A polymorphism linked to RRAS, SCAF1, IRF3 and BCL2L12 genes is associated with cirrhosis in hepatitis C virus carriers.

BACKGROUND & AIMS: Host genetic factors could play a primary role in determining risk for cirrhosis development in HCV-infected patients. The aims of this study were to discover new genetic variants associated with this trait and to replicate some associations formerly reported. METHODS: Three hundred and thirty-seven HCV carriers with available data about liver fibrosis status, who initiated treatment with pegylated interferon plus ribavirin, were included. Of them, 77 (22.85%) were cirrhotic. One hundred and forty-four SNPs from 40 genes related to cholesterol metabolism/transport, sustained viral response to HCV therapy, liver fibrosis, or immune response, were genotyped in all samples. Plink software was used to perform univariate association analyses. The results obtained were adjusted by other parameters related to cirrhosis using multivariate logistic regression models. RESULTS: Only the SNP rs12104272, linked to RRAS, SCAF1, IRF3 and BCL2L12 genes, was associated with cirrhosis. It was observed a higher proportion of rs12104272 A allele carriers in the non-cirrhotic group (60.63%) than in the cirrhotic group (38.15%) (adjusted OR = 0.36, 95% CI = 0.180-0.746, P = 0.006). This effect was stronger in the background of rs12979860 CC genotype of IL28B (adjusted OR = 0.069, 95% CI = 0.014-0.349, P = 0.001). CONCLUSION: The rs12104272 SNP could have clinical value to select those individuals at lower risk for cirrhosis development.

Sustained virological response to pegylated interferon plus ribavirin leads to normalization of liver stiffness in hepatitis C virus-infected patients.

INTRODUCTION: Pegylated interferon plus ribavirin (Peg-IFN/RBV) therapy leads to improvements in liver stiffness measurements (LSM) in hepatitis C virus (HCV)-infected patients. However, the rate of LSM return to normal values in response to Peg-IFN/RBV is unclear. Thus, our aim was to assess the probability and factors associated with LSM normalization in HCV-infected patients receiving Peg-IFN/RBV. METHODS: This prospective observational longitudinal study included 160 HCV-infected patients, 111 (69%) with human immunodeficiency virus and receiving Peg-IFN/RBV, with baseline LSM ≥ 7kPa. The outcome variable was LSM normalization, i.e. a stable decrease in LSM below 7kPa after starting Peg-IFN/RBV. RESULTS: After starting Peg-IFN/RBV, 56 [35%, 95% confidence interval (95% CI): 28-42%] patients showed LSM normalization. The probability of LSM normalization was 21% (95% CI: 13.2-32.4%) at 12 months, and 51.3% (95% CI: 39.9-63.9%) at 24 months after Peg-INF/RBV initiation for individuals with sustained virological response (SVR), and 8.3% (95% CI: 4-16.6%) at 12 months and 11.3% (95% CI: 6-20.7%) at 24 months for those without SVR (p<0.001). For individuals with LSM ≥ 7kPa 24 weeks after the pre-planned end of treatment, LSM normalizations were only observed among those with SVR. Achievement of SVR [Hazard ratio (HR, 95% CI): 6.84 (3.39-13.81)] and lack of baseline cirrhosis [HR (95% CI): 4.17 (1.69-10)] were independently associated with LSM normalization after starting Peg-IFN/RBV. CONCLUSIONS: LSM normalizations during Peg-IFN/RBV treatment are more likely, and occur earlier among patients with SVR. In addition, LSM normalizations continue 24 weeks after the scheduled end of therapy, but only among individuals who reach SVR.

Prediction of response to pegylated interferon plus ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients using HCV genotype, IL28B variations, and HCV-RNA load.

BACKGROUND & AIMS: This study aimed at developing a predictive algorithm based on interleukin 28B (IL28B) genotype, hepatitis C virus (HCV) genotype, and plasma HCV-RNA load, which could accurately allow us to define the probability of response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy in HIV/HCV-coinfected patients. METHODS: Five hundred and twenty-one treatment-naive HIV-infected patients, who initiated HCV therapy with Peg-IFN/RBV, were analysed in an on-treatment basis. Patients were categorized as unlikely responders, uncertain responders, and anticipated responders (<20%, 20-60%, and >60% probability to achieve SVR, respectively). RESULTS: HCV genotype, baseline HCV-RNA load, and IL28B genotype were confirmed as independent predictors of SVR in a logistic regression analysis. A stepwise algorithm based on these three variables was created based on 321 patients and evaluated in the remaining 200 patients. Unlikely responders included patients with genotype 1 or 4, HCV-RNA load ≥600,000IU/ml, and rs12979860 non-CC (rate of SVR: 17.3%). Anticipated responders were those with HCV genotype 2-3, patients harboring HCV genotype 4 and IL28B CC, as well as those who simultaneously bore HCV genotype 1, HCV-RNA load <600,000IU/ml, and IL28B CC (rate of SVR 74.1%, 77.8%, and 64.4%, respectively). The area under the receiver operating characteristic curve of the model was 0.77 (0.733-0.814). CONCLUSIONS: The combined use of IL28B genotype, HCV genotype, and HCV-RNA load enables to easily identify patients with a high and very low likelihood of SVR. HCV therapy could be deferred in the latter patients, until more effective options are available, at least if they do not show advanced liver fibrosis.

Twelve week post-treatment follow-up predicts sustained virological response to pegylated interferon and ribavirin therapy in HIV/hepatitis C virus co-infected patients.

OBJECTIVES: The aim of this study was to evaluate whether the assessment of hepatitis C virus (HCV) RNA serum at 12 weeks after the end of treatment (W12) was as informative as after 24 weeks (W24) for determining sustained virological response (SVR) in HIV/HCV co-infected patients who received a combination of pegylated interferon (PEG-INF) plus ribavirin (PEG-INF/RBV) and had a virological response at the end of treatment. METHODS: Treatment-naive HIV/HCV patients were included in this prospective study if they had completed a full course of therapy with PEG-INF/RBV, had an undetectable serum HCV RNA at the end of treatment and complied with the W12 and W24 schedule for determining HCV RNA. HCV RNA levels were measured using a quantitative PCR assay (detection limit = 15 IU/mL). Positive predictive value (PPV) was defined as the probability of an undetectable serum HCV RNA at W12 and W24 after the end of treatment. RESULTS: Of 186 patients treated during the study period, 104 (55.9%) were included in the study. At W24, 83 (79.8%) patients had an SVR and 21 (20.2%) had a virological relapse. At W12, HCV RNA was undetectable in 83 (79.8%) patients and all of these had SVR. Undetectable HCV RNA at W12 had a 100% PPV [95% confidence interval (CI) 96.5%-100%] for SVR. CONCLUSIONS: Our results show that undetectable HCV RNA at W12 post-treatment has a high PPV for SVR. Testing for HCV RNA at this moment may therefore be considered an appropriate point in time for identifying SVR and relapse in HIV/HCV co-infected patients receiving treatment with PEG-INF/RBV.

Prediction of response to pegylated interferon plus ribavirin by IL28B gene variation in patients coinfected with HIV and hepatitis C virus.

BACKGROUND: Variation in the IL28B gene is associated with sustained virologic response (SVR) to pegylated interferon plus ribavirin in hepatitis C virus (HCV)-monoinfected patients with genotype 1. Data on other genotypes and on patients coinfected with human immunodeficiency virus (HIV) and HCV are more limited. We aimed to assess the predictive ability of variations in the single-nucleotide polymorphism rs12979860 for SVR in HIV/HCV-coinfected patients, regardless of HCV genotype. METHODS: The rs12979860 genotype was determined by polymerase chain reaction in 154 patients who had received therapy against HCV with pegylated interferon plus ribavirin. RESULTS: rs12979860 genotype was TT in 20 patients (13%), TC in 66 patients (43%), and CC in 68 patients (44%). Rates of SVR in patients with genotype CC and in those with genotype TC or TT, according to HCV genotype, were, respectively, 50% and 17% (P < .001) in patients with genotype 1, 80% and 25% (P = .027) in patients with genotype 4, and 93% and 77% (P = .115) in patients with genotype 3. The median (interquartile range) low-density lipoprotein cholesterol level in patients with rs12979860 CC was 89 mg/dL (73-120 mg/dL) versus 75 mg/dL (55-91 mg/dL) (P = .001) in those with TC or TT. Independent predictors of SVR were HCV genotype 2-3 (odds ratio [OR], 13.98; 95% confidence interval [CI], 4.87-40.1; P < .001), rs12979860 CC (OR, 5.05; 95% CI, 2.04-12.5; P < .001), baseline plasma HCV RNA load of < or =600,000 IU/mL (OR, 1.99; 95% CI, 1.18- 3.34; P = .009), and female sex (OR, 4.28; 95% CI, 1.08-16.96; P = .039). CONCLUSIONS: IL28B gene variations independently predict SVR in HIV/HCV-coinfected patients with HCV genotype 1 and non-genotype 1 HCV infection. The association between rs12979860 and plasma low-density lipoprotein cholesterol suggests that the system low-density lipoprotein ligand/receptor might be involved in the effect of this genotype.

Modeling the probability of sustained virological response to therapy with pegylated interferon plus ribavirin in patients coinfected with hepatitis C virus and HIV.

BACKGROUND: A single-nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) strongly predicts sustained virological response to pegylated interferon plus ribavirin (pegIFN-RBV) treatment for chronic hepatitis C virus (HCV) infection. Given that therapy is poorly tolerated and rates of response are lower in patients coinfected with HCV and human immunodeficiency virus (HIV), the recognition of predictors of response is a high priority in this population. METHODS: A baseline noninvasive index was derived on the basis of the probability of achieving sustained virological response in a group of 159 HIV-HCV-coinfected patients treated at one clinic in Spain. The index was then validated using data from a separate cohort of 86 coinfected individuals. Only individuals who had completed a course of pegIFN-RBV therapy and had validated outcomes were considered. RESULTS: The final score included 4 variables: 2 host-related variables (IL28B SNP rs12979860 and liver stiffness) and 2 HCV-related variables (genotype and viral load). The area under the receiver operating characteristic curve was 0.89 in the derivation group and 0.85 in the validation group. CONCLUSIONS: The probability of achieving sustained virological response with pegIFN-RBV therapy in HIV-HCV-coinfected patients can be reliably estimated prior to initiation of therapy using an index that includes 4 noninvasive parameters.

Changes in liver stiffness in patients with chronic hepatitis C with and without HIV co-infection treated with pegylated interferon plus ribavirin.

OBJECTIVES: To evaluate the changes in liver stiffness measurement (LSM) in patients infected by hepatitis C virus (HCV) under pegylated interferon (Peg-IFN) plus ribavirin therapy. METHODS: One hundred and forty-three HCV-infected patients, of whom 97 (68%) were also carrying HIV, who started treatment with Peg-IFN/ribavirin were included in this prospective cohort study. The outcome variable of the study was the change in LSM between baseline and the scheduled date for evaluating sustained virological response (SVR). RESULTS: The median (Q1-Q3) LSM values at baseline and at the SVR assessment date were 8.1 (6.2-11.6) kPa and 6.8 (5.2-9.8) kPa (P<0.001), respectively. The median (Q1-Q3) decrease between both timepoints was -1 (-2.75, 0.3) kPa. The baseline LSM decreased ≥20% in 37 (46%) patients with SVR and in 19 (30%) without SVR (P=0.05). In the linear regression analysis, baseline LSM {beta [standard error (SE)] -0.712 (0.044), P=0.004}, alcohol intake ≥50 g/day [beta (SE) 0.202 (0.030), P=0.014] and achievement of SVR [beta (SE) -0.238 (0.026), P=0.029] were independently associated with changes in LSM. CONCLUSIONS: LSM decreases significantly among patients with chronic HCV infection who achieve SVR with Peg-IFN/ribavirin. These patients show a higher frequency of LSM reduction ≥20% at the date of SVR evaluation.

Impact of IL28B genotype on first-week response to telaprevir-based therapy in HIV-HCV coinfection.

BACKGROUND: IL28B genotype predicts response to treatment against HCV with pegylated interferon/ribavirin (PR) and impacts on the outcome of therapy including telaprevir (TVR). This study aimed to determine the influence of the favourable IL28B genotype on early viral kinetics during therapy with TVR/PR in HIV-HCV-coinfected patients. METHODS: All HIV-HCV genotype 1 coinfected subjects who received TVR/PR for at least 4 weeks were included from populations prospectively followed in 22 centres throughout Germany, Switzerland and Spain. RESULTS: Of the 129 subjects included, 38 (29.5%) presented with IL28B genotype CC and 94 (72.9%) were treatment-experienced. A total of 96 (73.8%) patients showed undetectable plasma HCV RNA at treatment week (W)4: 30 (78.9%) of the IL28B-CC carriers and 65 (71.4%) of the non-CC carriers (P=0.377). Among treatment-naive patients, proportions of undetectable HCV RNA among IL28B-CC versus non-CC carriers were 8/9 (88.9%) versus 3/9 (33.3%; P=0.016) and 14/17 (82.4%) versus 11/18 (61.1%; P=0.164) at W2 and W4. The decrease of HCV RNA at W2 and W4 was similar among the IL28B carriers. CONCLUSIONS: IL28B genotype does not predict W4 response to TVR/PR in HIV-HCV-coinfected patients, regardless of their treatment history. However, there is evidence of an impact on response during the first weeks in treatment-naive patients.

Strategies for assignment of HIV-HCV genotype-1-coinfected patients to either dual-therapy or direct-acting antiviral agent-based triple-therapy.

BACKGROUND: The aim of this study was to evaluate strategies for assignment of HIV-HCV genotype-1-coinfected patients (HIV-HCV-GT1) to either dual-therapy or direct-acting antiviral agent (DAA)-based triple-therapy. METHODS: A total of 148 treatment-naive HIV-HCV-GT1 who received antiviral therapy with pegylated interferon/ribavirin were included in this multinational, retrospective analysis. Patients with rapid virological response (RVR) were treated for 48 weeks, while patients without RVR received either 48 or 72 weeks of treatment. IL28B rs12979860 (IL28B) non-C/C, advanced liver fibrosis and high HCV RNA were considered as established risk factors for treatment failure. RESULTS: A trend toward higher sustained virological response (SVR) rates in patients with IL28B C/C (65% [37/57] versus 51% [40/79]; P=0.097) was observed. Higher SVR rates were observed in patients without advanced liver fibrosis (61% [47/77] versus 42% [22/52]); P=0.036) and without high HCV RNA (73% [35/48] versus 49% [49/100]; P=0.006), as well as in patients with RVR (90% [35/39] versus 45% [49/109]; P<0.001). SVR rates varied statistically significantly between the risk factors for treatment failure subgroups (86% [6/7] versus 69% [34/49] versus 48% [21/44] versus 20% [4/20] for zero, one, two and three risk factors, respectively; P<0.001). In patients without RVR, higher rates of SVR were observed in those treated for 72 weeks (62% [23/37]), when compared to patients treated for 48 weeks (36% [26/72]; P=0.01). CONCLUSIONS: RVR had an excellent positive predictive value for the response to dual-therapy in HIV-HCV-GT1, emphasizing the utility of a lead-in phase for assigning these patients to dual-therapy or DAA-based triple-therapy. The use of an IL28B-guided approach was suboptimal, while a combination of established baseline predictors may provide guidance for individual treatment decisions prior to the initiation of antiviral therapy. However, the extension of treatment duration to 72 weeks in HIV-HCV-GT1 without RVR should be strongly considered if triple-therapy is not available.

Pegylated interferon plus ribavirin is suboptimal in IL28B CC carriers without rapid response.

OBJECTIVE: Some experts consider that hepatitis C virus (HCV) genotype 1-infected patients harboring IL28B genotype CC should be treated with interferon (Peg-IFN) plus ribavirin (RBV). This study aimed to assess the rate of sustained virological response (SVR) in these subjects, according to whether they achieve rapid virological response (RVR) or not. METHODS: Prospective cohort study conducted at the Infectious Diseases Units of three Spanish hospitals. 220 treatment-naive, HCV genotype 1-infected patients, 160 of them HIV/HCV-coinfected, who initiated dual therapy with peg-IFN plus RBV were analyzed in an on-treatment approach. RESULTS: 29 (18%) HIV/HCV-coinfected and 14 (23%) HCV-monoinfected (p = 0.44) individuals developed RVR. In the overall population, 32 (39%) patients with IL28B genotype CC versus 11 (8%) bearing genotype non-CC achieved RVR (p < 0.0001). In HCV-monoinfected patients with IL28B genotype CC, SVR was observed in 12 (92%) of those who achieved RVR and in 3 (30%) of those who did not (p = 0.0018). The corresponding figures for HIV/HCV-coinfected individuals were 19 (100%) and 14 (35%), respectively (p < 0.0001). CONCLUSION: Treatment-naïve HCV-genotype 1-infected patients bearing favorable IL28B genotype should not be treated with dual therapy including Peg-IFN plus RBV if they do not achieve RVR. These subjects clearly represent candidates for more effective therapy with direct-acting antivirals. SUMMARY: Some experts consider that hepatitis C virus (HCV) genotype 1-infected patients harboring the favorable IL28B genotype CC should be treated with interferon plus ribavirin. However, patients harboring favorable IL28B genotype should not be considered likely responders to the same extent. This prospective cohort study conducted in 220 treatment-naive HCV-infected patients with or without HIV coinfection patients shows that among the IL28B CC carriers, while the subset of those patients who achieve negative plasma HCV-RNA after 4 weeks (rapid virological response, RVR) of dual therapy have a rate of sustained virological response near to 100%, those who do not present RVR show a response rate lower than 40%. Therefore, treatment-naïve HCV-genotype 1-infected patients bearing favorable IL28B genotype who do not achieve RVR should be considered candidates for more effective therapy with direct-acting antivirals like boceprevir or telaprevir.

Differences in virological response to peginterferon-α plus ribavirin in HIV-positive patients coinfected with HCV subtypes 1a or 1b.

BACKGROUND: Both viral and host factors influence response to peginterferon-α plus ribavirin (pegIFNα/RBV) in patients with chronic hepatitis C. The impact of these variables is more pronounced in HIV/Hepatitis C virus (HCV)-coinfected individuals, in whom treatment response rates are lower. METHODS: Virological responses at multiple time points were assessed in all HIV/HCV-coinfected patients that completed a first course of pegIFNα/RBV. Viral responses were stratified by HCV geno/subtypes and IL28B rs12979860 variants. RESULTS: A total of 331 HIV/HCV-coinfected patients were analyzed. HCV geno/subtype distribution was as follows: HCV-1a in 97, HCV-1b in 62, HCV-3 in 122, and HCV-4 in 50. Age, gender, CD4 counts, plasma HIV RNA and liver fibrosis stage did not differ significantly across HCV geno/subtypes. In contrast, mean serum HCV RNA was greater in HCV-1a compared with the rest (P < 0.0001). The proportion of IL28B CC variants was higher in HCV-3 compared with the rest (P = 0.001). Virological responses were better in HCV-1b than HCV-1a at any given time point during therapy. IL28B variants significantly influenced virological responses across all HCV-1 subtypes, with the strongest effect seen in HCV-1a. In a multivariate linear regression analysis, both HCV-1b and IL28B CC variants were significantly associated with greater HCV RNA drops at weeks 4 (R = 0.52, p < 0.0001) and 12 (R = 0.49, P < 0.0001) of therapy. CONCLUSIONS: The response to pegIFNα/RBV therapy is lower in HCV-1a than HCV-1b in HIV/HCV-coinfected patients. The strongest influence of IL28B variants is seen in HCV-1a. This information may be relevant when using most directly acting antivirals in coinfected patients along with pegIFNα/RBV, given that selection of drug resistance occurs more frequently in HCV-1a than HCV-1b.

Low-density lipoprotein receptor genotyping enhances the predictive value of IL28B genotype in HIV/hepatitis C virus-coinfected patients.

OBJECTIVE: The aims of this study were to appraise the predictive value of variations in a single-nucleotide polymorphism (SNP) in the low-density lipoprotein receptor (LDLR) gene for sustained virological response (SVR) to pegylated interferon (Peg-IFN) and ribavirin (RBV), as well as to analyze the relationship between LDLR genotype and other predictors of SVR, particularly IL28B genotype, in patients coinfected with HIV and hepatitis C virus (HCV). METHODS: One hundred and eighty-four HIV/HCV-coinfected, treatment-naive patients with chronic HCV infection, who received Peg-IFN and RBV, were included. Variations in the SNP rs14158 and rs12979860 were tested by Taqman PCR assay. RESULTS: Twenty-eight (38%) patients with rs14158 TT/TC and 61 (55%) with CC (P = 0.028) achieved SVR. The rates of SVR in patients with rs14158 TT/TC and with CC harboring HCV 1-4 were 20 and 41% (P = 0.020), respectively, and, in those with HCV genotype 2-3, 75 and 84% (P = 0.513), respectively. Patients with rs14158 CC showed less commonly plasma HCV-RNA load at least 600000 IU/ml (57 vs. 71%, P = 0.047) and lower likelihood of relapse (13 vs. 30%, P = 0.023). In patients with HCV genotype 1-4, the rates of SVR according to the combination of IL28B/LDLR genotypes were: CC/CC = 69%; CC/non-CC: 30%; non-CC/CC: 25%; non-CC/non-CC: 14% (P < 0.001). CONCLUSION: Variations in rs14158 are associated with SVR to Peg-IFN and RBV in HIV/HCV-coinfected patients harboring HCV genotype 1-4. LDLR and IL28B genotypes seem to have a synergistic effect on SVR. The combined use of LDLR and IL28B genotypes in routine clinical practice could enhance the predictive value of IL28B genotype alone.

Impact of IL28B polymorphisms on response to peginterferon and ribavirin in HIV­hepatitis C virus-coinfected patients with prior nonresponse or relapse.

IL28B polymorphisms predict treatment response in chronic hepatitis C. However, no information exists in prior treatment failures. A total of 62 HIV/hepatitis C virus (HCV) patients who completed retreatment with peginterferon-α/ribavirin were examined, of whom 25 (40%) had been cured. Predictors of response [odds ratio, OR (95% confidence interval, CI)] were HCV genotypes 2/3 [16.1 (2.7-90.9)], prior relapse [9.6 (1.5-62.4)] and ribavirin plasma trough concentrations at week 4 [4.9 (1.3-18.4)]. IL28B-CC only predicted response in prior nonresponders carrying HCV genotypes 1/4 [25.1 (1.9-337)].

A review of current anti-HCV treatment regimens and possible future strategies.

BACKGROUND: Hepatitis C virus (HCV) infection remains a serious health problem worldwide. The current standard treatment of HCV infection is pegylated interferon-alpha plus ribavirin, but this is clearly not sufficiently effective and tolerable. OBJECTIVE: To review current HCV treatment strategies and future options. METHODS: Review of major clinical trials or observational studies when no trial is available. RESULTS/CONCLUSION: Rates of sustained virologic response are widely variable, approximately 40-80%, depending on genotype, and even lower when HIV coinfection occurs. New agents, like small molecules that specifically target the HCV life cycle, may improve response rates; but safety is a concern.