Leonardo Mottola

An IL28B Polymorphism Determines Treatment Response of Hepatitis C Virus Genotype 2 or 3 Patients Who Do Not Achieve a Rapid Virologic Response

BACKGROUND & AIMS Polymorphisms in the region of the interleukin (IL)-28B gene on chromosome 19 have been associated with peginterferon-alfa-induced clearance of genotype 1 hepatitis C virus (HCV); there are no data for patients with genotype 2 or 3 HCV. We evaluated the effects of IL-28B polymorphisms on response to treatment with peginterferon and ribavirin in a well-characterized cohort of genotype 2/3 patients. METHODS DNA was analyzed from 268 patients (Caucasian: genotype 2, 213; genotype 3, 55). Patients were randomly assigned to groups that received standard duration (24 wk; n = 68) or variable durations of therapy. Patients who received variable durations (VD) and had a rapid virologic response (RVR) were treated for 12 weeks (VD12; n = 122); those without an RVR were treated for 24 weeks (VD24; n = 78). IL-28B genotypes (rs12979860) were analyzed for association with treatment response. RESULTS The frequencies of the IL-28B genotypes were as follows: CC, 37%; CT, 48%; and TT, 15%; 82% of patients with the CC genotype achieved a sustained virologic response (SVR), compared with 75% with the CT and 58% with the TT genotypes (P = .0046). Differences between IL-28B genotypes were greatest among patients who failed to attain RVR (VD24 SVR rates: CC, 87%; CT, 67%; and TT, 29%; P = .0002). Among patients with RVRs (61%), the IL-28B genotype was not associated with SVR (>70% for all IL-28B genotypes). In a multivariable logistic regression model, IL-28B genotype predicted SVR (odds ratio, 1.76; 95% confidence interval, 1.16-2.7). CONCLUSIONS An IL-28B polymorphism was associated with an SVR in patients infected with genotype 2/3 HCV who did not achieve a RVR. Analysis of IL-28B genotype might be used to guide treatment for these patients.

Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial

It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48‐week treatment. Patients (n = 696) received peginterferon alfa‐2a, 180 mg/week, or peginterferon alfa‐2b, 1.5 mg/kg/week, plus ribavirin, 1000‐1200 mg/day, for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if HCV‐RNA–negative at weeks 4, 8, or 12, respectively (variable, n = 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8‐51.4] of the patients in the standard group and in 48.8% (CI 44.2‐53.3) of the patients in the variable group (P = 0.37). The percentages of patients who first achieved undetectable HCV RNA at weeks 4, 8, or 12 were 26.7%, 27.8%, and 11.3%, respectively. In the standard treatment group, 87.1%, 70.3%, and 38.1% of patients who first achieved undetectable HCV RNA at 4, 8, or 12 weeks attained SVRs, respectively. In the variable group, corresponding SVR rates were 77.2%, 71.9%, and 63.5%. Low viremia levels and young age were independent predictors of response at week 4 [rapid virologic response (RVR)]. RVR patients with baseline viremia ≥400,000 IU/mL achieved higher SVR rates when treated for 48 weeks rather than 24 weeks (86.8% versus 73.1%, P = 0.14). The only predictive factor of SVR in RVR patients was advanced fibrosis. Conclusion: Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs. (HEPATOLOGY 2007.)

Inosine Triphosphatase Genetic Variants are Protective Against Anemia During Antiviral Therapy for HCV2/3 But Do Not Decrease Dose Reductions of RBV Or Increase SVR

Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphosphatase (ITPase) deficiency protect against ribavirin (RBV)‐induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on‐treatment anemia in a well‐characterized cohort of genotype 2/3 patients treated with variable‐duration pegylated interferon alfa‐2b (PEG‐IFN‐α2b) and RBV. Two hundred thirty‐eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG‐IFN‐α2b plus weight‐based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10−6 for rs1127354 and P = 10−7 for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10−11). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08‐0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR. Conclusion: Two ITPA variants were strongly associated with protection against treatment‐related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR. (HEPATOLOGY 2011;53:389‐395.)

Limited use of interleukin 28B in the setting of response‐guided treatment with detailed on‐treatment virological monitoring

A single‐nucleotide polymorphism upstream of the interleukin‐28B (IL28B) gene is associated with pegylated interferon‐alfa–induced viral clearance in hepatitis C virus (HCV) genotype 1 patients. Using a well‐characterized cohort of patients randomized to standard versus response‐guided therapy, we studied whether the favorable CC type allows shortening of treatment duration. Association with viral kinetics, sustained viral response (SVR), and predictors of response were also analyzed. In the original study, 696 patients were randomized to either standard or variable therapy of 24, 48, or 72 weeks according to first undetectable HCV RNA. Association between IL28B determined by genotyping rs12979860 and end of treatment response and SVR by treatment arm was tested; baseline predictors of response were analyzed using multiple logistic regression. A total of 454 patients were evaluated. The frequency of IL28B type was CC = 29%, CT = 53%, TT = 18%. CC type was strongly associated with rapid virological response (RVR) as well as higher rates of week 8 and week 12 response. CC type was associated with SVR in both arms. In patients with RVR, SVR was high and IL28B type was not associated with SVR. In RVR patients, there was no significant difference in SVR or relapse rates after 24 or 48 weeks by IL28B type. Among non‐RVR patients, CC type was associated with SVR at a higher rate than CT/TT, both in standard and variable analysis. However, when week 8 and week 12 responders were considered separately, IL28B type was no longer predictive of SVR. Few CC patients remained viremic beyond week 8 to allow the analysis of relationships between IL28B type and extended treatment.

Individualized treatment with combination of Peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3

BACKGROUND & AIMS The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established. METHODS Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200 mg of ribavirin daily according with body weight > or <75 kg. Patients were randomized to standard 24 weeks (Std24) or to a 12 or 36 weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36 weeks duration. RESULTS At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treatment (EOT) responses were 80.4% (CI 85.4-95.3) and 97.6% (CI 94.9-99.9) in the two arms, respectively (p=0.019). In patients without wk4-R, corresponding rates were 61.9% (50.6-73.2) and 75.3% (CI 65.9-84.6) (p=0.08). SVR was attained in 302 patients, 71.4% (CI 65.3-77.6) in the St24 group and 74.3% (CI 58.4-80.3) in the variable 12/36 arm. Among patients with wk4-R, SVR was 81.6% (CI 75.1-88.1) and 82.5% (75.9-89.1), respectively. In patients without wk4-R, SVR amounted to 52.1% (CI 40.4-63.7) and 61.7 (CI 51.1-72.3) in the two arms (p=0.25). CONCLUSIONS HCV genotype 3 patients with week4-R may be treated safely with 12 weeks of therapy, provided that sufficiently high doses of ribavirin are administered. For patients still viremic at treatment week 4, SVR rates were numerically higher after 36 weeks of treatment than after the currently recommended 24 weeks.

Treatment optimization and prediction of HCV clearance in patients with acute HCV infection

BACKGROUND & AIMS The lack of consensus on the optimal timing, regimen, and duration of treatment, in patients with acute HCV infection, stimulates the research on both favourable outcome predictors and individualized treatment regimens. This study aimed at investigating the impact of IL28B SNP rs12979860 alone or in combination with HLA class II alleles in both predicting spontaneous viral clearance and individualizing treatment strategies for patients with HCV persistence, after acute HCV exposure. METHODS 178 patients with AHC, consecutively treated with interferon alone or in combination with ribavirin, starting within or after 48 weeks from the diagnosis of AHC, were tested for IL28B SNPs and HLA class II alleles. RESULTS Spontaneous viral clearance was achieved in 28% of 169 patients available for genetic testing. Factors associated with HCV elimination were jaundice (OR 2.75, 95% CI 1.31-5.77) and IL28B CC (OR 3.87, CI 1.71-8.51), but not HLA alleles. In CT/TT patients without jaundice, NPV for virus persistence was 98%. In patients with IL28B CT/TT, starting treatment 48 weeks after the onset was significantly associated with lower rates of response (28% vs. 100%, p=0.027). By contrast, no significant differences in the rate of SVR were observed for CC carriers who started treatment later (65% vs. 85%, p=1.0). CONCLUSIONS In patients with acute HCV hepatitis, lack of viral clearance may be predicted by absence of jaundice and IL28B CT/TT genotype; in patients with these characteristics, treatment needs to be started immediately.

Interleukin 28B polymorphisms as predictor of response in hepatitis C virus genotype 2 and 3 infected patients

Single nucleotide polymorphisms near the interleukin 28B (IL-28B) gene have been identified as strong predictors of both spontaneous or Peg-interferon (Peg-IFN) and ribavirin (RBV) induced clearance of hepatitis C virus (HCV). Several studies have shown that, in patients with genotype 1 (GT-1), rs12979860 C/C and rs8099917 T/T substitutions are associated with a more than twofold increase in sustained virological response rate to Peg-IFN and RBV treatment. Although new treatment regimens based on combination of DAA with or without IFN are in the approval phase, until combination regimens with a backbone of Peg-IFN will be used, we can expect that IL28B holds its importance. The clinical relevance of IL28B genotyping in treatment of patients infected with HCV genotype 2 (GT-2) and 3 (GT-3) remains controversial. Therefore, after a careful examination of the available literature, we analyzed the impact of IL28B in GT-2 and -3. Simple size of the studies and GT-2 and GT-3 proportion were discussed. An algorithm for the practical use of IL28B in these patients was suggested at the aim of optimizing treatment.

What's new in HCV genotype 2 treatment

Genotype 2 (HCV‐2) accounts for 8% of the patients with chronic hepatitis C virus in Europe. Because of the favourable response to interferon (IFN)‐based treatment, this group is considered an ‘easy‐to‐treat’ genotype along with HCV‐3. However, experimental and clinical data suggest possible differences between HCV‐2 and ‐3. Recently, subtle differences in treatment efficacy have also been shown in response‐guided treatment studies. In these studies, the duration of pegylated interferon (PEG‐IFN) and ribavirin (RBV) treatment was tailored according to treatment response. Although SVR rates were similar between HCV‐2 and HCV‐3 patients after a rapid virological response (RVR), in the absence of RVR, the rates were lower in HCV‐3 than in HCV‐2. The triple combination treatment, including direct‐acting antivirals (DAA) that will be commercialized in the coming months might increase SVR rates in this particular subgroup of patients. According to existing results, telaprevir might be beneficial in HCV‐2 but not in HCV‐3 patients. A nucleotide analogue polymerase inhibitor, PSI‐7977 by Pharmasett has been shown to be active against both. The role of the IL28B polymorphism as a predictor of response to the current standard of care (SoC), PEG‐IFN and RBV treatment is the subject of debate, but this mainly seems to be because of the small size of the samples in the studies performed so far. Existing results suggest that the genetic evaluation of IL28B may be useful in patients with HCV‐2 for predicting response in patients without RVR.

IL28B CC-genotype association with HLA-DQB1*0301 allele increases the prediction of spontaneous HCV RNA clearance in thalassaemic HCV-infected patients.

BACKGROUND A single nucleotide polymorphism (SNP), upstream of the IL28B gene has been recently associated with natural clearance of HCV. In a well-characterized cohort of patients with thalassaemia major exposed to the risk of acquiring HCV infection by blood transfusions, we aimed to replicate this finding and to evaluate whether combining the IL28B genotype and HLA class II alleles allow viral clearance to be accurately predicted. METHODS Of 168 patients, 130 with complete clinical history were included in the analysis. According with their HCV antibodies status 13 were defined HCV resistant, and 117 infected. Infected patients were subdivided, giving 49 with self-limiting and 68 with ongoing infection. RESULTS IL28B CC-genotype was observed in 32 patients with self-limiting and in 23 with ongoing infection (64% versus 34%; P=0.004). HLA DQB1*0301 allele was associated with viral clearance in 36 cases (73%; P<0.0001). Both DQB1*0301 and IL28B CC-genotype were found to be independent predictors of HCV clearance (OR=5.64, 95% CI 1.52-20.9 and OR=5.76, 95% CI 2.16-15.33, respectively). With the addition of DQB1*0301, the accuracy of the prediction increased from 63% to 69%. CONCLUSIONS In addition to IL28B CC-genotype, HLA DQB1*0301 helps in predicting natural clearance of HCV after acute infection.

Ribavirin dosage in patients with HCV genotypes 2 and 3 who completed short therapy with peg‐interferon α‐2b and ribavirin

Aliment Pharmacol Ther 31, 1346–1353