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Aim: This study aimed to clarify the factors associated the efficacy of re-treatment with pegylated interferon (PEG IFN) plus ribavirin combination therapy for patients with chronic hepatitis C who had failed to respond to previous treatment.
Methods: One hundred and forty-three patients who had previously shown relapse (n = 79), non-response (n = 34) or intolerance (n = 30) to PEG IFN plus ribavirin were re-treated with PEG IFN plus ribavirin.
Results: Twenty-five patients with intolerance to previous treatment completed re-treatment and the sustained virological response (SVR) rates were 55% and 80% for hepatitis C virus (HCV) genotype 1 and 2, respectively. On re-treatment of the 113 patients who completed the previous treatment, the SVR rates were 48% and 63% for genotype 1 and 2, respectively. Relapse after previous treatment and a low baseline HCV RNA level on re-treatment were associated with SVR in genotype 1 (P < 0.001). Patients with the interleukin-28B major genotype responded significantly better and earlier to re-treatment, but the difference in the SVR rate did not reach a significant level between the major and minor genotypes (P = 0.09). Extended treatment of 72 weeks raised the SVR rate among the patients who attained complete early virological response but not rapid virological response with re-treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05).
Conclusion: Relapse after previous treatment and a low baseline HCV RNA level have predictive values for a favorable response of PEG IFN plus ribavirin re-treatment for HCV genotype 1 patients. Re-treatment for 72 weeks may lead to clinical improvement for genotype 1 patients with complete early virological response and without rapid virological response on re-treatment.
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PEGYLATED INTERFERON (PEG IFN) plus ribavirin combination therapy can show antiviral efficacy for patients with chronic hepatitis C (CH-C). However, a sustained virological response (SVR), which is defined as undetectable serum hepatitis C virus (HCV) RNA at 24 weeks after the treatment, remains at 50% for patients with HCV genotype 1 and 80% for those with HCV genotype 2 treated with PEG IFN plus ribavirin.1–6 The number of patients who fail to achieve a SVR increases over time, requiring urgent action to eradicate HCV in them.
Recently, addition of the first-wave protease inhibitor telaprevir to PEG IFN plus ribavirin combination therapy, which has been reported to improve antiviral efficacy, has become commercially available, but this triple therapy increases side-effects, especially severe anemia and skin rash.7–11 Second-wave protease inhibitors, such as TMC435, which not only improve antiviral efficacy but also decrease side-effects, have been developed and are undergoing clinical trials.12 Also, IFN-free regimens, such as protease inhibitor and polymerase inhibitor combination therapy, have been developed.13,14 In Japan, HCV carriers are increasing in an aging population, and large numbers of patients are ineligible for triple therapy with telaprevir due to potential anemia. That is why re-treatment with PEG IFN plus ribavirin is a possible choice for patients who failed to achieve SVR to previous antiviral therapy or patients ineligible for triple therapy with telaprevir who must wait until next-generation antiviral therapies, such as triple therapy with second-wave protease inhibitors or IFN-free regimens, become commercially available.
As for re-treatment with PEG IFN plus ribavirin, some studies have been reported but the subjects and treatment protocols were varied.15–20 According to past reports, the previous treatment response is associated with the efficacy of the re-treatment17,20 and the SVR rates in re-treatment ranged 4–23%.16–18 Recently, host factors, such as single nucleotide polymorphisms (SNP) located near the interleukin (IL)-28B gene, and virus factors, such as the amino acid substitutions in the HCV core region, were revealed to have a strong impact on SVR in PEG IFN plus ribavirin combination therapy for naïve CH-C patients.21–26 Moreover, response-guided therapy which extends treatment duration until 72 weeks for patients with a slow virological response can raise the SVR rate for naïve CH-C patients.27–29 However, the value of IL-28B SNP has been uncertain in re-treatment and the most appropriate treatment duration in re-treatment is still unclear. Although it remains obscure which factors are associated with SVR in re-treatment with standard PEG IFN plus ribavirin therapy as pointed out above, some patients do respond to re-treatment and it is very important to be able to identify them. Such findings will be valuable for optimizing the antiviral treatment for CH-C patients by making it possible to decide which patients should be considered for re-treatment with PEG IFN plus ribavirin therapy and which should wait for next-generation antiviral treatment.
In the present study, we tried to determine which patients could benefit from re-treatment and to identify the factors associated with SVR in re-treatment, including the host genome SNP and treatment duration.
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THE PATIENT FLOW in this study is shown in Figure 1. Among the patients who had previously discontinued PEG IFN-α-2b plus ribavirin combination therapy, two patients underwent splenectomy to increase platelet count prior to re-treatment, 25 completed re-treatment of PEG IFN plus ribavirin combination therapy and 15 achieved SVR (genotype 1, n = 11; genotype 2, n = 4).
All of the patients who completed previous treatment also completed re-treatment and the baseline characteristics of those patients are shown in Table 1. Of the 86 genotype 1 patients, 54 were relapsers and 32 had shown NR to previous treatment. Of the 27 patients with genotype 2, 25 were relapsers and two had shown NR to previous treatment. Thirty-seven patients with genotype 1 and 14 patients with genotype 2 were assessed as IL-28B genotype, and 27 patients with genotype 1 and 10 patients with genotype 2 were assessed as ITPA genotype. There was no significant difference in the baseline characteristics between the previous treatment and the re-treatment with respect to peripheral blood cell counts, amino transaminase level and serum HCV RNA at the start of treatment (Table 1).
Table 1. Baseline characteristics of patients and treatment factors in previous treatment and re-treatment
|Factor||Genotype 1||Genotype 2|
|Effect of previous treatment: relapse/NR||54/32||25/2|
| ||Previous treatment||Re-treatment||Previous treatment||Re-treatment|
|PEG IFN type: α-2a/α-2b||0/86||41/45||0/27||6/21|
|Age (years)||58.1 ± 8.3||60.0 ± 8.5||58.9 ± 8.2||60.0 ± 8.1|
|White blood cells (/mm3)||4779 ± 1383||4610 ± 1443||5195 ± 1473||4724 ± 1266|
|Neutrophils (/mm3)||2478 ± 930||2355 ± 1071||2561 ± 827||2389 ± 941|
|Hemoglobin (g/dL)||13.7 ± 1.2||13.5 ± 1.7||14.4 ± 1.3||14.0 ± 1.2|
|Platelets (×104/mm3)||16.0 ± 5.9||16.6 ± 6.2||18.0 ± 5.7||16.8 ± 5.2|
|ALT (IU/L)||75 ± 51||73 ± 72||57 ± 46||42 ± 32|
|Histology: activity, 0–1/2–3||29/29|| ||11/7|| |
|Fibrosis, 0–2/3–4||45/14|| ||17/1|| |
|Serum HCV RNA (KIU/mL)||1600||850||1500||700|
|IL-28B SNP: rs8099917; TT/TG||26/11|| ||10/4|| |
|ITPA SNP: rs1127354; CC/CA||20/7|| ||9/1|| |
|Core 70: wild/mutant||11/11|| || || |
|Core 91: wild/mutant||15/7|| || || |
|ISDR: 0–1/≥2||15/1|| || || |
The baseline characteristics of patients with genotype 1 according to antiviral efficacy of the previous treatment are shown in Table 2. Among those with NR in the previous treatment, the rate of the minor allele of IL-28B was significantly higher than those with relapse in the previous treatment (P < 0.01). For genotype 1, the HCV RNA negative rate on re-treatment was 20% (17/86) at week 4, 61% (52/85) at week 12 and 76% (65/86) at week 24, and the SVR rate was 48% (41/86). The factors associated with SVR were assessed by univariate analysis and the factors of relapse after previous treatment and the serum HCV RNA level at the start of re-treatment were selected as being significant (Table 3). The SVR rates of relapsers were significantly higher than those of patients with NR in the previous treatment (relapse, 67%, 36/54 vs NR, 16%, 5/32, P < 0.0001). As for the serum HCV RNA level at the start of re-treatment, although the SVR rate of those patients with 5 log10 IU/mL or more of HCV RNA was 38% (26/69), all patients with less than 5 log10 IU/mL of HCV RNA attained SVR (11/11) (P = 0.0001). As for the IL-28B genotype, among the patients with the major allele, the p-EVR rate was significantly higher and the EOT response rate showed marginal significance compared to that with the minor allele (p-EVR rate, 100%, 23/23 vs 30%, 3/10, P < 0.0001, EOT rate, 92%, 24/26 vs 64%, 7/11, P = 0.05). There was no significant difference of the SVR rate between major and minor alleles (major, 65%, 17/26 vs minor, 36%, 4/11, P = 0.15).
Table 2. Baseline characteristics of patients and treatment factors according to the virological response in previous treatment among patients with genotype 1
|Factor||Relapser in previous treatment||NR in previous treatment|
| ||Previous treatment||Re-treatment||Previous treatment||Re-treatment|
|PEG IFN type: α-2a/α-2b||0/54||29/25||0/32||12/20|
|Age (years)||58.1 ± 8.1||60.3 ± 8.4||57.9 ± 8.9||59.6 ± 8.8|
|White blood cells (/mm3)||4917 ± 1290||4692 ± 1035||4546 ± 1520||4462 ± 1993|
|Neutrophils (/mm3)||2618 ± 846||2479 ± 805||2225 ± 1033||2105 ± 1454|
|Hemoglobin (g/dL)||13.9 ± 1.2||13.7 ± 1.6||13.5 ± 1.3||13.1 ± 1.9|
|Platelets (×104/mm3)||17.1 ± 6.3||17.7 ± 6.1||14.1 ± 4.7||14.7 ± 6.2|
|ALT (IU/L)||75 ± 57||70 ± 76||75 ± 39||78 ± 64|
|Histology: activity, 0–1/2–3||20/18|| ||9/11|| |
|Fibrosis, 0–2/3–4||31/8|| ||14/6|| |
|Serum HCV RNA (KIU/mL)||1600||980||1550||800|
|IL-28B SNP: rs8099917; TT/TG||24/5|| ||2/6|| |
|ITPA SNP: rs1127354; CC/CA||15/6|| ||5/1|| |
|Core 70: wild/mutant||6/6|| ||5/5|| |
|Core 91: wild/mutant||9/3|| ||6/4|| |
|ISDR: 0–1/≥2||9/0|| ||6/1|| |
Table 3. Factors associated with a sustained virological response in re-treatment with PEG IFN plus ribavirin in patients with genotype 1
|Factor|| ||SVR||Non-SVR|| P-value|
|No. of patients|| ||41||45|| |
|Age (years)|| ||60.2 ± 7.1||59.9 ± 9.6||0.71|
|Sex: male/female|| ||24/17||22/23||0.40|
|Serum HCV RNA (log IU/mL)|| ||5.8 ± 1.4||6.4 ± 0.6||0.11|
|Serum HCV RNA: <5 log/≥5 log|| ||11/28||0/43||<0.001|
|White blood cells (/mm3)|| ||4656 ± 1029||4566 ± 1763||0.42|
|Neutrophils (/mm3)|| ||2443 ± 804||2259 ± 1301||0.16|
|Hemoglobin (g/dL)|| ||13.5 ± 1.6||13.4 ± 1.8||0.80|
|Platelets (×104/mm3)|| ||16.9 ± 5.7||16.3 ± 6.7||0.36|
|ALT (IU/L)|| ||68 ± 69||78 ± 75||0.43|
|IL-28B SNP: TT/TG|| ||17/4||9/7||0.15|
|ITPA SNP: CC/CA|| ||13/3||7/4||0.39|
|Core 70: wild/mutant|| ||5/4||6/7||1.00|
|Core 91: wild/mutant|| ||7/3||8/5||1.00|
|ISDR: 0–1/≥2|| ||9/0||6/1||0.44|
|PEG IFN: α-2a/α-2b|| ||16/25||25/20||0.14|
|PEG IFN dose (µg/kg per week)||α-2a||2.91 ± 0.77||2.74 ± 0.69||0.61|
| ||α-2b||1.25 ± 0.39||1.20 ± 0.32||0.59|
|Ribavirin dose (mg/kg per day)|| ||9.34 ± 2.72||9.64 ± 3.20||0.51|
|1st treatment virological response||Relapse/NR||36/5||18/27||<0.001|
Figure 2(a) shows the result of stratified analysis according to the previous treatment response and HCV RNA at the start of re-treatment. The significant difference in SVR observed between high (≥5 log10 IU/mL) and low (<5 log10 IU/mL) baseline viral loads was still found in both previous relapsers (P = 0.02) and previous non-responders (P = 0.02). In patients with a high baseline viral load, previous relapsers achieved a higher SVR rate than previous non-responders (P < 0.0001). Next, the results of stratified analyses according to IL-28B genotype and previous treatment response or HCV RNA at the start of re-treatment showed no significant difference in SVR rates between the IL-28B genotype in patients with relapse after previous treatment (P = 0.63) (Fig. 2b). All patients with less than 5 log10 IU/mL of HCV RNA achieved SVR despite their IL-28B genotype and the SVR rates of patients with 5 log10 IU/mL or more of HCV RNA did not differ between IL-28B genotypes (Fig. 2c). Multivariate analysis among the factors of relapse to previous treatment response, HCV RNA at the start of re-treatment and IL-28B genotype showed that relapse after previous treatment response bore the most predictable relationship to SVR in re-treatment (P = 0.074).
As for the efficacy of re-treatment according to treatment duration among patients with HCV RNA negativity during re-treatment, the SVR rate of 72-week treatment was significantly higher than that of 48-week treatment (72 weeks, 73%, 29/40, vs 48 weeks, 52%, 12/25, P < 0.05). This significant difference was especially found in patients who attained c-EVR but not RVR on re-treatment (72 weeks, 73%, 16/22, vs 48 weeks, 38%, 5/13, P < 0.05) but not in patients who attained RVR or LVR (Fig. 3).
Figure 3. Sustained virological response (SVR) rates according to virological response in re-treatment and treatment duration in patients with genotype 1. , Patients treated for 48 weeks; , patients treated for 72 weeks. RVR, rapid virological response; cEVR, complete early virological response; LVR, late virological response. *P < 0.05; compared to 48 weeks of treatment.
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In genotype 2, the HCV RNA negative rate on re-treatment was 59% (16/27) at week 4, 85% (23/27) at week 12 and 93% (25/27) at week 24, and the SVR rate was 63% (17/27). The two patients with NR in previous treatment did not attain SVR with re-treatment. The factors associated with SVR were assessed by univariate analysis and only the factor of younger age at the start of re-treatment showed marginal significance (P = 0.06) (Table 4). Among the patients with RVR on re-treatment, the SVR rates were similar at 75% (6/8) to those with 24-week and 48-week treatment.
Table 4. Factors associated with a sustained virological response in re-treatment with PEG IFN plus ribavirin in patients with genotype 2
|Factor|| ||SVR||Non-SVR|| P-value|
|No. of patients|| ||17||10|| |
|Age (years)|| ||57.7 ± 8.8||63.7 ± 5.1||0.06|
|Sex: male/female|| ||7/10||8/2||0.11|
|Serum HCV RNA (log IU/mL)|| ||5.4 ± 1.4||6.1 ± 0.8||0.15|
|Serum HCV RNA: <5 log/≥5 log|| ||5/11||1/9||0.35|
|White blood cells (/mm3)|| ||5049 ± 1355||4171 ± 910||0.10|
|Neutrophils (/mm3)|| ||2556 ± 1064||1999 ± 404||0.24|
|Hemoglobin (g/dL)|| ||14.1 ± 1.3||13.8 ± 1.6||0.51|
|Platelets (×104/mm3)|| ||17.9 ± 5.4||14.8 ± 4.3||0.17|
|ALT (IU/L)|| ||38 ± 19||48 ± 47||0.71|
|IL-28B SNP: TT/TG|| ||6/2||4/2||1.00|
|ITPA SNP: CC/CA|| ||5/1||4/0||1.00|
|PEG IFN: α-2a/α-2b|| ||4/13||2/8||1.00|
|PEG IFN dose (µg/kg per week)||α-2a||3.23 ± 0.34||2.24 ± 2.25||1.00|
| ||α-2b||1.32 ± 0.28||1.18 ± 0.23||0.21|
|Ribavirin dose (mg/kg per day)|| ||10.4 ± 2.21||10.1 ± 1.31||0.44|
|1st treatment virological response||RVR/non-RVR||4/13||3/7||1.00|
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PAST STUDIES HAVE revealed that the factors of age, sex, progression of liver fibrosis, value of HCV RNA, number of mutations in the ISDR, amino acid substitutions in the core region, drug adherence and treatment duration show association with HCV eradication in PEG IFN plus ribavirin combination for naïve patients with CH-C.3–5,25–33 Recently, the IL-28B genotype has been reported to be the most powerful factor associated with the antiviral effect of this combination therapy.21–25 While the predictive factors for SVR in PEG IFN plus ribavirin combination therapy for naïve patients have been actively analyzed, those factors for patients who had already experienced this therapy are still unclear. Especially needing assessment is the correlation between IL-28B SNP or the previous treatment response and the antiviral effect in re-treatment. In this study, we tried to determine which factors could most effectively predict the antiviral effect in re-treatment.
In the present study, patients with relapse after the previous treatment and patients with a low serum HCV RNA level at the start of re-treatment showed significantly different results in this study of re-treatment of CH-C patients who had previously failed to attain SVR with PEG IFN plus ribavirin therapy. This result was similar to those of the EPIC3 study on relapse and NR17 and the SYREN trial of NR.18 On the other hand, there was no significant difference between the influence of the IL-28B genotype and SVR. More specifically, if the previous treatment response was the same, there was no difference regardless of the IL-28B genotype. Considering this result, in re-treatment, the previous treatment response was a more effective predictive factor than IL-28B genotype. However, further investigation is needed to clarify the association between IL-28B genotype and antiviral effect of re-treatment because of their small number in this study. In this study, only one patient with the minor allele of IL-28B and NR in previous treatment could start and continue with the increased dose of PEG IFN (from 1.37 µg/kg in the previous treatment to 1.79 µg/kg in re-treatment) and ribavirin (from 10.3 mg/kg per day in the previous treatment to 11.1 mg/kg per day in re-treatment) and attained SVR by extended treatment. If the drug adherence does not improve, patients with the minor allele of IL-28B who show NR in the previous treatment should be treated with new drugs.
The next question is how the patients should be re-treated in order to attain SVR on re-treatment. In this study, the patients with a low serum HCV RNA level (<5 log10 IU/mL) at the start of re-treatment showed a significant rate of cure on re-treatment, and this is almost the same result as that previously reported.16,17 In this study, the two patients with NR in the previous treatment and with less than 5 log10 IU/mL of HCV RNA level (20 KIU/mL and 52 KIU/mL of HCV RNA) at the start of re-treatment attained SVR. On the other hand, even if the previous treatment response was a relapse, the SVR rates were 58% (25/43) among the patients with 5 log10 IU/mL or more of HCV RNA. Because the HCV RNA level changed after the antiviral treatment, it is important to not miss the timing of when the HCV RNA level is low.
With respect to treatment duration among patients with HCV RNA negativiation during re-treatment, 72 weeks of treatment significantly increased the SVR rate compared to 48 weeks. This result was almost the same as that of the REPEAT study.16 In our present study, the SVR rate among the patients with c-EVR but not RVR in re-treatment was significantly high by 72 weeks of treatment. On the other hand, the SVR rates among the patients with RVR in re-treatment were similar between the patients with 48 weeks and 72 weeks of treatment. Thus, patients with c-EVR but not RVR in re-treatment should be re-treated for a longer period. In order to attain better SVR, extended treatment duration is generally recommended for patients with on-treatment LVR, whereas standard treatment duration is considered to be sufficient for patients with on-treatment c-EVR. However, the present study revealed that, even if patients achieved c-EVR on re-treatment, 72 weeks of treatment seems to be better than 48 weeks for treatment-experienced patients. The majority of naïve patients showing on-treatment c-EVR could eradicate HCV with 48 weeks of treatment while some could not. In a treatment-experienced setting, patients who are able to respond early but not eradicate HCV would be selected, and therefore extended treatment may be needed.
With genotype 2, the SVR rate was relatively high (63%). The patients who could not attain SVR in re-treatment (two patients) showed NR in the previous treatment. Thus, the patients with genotype 2 and showing NR in previous treatment seemed to be difficult to treat and could be treated with other drugs. Among the patients with RVR in re-treatment, the SVR rates were similar among those with RVR in re-treatment between 24 weeks and 48 weeks of treatment. The effectiveness of extended treatment for the patients with genotype 2 in re-treatment could not be demonstrated because of their small number in this study. Further investigation is needed to clarify this.
In conclusion, this study shows that the efficacy of re-treatment for genotype 1 patients who failed to show SVR to previous treatment with PEG IFN plus ribavirin could be predicted from the previous treatment response and a low HCV RNA level at the start of re-treatment. Re-treatment for 72 weeks led to clinical improvement for genotype 1 patients with c-EVR and without RVR on re-treatment.