.).

Evaluation of the efficacy of PEG-IFN α2a therapy

Patients were categorized into the sustained virological response (SVR) group, if serum HCV RNA remained negative for 24 wk after the end of PEG-IFN α2a therapy. Patients were categorized into the relapse group if serum HCV RNA reappeared after the end of the treatment course.

Informed consent

All patients provided informed consent prior to their participation in this study. The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.

RESULTS

Completion of treatment

Figure 1 presents the dose and duration of PEG-IFN α2a administration for each patient. Of 38 patients enrolled in this study, 26 (Pts. 1-26, 68.4%) completed a 12-wk treatment course. It was necessary to reduce the dose of PEG-IFN α2a in 5 (Pts. 22-26) of these 26 patients. Twelve patients (Pts. 27-38, 31.6%) discontinued treatment prior to completion of the 12-wk course. In 6 (Pts. 30, 31 and 35-38, 15.8%) of these 12 patients, either self-withdrawal or financial problem was the cause for discontinuation. In 3 cases (Pts. 27, 28 and 32), the dose was reduced during the treatment, but the treatment was discontinued before completion of the 12-wk course.

Figure 1 Administration of peg-interferon (PEG-IFN) α2a. The patients received subcutaneous injections of 180 μg of PEG-IFN α2a (rotundity) once per week. Twenty-one patients (Pts. 1-21) completed a 12-wk treatment course without dose reduction. In 17 patients (Pts. 22-38), the dose was reduced to 90 μg (triangle) or the treatment was terminated before completion of the 12-wk course.

Efficacy of the therapy

An intention-to-treat analysis was performed. Two patients (Pts. 27 and 35, 5.3%) withdrew from this study during the 24-wk follow-up period because they did not attend the hospital appointments. Thirty-five patients (92.1%) were negative for serum HCV RNA 24 wk after the end of treatment and were categorized into the SVR group (Figure 2). One patient (Pt. 6, 2.6%) was positive for serum HCV RNA 24 wk after the end of treatment and was categorized into the relapse group.

Figure 2 Efficacy of the therapy. A: The sustained virological response (SVR) rate in all patients; B: The efficacy of the therapy for each genotype.

With regard to the HCV RNA genotype, the SVR rates were 100% (4/4) for genotype 1b, 95.7% (22/23) for genotype 2a and 100% (4/4) for genotype 2b (Figure 2). The SVR rate in 7 patients, whose HCV RNA genotypes were not determined, was 71.4% (5/7), as we could not evaluate the treatment effect for 2 patients because of self-withdrawal during the follow-up period.

Adverse events

The most frequent adverse events were flu-like symptoms, such as fever and pain. Fatigue appeared as the second most frequent. Other adverse events are summarized in Table 2. Some patients who complained of insomnia were treated with hypnotics. Thrombocytopenia (< 50 000/mm³) occurred in 1 case (Pt. 23) and the dose was reduced for the 4th and 5th administration during the treatment course. Neutropenia (< 750/mm³) appeared in 3 cases, and in 1 case (Pt. 32) it was necessary to reduce the dose of PEG-IFN α2a from the 2nd to 5th administration. Anemia (Hb < 8.5 g/dL) did not occur in any of the patients. In 6 cases, it was necessary to reduce the dose of PEG-IFN α2a because of fatigue (Pts. 22, 25 and 28), emotional lability (Pts. 26 and 27) or vertigo (Pt. 24). None of the patients discontinued the treatment course because of bone marrow suppression. In 5 cases it was necessary to discontinue the treatment course for the following reasons: 2 with fatigue (Pts. 28 and 34), 1 with stomatitis (Pt. 27), 1 with skin symptoms and diarrhea (Pt. 29) and the other with viral influenza infection (Pt. 32). These adverse events were not particularly severe. One case (Pt. 33) discontinued the treatment course because of bacterial pneumonia, and recovered after antibiotic administration.

Table 2 Adverse events.

Adverse event	n (%)
Flu-like symptoms
Fever	20 (52.6)
Pain	12 (31.5)
Fatigue	13 (34.2)
Insomnia	7 (18.4)
Neutropenia (< 750/mm3)	3 (7.9)
Skin symptoms	3 (7.9)
Emotional lability	3 (7.9)
Gastrointestinal symptoms	2 (3.3)
Thrombocytopenia (< 50 000/mm3)	1 (2.6)
Bacterial pneumonia	1 (2.6)
Influenza viral infection	1 (2.6)
Vertigo	1 (2.6)
Stomatitis	1 (2.6)

DISCUSSION

In the present study, we defined an “immediate virological response (IVR)” as the loss of serum HCV RNA 7 d after the first administration of PEG-IFN α. We then conducted a 12-wk treatment course of PEG-IFN α2a in a population of patients who had low pretreatment HCV RNA load and who achieved IVR. This short-term PEG-IFN α2a monotherapy without the addition of RBV exhibited an extremely high SVR rate.

The current standard therapy to eliminate HCV in patients with chronic hepatitis C is combination therapy with PEG-IFN α and RBV. While the SVR rate for 24 wk of PEG-IFN α/RBV therapy in patients with genotypes 2 and 3 is 78%-93%, the SVR rate for 48 wk of treatment for genotype 1 is 40%-51%[1,2,10-13]. New methods of determining the adequate dose and duration of PEG-IFN α/RBV administration have been devised to increase the probability of SVR in the treatment for patients with genotype 1 and high pretreatment viral load[9,14]. High dose and long-term IFN treatments, however, are expensive and contribute to additional risk for many adverse events.

Major contributory factors for SVR are viral genotype (except genotype 1), low pretreatment viral load (< 1.0 × 10⁵ IU/mL) and early loss of serum HCV RNA[3-7]. Early virological response (EVR) and rapid virological response (RVR), which are indicated by loss of serum HCV RNA at weeks 12 and 4, respectively, are closely related to the SVR rate[6,7,15,16]. Furthermore, Mangia et al[8] have reported that 12 wk of administration of PEG-IFN α/RBV to patients with HCV genotype 2 or 3 and who achieve RVR, results in a high probability of SVR. Tabaru et al[17] reported that the SVR rate was 100% after treatment with IFN α2b for 6 wk for patients infected with HCV genotype 2a and low viral load. Establishing the minimum, and yet sufficient, IFN therapy period is important in terms of financial efficiency and for reduction of the risk of adverse events. Therefore, it is essential to establish a guideline to make the treatment period shorter than the standard length for patients who have a high probability of achieving SVR. For patients with low pretreatment HCV RNA load, the current standard IFN therapy which is allowed by Japanese National Medical Insurance, is 24-48 wk of PEG-IFN α2a monotherapy without the addition of RBV. RBV causes hemolytic anemia, and severe anemic symptoms sometimes appear in PEG-IFN α/RBV combination treatment[18]. PEG-IFN α monotherapy can avoid these adverse events induced by RBV.

Thus, in the current study, we studied the efficacy of short-term PEG-IFN α2a monotherapy for patients who had a low pretreatment HCV RNA load and exhibited IVR. Remarkably, 35 (97.2%) out of 36 cases that we were able to follow up to 24 wk after the last administration, were categorized into the SVR group. With regard to the HCV RNA genotype, SVR rates were 100% (4/4) for genotype 1b, 95.7% (22/23) for genotype 2a and 100% (4/4) for genotype 2b (Figure 2). These data might suggest that the efficacy of short-term PEG-IFN α2a monotherapy for patients exhibiting IVR is independent of HCV genotype. Further analyses with a large population of patients should be conducted for each genotype of HCV, because the number of patients enrolled in this study, especially for genotype 1b, was small.

The patient (Pt. 6) who relapsed during this treatment course subsequently received 24 wk of PEG-IFN α2a therapy and succeeded in achieving SVR. We consider that if short-term treatment failed to induce SVR, those non-SVR patients could be re-treated with long-term PEG-IFN α monotherapy (24-48 wk) or PEG-IFN α/RBV combination therapy. Thus, it is suggested that we should select short-term monotherapy at the first approach for patients with low pretreatment HCV RNA load and IVR.

Nine out of 35 cases who achieved SVR received less than 9 wk (4-8 wk) of drug administration. Therefore, there is the possibility that the treatment period could be shortened to less than 12 wk for a certain group of patients. Further analyses in randomized controlled trials with a large population of patients should be conducted to examine the efficacy of shorter treatment courses, such as 4 wk or 8 wk.

Frequent adverse events that generally appear during IFN therapy were seen in this study group of patients. However, no severe events were observed. None of the patients required discontinuation of therapy because of bone marrow suppression. While 1 case exhibited bacterial pneumonia as a severe complication, the patient recovered with antibiotic treatment. Thus, we consider that short-term monotherapy is safe.

PEG-IFN α monotherapy clearly has the advantage of avoiding adverse events induced by RBV. However, we have to consider the possibility that adding RBV to this short term PEG-IFN α therapy could offer shorter treatment duration or higher SVR rates. This option should be investigated in larger studies.

In conclusion, short-term PEG-IFN α2a monotherapy is highly effective for chronic hepatitis C patients who have low pretreatment HCV RNA load and exhibit IVR. IVR is a simple and useful indicator of early viral kinetics to predict the high probability of SVR.

COMMENTS

Background

The efficacy of interferon (IFN) therapy for chronic hepatitis C depends on the hepatitis C virus (HCV) genotype, pretreatment viral load and early viral kinetics. Therefore, IFN therapy must be individualized and optimized according to the virological and clinical status of each patient.

Research frontiers

Focusing on the initial response to PEG-IFN α administration, the authors proposed a new concept, the “immediate virological response (IVR)”. Then the efficacy of short-term PEG-IFN α2a monotherapy was investigated for patients who had low pretreatment HCV RNA load and exhibited IVR.

Innovations and breakthroughs

A 12-wk treatment course of PEG-IFN α2a without the addition of RBV was highly effective for patients who achieved IVR. SVR rate for all patients in this study was 92.1% (35/38).

Applications

The present study has shown that short-term PEG-IFN α2a monotherapy is an excellent treatment regimen for chronic hepatitis C patients who have low pretreatment HCV RNA load and exhibit IVR. It is also suggested that IVR is a simple and useful indicator of early viral kinetics to predict the high probability of SVR.

Terminology

An “IVR” was defined as the loss of serum HCV RNA 7 d after the first administration of PEG-IFN α.

Peer review

Yada et al reported that a 12-wk treatment course of PEG-IFN α2a alone in a population of patients who had low pretreatment HCV RNA load and achieved immediate virological response results in extremely high SVR rates. The data are encouraging and important from a cost-effectiveness point of view.