Modeling the Probability of Sustained Virological Response to Therapy with Pegylated Interferon plus Ribavirin in Patients Coinfected with Hepatitis C Virus and HIV

Department of Infectious Diseases, Hospital Carlos III, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
Clinical Infectious Diseases (Impact Factor: 8.89). 11/2010; 51(10):1209-16. DOI: 10.1086/656811
Source: PubMed


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.
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.
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.
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.

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Available from: Salvador Resino, Dec 27, 2013
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    • "The third independent factor associated with a SVR was the absence of significant liver fibrosis. Explanations about the influence of liver fibrosis are varied: 1) the influence of liver fibrosis could be attributed to the higher number of secondary effects detected in these patients [10], [25]; 2) an alternative explanation is that lower percentages of HCV infected hepatocytes and hepatocyte infection rate are predictors of SVR [35]. Interestingly, the absence of significant liver fibrosis was a predictive parameter of SVR mainly in those patients without RVR. "
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    ABSTRACT: Objective To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism). Patients and Methods A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, −238 TNF-α and −592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count. Results Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of −238 TNF-α genotype GG was detected in patients with significant liver fibrosis. Conclusions In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a −238 TNF-α polymorphism in these patients.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Individuals with chronic HCV genotype 3 and with the favorable haplotype block CTA CTA had higher median HCV RNA levels than those with unfavorable haplotype blocks. Medrano et al106 developed and validated a noninvasive index including IL28B SNP rs12979860, liver stiffness, HCV genotype, and viral load to predict SVR in patients coinfected with HCV and HIV. "
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    ABSTRACT: Hepatitis C virus (HCV) has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world's population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL28B) gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.
    Full-text · Article · Jun 2014 · Hepatic Medicine: Evidence and Research
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    • "The baseline concentration of HCV-RNA predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. The likelihood of achieving sustained virological response in patients treated with peginterferon plus ribavirin is low in the presence of high vial load [1] even using some of the new directacting antivirals [2] [3]. On the other hand, measuring HCV-RNA at different time points on antiviral therapy predicts final outcomes. "
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    ABSTRACT: The concentration of circulating viral RNA at baseline and during antiviral therapy predicts response in both HIV infection and chronic hepatitis C. Retrospective review of longitudinal plasma HCV-RNA determinations in untreated chronic hepatitis C patients. As comparison, longitudinal plasma HIV-RNA measurements were performed in untreated HIV individuals. A total of 3169 HCV-RNA determinations over 43.0±31.6 months were available for 818 chronic hepatitis C patients. For 333 HIV individuals, 1998 HIV-RNA measurements were examined over 27.3±17.5 months. Overall 44% consecutive specimens had >0.5 log variation in HCV-RNA values compared to 23% for HIV-RNA (p<0.001). These rates were 15% and 4%, respectively, for variations >1 log (p<0.001). In multivariate analysis (odds ratio, 95% confidence interval, p), the likelihood of experiencing HCV-RNA variations >0.5 log IU/mL was greater in patients with lower HCV-RNA (0.35 per log[0.26-0.47], 0.001), HIV coinfection (2.57[91.56-4.23], <0.001) and IL28B-CC (1.87[1.28-2.74], 0.001). Fluctuation in circulating HCV-RNA may be clinically meaningful in a substantial proportion of chronic hepatitis C patients. It may influence the best time to prescribe antiviral therapy. Moreover, decisions based on early viral kinetics, such as early stopping rules, may require testing of baseline specimens the closest to treatment initiation.
    Full-text · Article · Jul 2013 · Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology
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