A Multicenter Study
C. Puoti; G. Barbarini; A. Picardi; M. Romano; A. Pellicelli; A. Barlattani; F. Mecenate; R. Guarisco; O. M. Costanza; L. Spilabotti; L. Bellis; M. E. Bonaventura; O. Dell' Unto; M. G. Elmo; A. M. Nicolini; L. Nosotti; and F. Soccorsi
Posted: 07/05/2011;
J Viral Hepat. 2011;18(6):393-399. © 2011 Blackwell Publishing
Abstract and Introduction
Abstract
Rapid virological response (RVR) is now considered the strongest predictor of sustained virological response (SVR) in patients with HCV undergoing antiviral treatment, and thus, shorter antiviral treatment for these patients has been suggested. However, no data exist on the predictive value of RVR in HCV carriers with normal ALT values. A total of 137 patients with persistently normal ALT treated with peginterferon alfa 2a and ribavirin were studied. Fifteen patients dropped out early because of side effects, and in 10 patients with HCV-1 treatment was discontinued because of lack of early virological response (EVR). RVR was observed in 68% of the patients (42% patients with HCV-1, 90% HCV-2 and 64% HCV-3). An end-of-treatment response was observed in 86% of the patients (68% HCV-1, 100% HCV-2 and 91% HCV-3). SVR was maintained in 91 patients (46% HCV-1, 97% HCV-2 and 82% HCV-3). Overall, 92% patients with rapid response did obtain HCV eradication vs only 38% of those without rapid response. HCV-1 patients with baseline HCV RNA <400 × 103 IU/mL were more likely to achieve RVR and SVR than those with higher HCV RNA levels. We conclude that patients with genotype 1 and normal ALT who achieve HCV RNA negativity at week 4 may have a higher probability of eradicating their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in these people might be shortened in the case of RVR. Persistently normal alanine aminotransferase levels patients with genotype 2 or 3 have a high chance of achieving SVR, so retesting of HCV RNA during treatment may have no additional practical value in these subjects.
Introduction
Historically, patients with chronic hepatitis C virus (HCV) infection and persistently normal alanine aminotransferase levels (PNALT) have been classified as 'healthy' or 'asymptomatic',[1–3] not thought to progress and thus excluded from antiviral treatment.[4,5] Thus, whether patients with chronic hepatitis C (CHC) and normal ALT should be offered antiviral treatment in clinical practice has been disputed until recently.[6–8] Interferon (IFN) treatment is associated with important side effects and is rather expensive, whereas the risk of progression of the disease in this setting is extremely low.[9–11] For these reasons, the first Consensus Conferences on HCV discouraged treatment in subjects outside clinical trials.[4,5] The introduction of the combination of peginterferon (PEG-IFN) plus ribavirin (RBV) resulted in higher response rates.[8–11] The first multicentric study[12] demonstrated the efficacy and safety of therapy with PEG-IFN a-2a plus RBV also in patients with PNALT; however, in this study, subjects with HCV-1 were treated with a fixed RBV dose lower than that universally recommended for this subset of patients (800 mg/day instead of 1000–1200 mg/day). Simulation studies suggest that sustained virological response (SVR) in HCV-1 patients with PNALT significantly increases when the standard weight-adjusted dose of RBV is administered.[13] More recently, an Italian multicentric study showed higher efficacy of the approved dosage of RBV (1000–1200 mg/day) in patients with HCV-1 and PNALT and excellent sustained responses in those with HCV-2 or 3 infection.[14]
Given the side effects and costs of antiviral therapy, the optimal duration of treatment, and the possibility of treating patients for shorter periods has been evaluated.[15–18] According to the new concept of 'response-guided therapy' (RGT), tailored duration of antiviral therapy with shorter treatment for patients with rapid virological response (RVR) has been suggested, chiefly for patients with HCV-1.[19] Despite several studies on the predictive value of RVR in HCV patients with abnormal ALT levels, no data thus far exist on its predictability of response in patients with persistently normal ALT levels. Thus, we have decided to conduct this multicentric study to assess whether RVR might be predictive of SVR also in this particular subset of patients with HCV and to evaluate the cost effectiveness to determine HCV RNA at 4 weeks in these 'easy-to-treat' subjects.
Patients and Methods
Eligibility and Definition
Hepatitis C virus carriers were defined as having HCV RNA positivity by polymerase chain reaction (PCR) and normal ALT in at least four different occasions 3 months apart over a 12-month period. Exclusion criteria were age <18 years or >70 years, HBsAg or human immunodeficiency virus positivity, previous IFN treatment, serum HCV RNA negativity, history of heavy alcohol abuse, clinical or ultrasound (US) signs of cirrhosis, hepatocellular carcinoma, abnormal ferritin levels, neutropaenia (absolute neutrophil count <1500 cells/mm3), thrombocytopaenia (<100 000 platelets/mm3), anaemia (haemoglobin concentration <12 g/dL in women and <13 g/dL in men) and any abnormality of other liver function tests or routine biochemical tests. Pregnant or lactating women were also excluded. All fertile men and women who participated in the trial were strongly advised to use effective contraception methods during treatment and for 6 months after the end of treatment. All patients reporting contraindications to IFN or RBV treatment and those suffering from significant coexisting medical conditions were excluded from this study. Scarce motivation or refusal to sign informed written consent to treatment was considered exclusion criteria.
Serum Virological and Biochemical Assays
Antibodies to HCV were tested by the ELISA III (Ortho Diagnostic System, Raritan, NJ, USA). HCV RNA quantification was obtained using a PCR-based commercially available test (Cobas Amplicor HCV Monitor v 2.0; Roche Molecular Systems, Basel, Switzerland). HCV genotyping was performed using a commercial kit (INNO-LiPA HCV II; Innogenetics, Ghent, Belgium). Aminotransferases and other serum liver function tests were determined by routine methods in the local laboratory. The upper limit of normal (ULN) ALT value was 40 IU/L.
Liver Histology
Liver biopsy specimens obtained within 6 months before study onset were evaluated using the Metavir classification.[20] Ultrasound-guided liver biopsy was performed using a modified Menghini needle. Formalin-fixed, paraffin-embedded specimens were routinely stained with haematoxylin–eosin and reviewed by local pathologists blinded to clinical and biochemical data.
Liver Stiffness Assessment
Liver stiffness (LS) was evaluated by transient elastography (Fibroscan®, Echosens SA, Paris, France). LS was assessed on the right lobe of the liver, through the intercostal spaces, with the patient in the supine position and the right arm in maximal abduction. Ten validated measures were performed in each patient. The success rate was calculated as the number of validated measures divided by the total number of measures. Results were expressed in kilopascals (kPa). The median value was considered representative of the hepatic stiffness. Only procedures with 10 validated measures and a success rate of at least 60% were considered reliable.
Study Design
All patients received PEG-IFN α-2a 180 μg once weekly plus RBV 800 mg/day for 24 weeks (patients with HCV-2 and HCV-3) or 1000–1200 mg/day for 48 weeks (patients with HCV-1, according to body weight). Stepwise reductions of the dosage of IFN and of RBV were permitted in patients experiencing clinically significant adverse events. The dosage of RBV was reduced in patients showing a decrease in the haemoglobin concentration to <10 g/dL, and treatment was discontinued if the haemoglobin concentrations decreased to <8.5 g/dL despite 4 weeks of treatment with a reduced dosage of the drug. Given the aims of this study, PEG-IFN monotherapy was not allowed. Serum HCV RNA concentration was determined at weeks 4, 12 and 24 in patients infected by genotypes 2 and 3 and at weeks 4, 12, 24, 36 and 48 in patients infected by genotype 1. HCV RNA was further evaluated in all patients 24 weeks after the end of the treatment.
Definition of Virological Responses
Rapid virological response (RVR) was defined as undetectable serum HCV RNA at week 4 of treatment. Early virological response (EVR) was defined as detectable serum HCV RNA at week 4 and either undetectable HCV RNA or >2 log10 decrease in serum HCV RNA level at week 12. End-of-treatment response (EoTR) was defined as the absence of detectable HCV RNA at the end of the treatment, while SVR was defined as the absence of detectable HCV RNA levels at end of the follow-up (24 weeks after the end of the treatment). Relapse (REL) was defined as the reappearance of HCV RNA during the follow-up in subjects with previous EoTR.[21]
Statistical Analysis
Statistical significance was assessed by the Chi-squared test with Yates' and Bonferroni's correction and 95% confidence intervals, analysis of variance (ANOVA) and Student's t-test for independent samples. Logistic regression and analysis of covariance were used to analyse categorical and continuous variables, respectively. A P-value of <0.05 was considered significant. Data are expressed as means ± SD.
Results
One hundred and thirty-seven consecutive patients (102 women, range 19–64 years) referred because of HCV positivity and PNALT to the Liver Units participating in this study were evaluated (see appendix). Fifty-eight of one hundred and thirty-seven patients (42%) had HCV-1, 67 had HCV-2 (49%) and 12 (9%) had HCV-3. The mean serum HCV RNA level was 220 ± 95 × 103 IU/mL (range 1.9–4.800 × 103 IU/mL). Only 35% of the 137 patients in study had a history of previous exposure to blood (transfusion, 16; previous intravenous drug addiction (IVDA), 11; unsafe sex with multiple partners, 4; occupational exposure, 6; unsafe tattooing or piercing, 11). In the other patients, discovery of HCV positivity occurred recently by chance as a result of blood donations, screening for endoscopic or surgical procedures, hospitalizations and screening of relatives of HCV-positive patients. In these patients, the actual duration of HCV infection cannot be evaluated. No differences in demographical, virological and histological features were seen between these patients and those with known risk factors for blood exposure.
Liver histology was available in 115/137 patients: 22 patients (19%) had normal liver, 89 (77%) showed F1 fibrosis, three had F2 fibrosis and one had F3 fibrosis. In the remaining 22 patients, histological data were not available because of refusal to perform biopsy (14 patients) or because of inadequate specimens (eight patients). These patients were offered transient elastography through Fibroscan® before treatment, showing normal or low values of LS in 14/22 patients (mean 3.2 ± 2.0 kPa, range 3.0–6.1 kPa), indicative of F0–F1 fibrosis; six patients had LS indicative of F2 fibrosis (mean 8.2 ± 3.4 kPa, range 7–12 kPa), whereas the latter two patients had higher values of stiffness (13.2 and 14.0 kPa, respectively). No demographical differences were seen between these patients and those undergoing liver biopsy. The main demographical, histological and virological features of the patients are shown in Table 1.
Fifteen patients (8 HCV-1, 6 HCV-2, 1 HCV-3) early dropped out because of side effects or refuse to continue treatment: severe pyrexia (one patient), depression (one patient), refuse to continue treatment (two patients), fatigue and other constitutional symptoms (four patients), private problems (three patients), failed to return (four patients). The mean duration of treatment in this group was 3 weeks (range 1–5 weeks). In these subjects, RVR was not evaluated.
The remaining 122 patients (50 HCV-1, 61 HCV-2, 11 HCV-3) did continue treatment (Fig. 1). RVR was seen in 83/122 patients (68%): 21/50 patients with HCV-1 (42%), 55/61 HCV-2 (90%) and 7/11 (64%) HCV-3 (χ2 = 29.416, P ≤ 0.0001) (Table 2). Ten out of the 50 patients harbouring HCV type 1 (20%) showed persistent HCV RNA positivity at 12 weeks (HCV RNA drop ≤2 log10 decrease); thus in these subjects, treatment was discontinued, according to the stopping rule policy for patients with HCV-1 (absence of EVR) (Figs 1 & 2).
Figure 1.
Overall rates of Rapid virological response (RVR) and sustained virological response (SVR) in the patients in study.
Figure 2.
Rates of sustained virological response (SVR) according to presence or absence of Rapid virological response (RVR) in patients with HCV-1.
End-of-treatment response was seen in 105/122 patients (86%): 34/50 of patients with HCV-1 (68%, 21 with RVR and 14 without RVR), all of those harbouring HCV-2 and 10/11 (91%, seven with RVR and three without RVR) of HCV-3 infected subjects were HCV RNA negative at the end of the antiviral treatment (Table 2).
Virological response at the month 6 of follow-up (SVR) was maintained in 91/122 patients (75%): 23/50 patients with HCV-1 (46%), 59/61 patients with HCV-2 (97%) and 9/11 (82%) patients with HCV-3 (χ2 = 24.397, P = 0.0001) (Table 2). Thus, REL after achieving EoTR was seen in 32% of patients with HCV-1 (11/34), 3% of HCV 2 (2/61) and 10% of HCV-3 (1/10: χ2 = 16.077, P < 0.0001).
Seventy-six of eighty-three (92%) subjects with RVR (Fig. 1) did obtain SVR vs only 38% of those without RVR (15/39; P < 0.0001). By stratifying SVR rates by genotype and RVR, we found that among patients with HCV-1 SVR was observed in 16/21 (76%) of subjects with RVR and only 7/29 (24%) of those without RVR (χ2 = 4.812, P < 0.02; Fig. 2); in patients with HCV-2, a SVR was achieved in 54/55 patients (98%) with RVR and 5/6 (83%) of those without RVR (χ2 = 0.536, P = 0.46, N.S.; Fig. 3), and in patients with HCV-3, SVR was found in 6/7 (86%) of subjects with RVR and 3/4 (75%) of those without RVR (χ2 = 0.136, P = 0.71, N.S.; Fig. 4).
Figure 3.
Rates of sustained virological response (SVR) according to presence or absence of Rapid virological response (RVR) in patients with HCV-2.
Figure 4.
Rates of sustained virological response (SVR) according to presence or absence of Rapid virological response (RVR) in patients with HCV-3.
HCV-1 patients with baseline HCV RNA <400 × 103 IU/mL were more likely to achieve RVR and SVR. Among the 40 patients with HCV 1 who had the full treatment course, 22 (55%) had HCV RNA <400 × 103 IU/mL and 18/40 had HCV RNA >400 × 103 IU/mL. RVR was seen in 16/22 of the former (73%) and only 5/18 of the latter (28%; χ2 = 6.320, P = 0.012), although continuation of the treatment did allow SVR in 13/16 (81%) and 3/5 (60%) of the patients, respectively (N.S.) (Table 3).
Forty-four of one hundred and twenty-two patients (36%) had ALT levels below 50% of the ULN (≤20 U/L) and 78 patients had ALT ≥ 20 U/L. However, we found that baseline ALT levels did not influence the rates of RVR and SVR, as no differences were seen between the two groups of patients. Logistic regression analysis was applied to identify predictors of SVR. Factors significantly associated (P < 0.05) with SVR on univariate analysis were lower baseline viral load (<400 × 103 IU/mL), non-1 genotype, female gender, lower BMI (<25 kg/m2) and HCV RNA undetectable at week 4 of treatment. At multivariate analysis, only RVR and non-1 genotype were predictors of SVR.
Safety of the treatment was excellent. Except for the 15 patients in which severe adverse events requiring very early treatment premature withdrawal were seen, in the others 122 subjects who did continue treatment no major side effects were reported. In particular, the appearance of anaemia was observed in 21 out of these 122 patients, but reduction of RBV according to the protocol study was needed in only six patients, three of which failed to have SVR. No signs or symptoms of severe thyroid dysfunction were seen.
In all these 122 subjects, side effects were very mild in severity and not different from those seen among patients with abnormal ALT treated with the same schedules during the same period. The more frequently reported events were mild asthenia, minor depression or irritability, fever following early IFN administrations.
Discussion
It is known that HCV carriers with persistently normal ALT levels overall show demographic and virological features (prevalence of women and non-1 HCV genotypes, younger age, often lean, mild liver damage or even absence of fibrosis) traditionally associated with higher response rates to combined treatment with PEG-IFN plus RBV,[2,22–24] and thus, they might achieve SVR even with shorter than usually recommended treatment periods.[25] Despite several studies have evaluated the ability of RVR to predict SVR in HCV patients with elevated ALT levels,[15–18] no data exist on this topic in subjects with PNALT. Furthermore, previous studies have shown that HCV subjects with PNALT have similar[12,13] or even higher[14] chances of SVR than those with abnormal ALT values, and thus, the identification of early parameters able to predict sustained HCV eradication in this setting is needed to avoid unnecessary prolongation of therapy in this population of 'super-responders'. The main predictive factor up till now identified is represented by the absence of HCV RNA at week 4 of treatment, the so-called RVR.
It has been shown that patients with chronic hepatitis C and persistently normal ALT have similar viral kinetics as those with elevated ALT levels during antiviral therapy.[26]
Recently, it has been reported that a 2 log drop in HCV RNA at day 28 was the best predictor of SVR in patients with HCV-1 infection and PNALT treated with PEG-IFN alpha 2 b plus RBV[27] and that a failure to reduce viral load by 2 logs correctly identified patients with a low (<15%) probability of achieving a SVR.
Our data clearly show that patients with PNALT and HCV RNA negativity after 4 weeks of treatment have higher probability to eradicate their HCV infection than those without RVR and that even HCV-1 patients with RVR have excellent rates of SVR: analysing the rates of SVR by genotype distribution, we found that among patients with RVR, an SVR was achieved in 76% of patients with HCV-1, 98% of HCV-2 and 86% of HCV-3. By contrast, in the absence of RVR, an SVR was observed in 7/29 (24%), 5/6 (83%) and 3/4 (75%) of the three groups of patients, respectively.
Thus, the presence or absence of RVR might have great clinical relevance mainly in patients with HCV-1 type. Indeed, whilst patients with HCV-2 or HCV-3 showed good SVR rates regardless of the presence of RVR, in those with HCV-1 genotype the probability to reach SVR significantly decreased from 76% in patients with RVR to 24% in those without RVR. It means that a 4-week stopping rule policy based on RVR does not seem to be cost effective in patients with PNALT and non-1 genotypes, given the exceedingly high virological responses in this group; by contrast, it could have important consequences for the practical management of HCV-1 patients with normal ALT. In fact, patients infected with HCV genotype 1 who became HCV RNA negative by week 4 were more likely to achieve SVR than those who did not become HCV RNA negative until week 12. However, persistent HCV RNA positivity at week 4 does not justify early stopping of the treatment, as 7 HCV-1 patients without RVR did finally achieve SVR.
Recent data suggest that a baseline level of 400 × 103 IU/mL is the most effective cut-off for a high or low probability to achieve SVR in genotype 1-infected patients.[19] Our findings confirm that low baseline HCV RNA values might influence the probability of reaching SVR in patients with HCV-1: in our series of patients, SVR was seen in 81% of HCV-1 patients with RVR and HCV RNA levels <400 × 103 IU/mL vs 60% of those with RVR but HCV RNA levels >400 × 103 IU/mL, although this trend was not significant. It has been shown that HCV-1 patients with abnormal ALT levels and with low baseline HCV RNA level (<400 × 103 IU/mL) and a RVR, there was no significant difference between 24 and 48 weeks of PEG-IFN plus RBV administration, thus suggesting that 24 weeks of therapy is the appropriate treatment duration in this group.[28] By contrast, ALT baseline levels did not influence the rates of RVR and SVR, according to previous studies[12,14] Recently, it has been demonstrated that HCV-1 patients with low baseline HCV RNA levels (<600 000 IU/mL) and an RVR achieve an SVR rate of up to 90.%[18] Jensen et al.[29] reported that up to 23% of HCV-1 patients treated with PEG-IFN plus RBV achieved RVR, 89% of these reaching SVR after treatment duration of 24 weeks.
The higher than usually SVR rates found in our study in patients with genotype 1 might be explained by several factors, such as the high prevalence of women, the mild degree of liver damage, the relatively low mean age and, last but not the least, the normal BMI values observed in the majority of the patients.
In summary, this is the first study showing that patients with genotype 1 and normal ALT reaching HCV RNA negativity at week 4 might have excellent probability to eradicate their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in patients with PNALT might be shortened in the case of RVR. By contrast, PNALT patients with genotype 2 or 3 in any case have a high chance of achieving SVR, so retesting of HCV RNA during treatment has no practical value in these subjects.[30]
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