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1.  Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients 
Triple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P = 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P = 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P = 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day−1) and was higher in patients who subsequently eradicated HCV (P = 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.
doi:10.1128/AAC.02611-14
PMCID: PMC4135822  PMID: 24982076
2.  Nanomedicines in the treatment of hepatitis C virus infection in Asian patients: optimizing use of peginterferon alfa 
Asia is endemic for hepatitis C virus (HCV) infection, which is the leading cause of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplantation worldwide. HCV has six major genotypes and each HCV genotype has its specific geographic distribution. HCV genotypes 1, 2, 3, and 6 are common in Asia. The aim of HCV treatment is to eradicate the virus by effective therapeutic agents; viral clearance is durable after long-term post-treatment follow-up. In most Asian countries, peginterferon alfa (PEG-IFN α) in combination with ribavirin remains the standard of care, and the overall sustained viral response (SVR) rate in Asian HCV patients is higher than that in Western patients. The differences are most significant in patients with HCV genotype 1 (HCV-1) infection, which is attributed to the higher frequency of IFN-responsive or favorable interleukin-28B (IL-28B) genotype in Asian populations than in other ethnic populations. In addition, the introduction of response-guided therapy, where the optimized treatment duration is based on the early viral kinetics during the first 12 weeks of treatment, increases the SVR rate. Recently, telaprevir or boceprevir-based triple therapy was found to further improve the SVR rate in treated and untreated HCV-1 patients and has become the new standard of care in Western and some Asian countries. Many novel direct-acting antiviral agents, either in combination with PEG-IFN α plus ribavirin or used as IFN-free regimens are under active investigation. At the time of this writing, simeprevir and sofosbuvir have been approved in the US. Because the SVR rates in Asian HCV patients receiving PEG-IFN α plus ribavirin therapy are high, health care providers should judiciously determine the clinical usefulness of these novel agents on the basis of treatment duration, anticipated viral responses, patient tolerance, financial burdens, and drug accessibility.
doi:10.2147/IJN.S41822
PMCID: PMC4008289  PMID: 24812506
PEG-IFN α; HCV; SVR; RGT; IL28B
3.  The Molecular Basis of Drug Resistance against Hepatitis C Virus NS3/4A Protease Inhibitors 
PLoS Pathogens  2012;8(7):e1002832.
Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. Available antiviral therapies cause severe side effects and are effective only for a subset of patients, though treatment outcomes have recently been improved by the combination therapy now including boceprevir and telaprevir, which inhibit the viral NS3/4A protease. Despite extensive efforts to develop more potent next-generation protease inhibitors, however, the long-term efficacy of this drug class is challenged by the rapid emergence of resistance. Single-site mutations at protease residues R155, A156 and D168 confer resistance to nearly all inhibitors in clinical development. Thus, developing the next-generation of drugs that retain activity against a broader spectrum of resistant viral variants requires a comprehensive understanding of the molecular basis of drug resistance. In this study, 16 high-resolution crystal structures of four representative protease inhibitors – telaprevir, danoprevir, vaniprevir and MK-5172 – in complex with the wild-type protease and three major drug-resistant variants R155K, A156T and D168A, reveal unique molecular underpinnings of resistance to each drug. The drugs exhibit differential susceptibilities to these protease variants in both enzymatic and antiviral assays. Telaprevir, danoprevir and vaniprevir interact directly with sites that confer resistance upon mutation, while MK-5172 interacts in a unique conformation with the catalytic triad. This novel mode of MK-5172 binding explains its retained potency against two multi-drug-resistant variants, R155K and D168A. These findings define the molecular basis of HCV N3/4A protease inhibitor resistance and provide potential strategies for designing robust therapies against this rapidly evolving virus.
Author Summary
Hepatitis C virus (HCV) infects over 170 million people worldwide and is the leading cause of chronic liver diseases, including cirrhosis, liver failure, and liver cancer. New classes of directly-acting antiviral agents that target various HCV enzymes are being developed. Two such drugs that target the essential HCV NS3/4A protease are approved by the FDA and several others are at various stages of clinical development. These drugs, when used in combination with pegylated interferon and ribavirin, significantly improve treatment outcomes. However HCV evolves very quickly and drug resistance develops against directly-acting antiviral agents. Thus, despite the therapeutic success of NS3/4A protease inhibitors, their long-term effectiveness is challenged by drug resistance. Our study explains in atomic detail how and why drug resistance occurs for four chemically representative protease inhibitors –telaprevir, danoprevir, vaniprevir and MK-5172. Potentially with this knowledge, new drugs could be developed that are less susceptible to drug resistance. More generally, understanding the underlying mechanisms by which drug resistance occurs can be incorporated in drug development to many quickly evolving diseases.
doi:10.1371/journal.ppat.1002832
PMCID: PMC3406087  PMID: 22910833
4.  Management of hepatitis C infection before and after liver transplantation 
Chronic hepatitis C (CHC) is the most common indication for liver transplantation (LT). Aggressive treatment of hepatitis C virus (HCV) infection before cirrhosis development or decompensation may reduce LT need and risk of HCV recurrence post-LT. Factors associated with increased HCV risk or severity of recurrence include older age, immunosuppression, HCV genotype 1 and high viral load at LT. HCV recurrence post-LT leads to accelerated liver disease and cirrhosis development with reduced graft and patient survival. Currently, interferon (IFN)-based regimens can be used in dual-agent regimens with ribavirin, in triple-agent antiviral strategies with direct-acting antivirals (e.g., protease inhibitors telaprevir or boceprevir), or before transplant in compensated patients to reduce HCV viral load to prevent or reduce the risk of post-LT recurrence and complications; they cannot be used in patients with decompensated cirrhosis. IFN-based regimens are used in less than half of HCV-infected patients waiting for LT due to extremely low efficacy and poor tolerability. However, antiviral therapy is indicated after LT in patients with histologically confirmed CHC despite tolerability issues. Improvements in side effect management have increased survival in patients achieving therapeutic targets. HCV treatment pre- and post-LT results in significant health care costs especially when lack of efficacy leads to disease worsening, although studies have shown sofosbuvir treatment before LT vs conventional post-LT dual antiviral is cost effective. The suboptimal efficacy and tolerability of IFN-based therapies, plus the significant economic burden, means the need for effective and well tolerated IFN-free anti-HCV therapy for pre- and post-LT remains high.
doi:10.3748/wjg.v21.i15.4447
PMCID: PMC4402292  PMID: 25914454
Hepatitis C virus; Orthotopic liver transplantation; Interferon-free treatment; Decompensated cirrhosis; Chronic hepatitis C
5.  Current progress in the treatment of chronic hepatitis C 
Over the last decade, the standard of care for the treatment of chronic hepatitis C has been the combination of pegylated-interferon-alfa (PEG-IFN) and ribavirin (RBV) which results in sustained virological response (SVR) rates of 75%-85% in patients with genotypes 2 or 3 but only of 40%-50% in patients with genotype 1. Currently, there are rapid and continuous developments of numerous new agents against hepatitis C virus (HCV), which are the focus of this review. Boceprevir and telaprevir, two first-generation NS3/4A HCV protease inhibitors, have been recently licensed in several countries around the world to be used in combination with PEG-IFN and RBV for the treatment of genotype 1 patients. Boceprevir or telaprevir based triple regimens, compared with the PEG-IFN/RBV combination, improve the SVR rates by 25%-31% in treatment-naïve genotype 1 patients, by 40%-64% in prior relapsers, by 33%-45% in prior partial responders and by 24%-28% in prior null responders. At the same time, the application of response-guided treatment algorithms according to the on-treatment virological response results in shortening of the total therapy duration to only 24 wk in 45%-55% of treatment-naïve patients. There are, however, several challenges with the use of the new triple combinations in genotype 1 patients, such as the need for immediate results of HCV RNA testing using sensitive quantitative assays, new and more frequent adverse events (anemia and dysgeusia for boceprevir; pruritus, rash and anemia for telaprevir), new drug interactions and increasing difficulties in compliance. Moreover, the SVR rates are still poor in very difficult to treat subgroups of genotype 1 patients, such as null responders with cirrhosis, while there is no benefit for patients who cannot tolerate PEG-IFN/RBV or who are infected with non-1 HCV genotype. Many newer anti-HCV agents of different classes and numerous combinations are currently under evaluation with encouraging results. Preliminary data suggest that the treatment of chronic HCV patients with well tolerated combinations of oral agents without PEG-IFN is feasible and may lead to a universal HCV cure over the next 5-10 years.
doi:10.3748/wjg.v18.i42.6060
PMCID: PMC3496882  PMID: 23155334
Chronic hepatitis C; Pegylated interferon; Ribavirin; Protease inhibitors; Nucleos(t)ide analogue inhibitors; Non-nucleos(t)ide analogue inhibitors; Hepatitis C virus polymerase; NS5A inhibitors; Cyclophilin inhibitors
6.  New Preclinical Antimalarial Drugs Potently Inhibit Hepatitis C Virus Genotype 1b RNA Replication 
PLoS ONE  2013;8(8):e72519.
Background
Persistent hepatitis C virus (HCV) infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir) has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed.
Methodology/Principal Findings
Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8) were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251) showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-α demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-α-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-α and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect.
Conclusions/Significance
We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.
doi:10.1371/journal.pone.0072519
PMCID: PMC3758303  PMID: 24023620
7.  New agents for the treatment of hepatitis C in patients co-infected with HIV 
Pilot trials evaluating the efficacy and safety of the first licensed hepatitis C virus (HCV) protease inhibitors (PIs), boceprevir (BOC) and telaprevir (TVR), for the treatment of genotype 1 infection in HCV/HIV co-infected patients revealed similar results as in HCV mono-infected patients. HCV liver disease progresses more rapidly in co-infected patients, particularly with advanced immunodeficiency. Therefore, HCV treatment in HIV is of great importance. However, dual therapy with pegylated interferon (PegIFN) and ribavirin (RBV) has been associated with lower cure rates and increased toxicities in co-infected subjects, thereby limiting overall HCV therapy uptake. The availability of HCV PIs opens new perspectives for HCV cure in co-infected patients, with a 70% sustained virologic response (SVR) rate in HCV treatment-naïve patients. Despite these impressive advances, the use of the new treatment options has been low, reflecting the complex issues with modern triple HCV therapy. Indeed pill burden, adverse events (AEs), drug–drug interactions (DDIs) and high costs complicate HCV therapy in HIV. So far, studies have shown no tolerability differences in mono- and co-infected patients with the early stages of liver fibrosis. Regarding DDIs between HVC PIs and antiretroviral drugs, TVR can be safely administered with efavirenz (with dose adjustment of TVR), etravirine (ETR), rilpivirine, boosted atazanavir (ATV/r) and raltegravir (RAL), while BOC can be safely administered with ETR, RAL and potentially ATV/r for treatment-naïve patients under careful monitoring. Currently, the great number of HCV molecules under development is promising substantially improved treatment paradigms with shorter treatment durations, fewer AEs, less DDIs, once-daily administration and even interferon-free regimens. The decision to treat now with the available HCV PIs or defer therapy until the second generation of HCV direct acting antivirals become available should be based on liver fibrosis staging and fibrosis progression during follow up. More data are urgently needed regarding the efficacy of triple therapy in HIV/HCV co-infected patients who previously failed PegIFN/RBV therapy as well as in patients with more advanced fibrosis stages.
doi:10.1177/2049936113479591
PMCID: PMC4040720  PMID: 25165545
HIV; hepatitis C; DAA; pegylated interferon; ribavirin
8.  Is Response-Guided Therapy Being Applied in the Clinical Setting? The Hepatitis C Example 
Background
Response-guided therapy (RGT) is a treatment model that bases adjustments to therapeutic regimens on individualized patient physiologic response. This approach is applied to patients with chronic hepatitis C virus (HCV) infection who are treated with a triple therapy regimen of boceprevir or telaprevir in combination with pegylated interferon and ribavirin. As RGT expands in other pharmacologic regimens, including the treatment of breast cancer and acute myeloid leukemia, a measurement of how this approach is applied in clinical practice is important to determine whether the benefits of RGT are being optimized.
Objective
To measure adherence to the RGT guidelines and to the treatment futility rules based on the drug labeling information for boceprevir and for telaprevir in the treatment of patients with chronic HCV infection.
Methods
A retrospective observational cohort study was conducted using the large Humana research database, which includes pharmacy, medical, and laboratory claims, as well as enrollment data for more than 1.5 million fully insured commercial members, 1.9 million Medicare Advantage members, and 2.4 million Medicare Part D members from all 50 states. The study population included patients aged ≥18 years to <90 years who were fully insured with commercial or Medicare Advantage coverage. A pharmacy claim for boceprevir or telaprevir was used to identify patients receiving triple therapy for HCV infection. Medical, pharmacy, and laboratory claims were reviewed from the date of the first boceprevir or telaprevir pharmacy claim between May 2011 and February 2012 through a 32-week follow-up period, during which patients were required to have continuous health plan enrollment eligibility. This time period allowed for the occurrences of required HCV RNA laboratory monitoring and the assessment of treatment patterns. The use of RGT for boceprevir and telaprevir includes the monitoring of HCV RNA levels at routine intervals to determine how to proceed with therapy. Adherence to HCV RNA monitoring was measured as the proportion of eligible patients who had an HCV RNA assay at each of the recommended time intervals. According to futility rules, patients with greater-than-expected HCV RNA levels are deemed to be nonresponders and should discontinue therapy. Adherence to futility rules was measured as the proportion of patients who stopped therapy among all patients who had an HCV RNA result, which indicated treatment futility at each monitoring interval.
Results
A total of 326 patients (65 in the boceprevir group; 261 in the telaprevir group) were eligible for the HCV RNA monitoring analysis, and 134 patients (20 receiving boceprevir and 114 receiving telaprevir) were eligible for the futility rules analysis. There were 1203 HCV RNA assays during the follow-up period. The percentage of patients who were adherent to HCV RNA monitoring during the entire treatment period was 29.2% in the boceprevir group and 32.2% in the telaprevir group. In both treatment groups, adherence to HCV RNA monitoring was highest at the first recommended time interval, followed by a downward trend in the second and third time intervals. Approximately 15% of 134 eligible patients met the futility rules for stopping therapy based on HCV RNA assay results, and 55% of those patients stopped the therapy in accordance with the treatment futility rules.
Conclusion
The implementation of RGT was suboptimal in this population of patients with chronic HCV infection; adherence to HCV RNA monitoring guidelines was less than 33%, and adherence to treatment futility rules was less than 50%. Managed care pharmacists should identify strategies to increase the adoption of RGT, which may, in turn, improve patient care and reduce unnecessary expenditures.
PMCID: PMC4415173  PMID: 25964830
response-guided therapy; hepatitis C virus; boceprevir; telaprevir; pegylated interferon; RNA assay
9.  A Pharmacological Profile of Ribavirin and Monitoring of its Plasma Concentration in Chronic Hepatitis C Infection 
Chronic hepatitis C (CHC) infection, usually an asymptomatic infection, has long-term serious complications such as cirrhosis, hepatocellular carcinoma, and end-stage liver disease requiring liver transplantation (LT). Several novel drugs against hepatitis C which form part of ‘specifically targeted antiviral therapy for hepatitis C’ (STAT-C) have been developed. These include NS3/4A protease inhibitors telaprevir, boceprevir, and nucleoside/non-nucleoside polymerase inhibitors (NS5A) which hold promise for future therapy. Despite the development of new anti-hepatitis C virus (HCV) drugs, ribavirin (RBV) remains the single most important drug to prevent relapse and is frequently included among newer regimens being developed with novel small molecule anti-HCV drugs. The current approved treatment is a combination therapy of once weekly subcutaneous pegylated-interferon (PEG-IFN)-α plus body-weight-based oral RBV regimen. The most significant dose-dependent side effect of RBV is hemolytic anemia warranting dose reduction or discontinuation in severe cases compromising sustained virological response (SVR). Monitoring RBV plasma concentration has been challenging due to its peculiar pharmacokinetics and has been done to predict both efficacy and toxicity. Herein, we review the pharmacological profile of RBV and the monitoring of its plasma concentration, monitoring in renal impairment, post-LT, and human immunodeficiency virus (HIV)-HCV co-infection in patients being treated with combination therapy of PEG-IFN-α and RBV.
doi:10.1016/S0973-6883(12)60090-5
PMCID: PMC3940409  PMID: 25755405
HCV; plasma concentration; ribavirin; TDM; ADSS, adenylosuccinate synthetase; ATP, adenosine-5′-triphosphate; AUC, area under concentration curve; BMD, bone mineral density; Css, concentration at steady-state; Ctrough, trough concentration; DAAs, directly acting antiviral agents; EPO, erythropoietin; EVR, early virological response; FDA, Food and Drug Administration; GTP, guanosine-5′-triphosphate; Hb, hemoglobin; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HPLC, high-performance liquid chromatography; IFN, interferon; IMPDH, inosine-5′-monophosphate dehydrogenase; ITPA, inosine triphosphate pyro-phosphatase; PEG-IFN, pegylated-interferon; PSH, protein sulfhydryl; RBC, red blood cell; RBV, ribavirin; RNA, ribonucleic acid; RSV, respiratory syncytial virus; RVR, rapid virological response; STAT-C, specifically targeted therapy for hepatitis C; SVR, sustained virological response; TDM, therapeutic drug monitoring
10.  Feasibility of Telaprevir-Based Triple Therapy in Liver Transplant Patients with Hepatitis C Virus: SVR 24 Results  
PLoS ONE  2013;8(11):e80528.
Management of recurrent Hepatitis C virus (HCV) infection following liver transplantation remains a major challenge. In non-transplanted HCV genotype 1 patients, the introduction of protease inhibitor-based regimens has significantly increased the rate of sustained virological response. In this follow-up study, on the first published cohort of post-liver transplant patients treated with telaprevir-based triple therapy, we investigated both efficacy and safety data in follow-up to 24 weeks (SVR 24) after end of treatment (EOT). SVR 24 efficacy and safety data from 9 liver transplant HCV patients being treated with telaprevir, pegylated interferon, and ribavirin, showed 5 of the transplanted patients accomplished the full duration of the 48 week triple therapy.
Notable were the 4 patients found to be HCV RNA-negative at week 4, and 8 patients at week 12. Upon EOT, at week 48, 6 patients were HCV RNA-negative. Importantly, at follow-up (24 weeks after EOT), a favorable sustained virological response rate was observed in 5 of these patients with HCV RNA remaining negative, including in one patient who discontinued treatment prematurely. Due to side effects, 2 patients discontinued, 2 suffered from virological breakthrough after the telaprevir treatment phase, and 1 patient had a relapse after EOT. Two thirds of patients exhibited hematological side effects requiring ribavirin dose reductions, administration of erythropoetin, or even blood transfusions.
This retrospective analysis provides evidence that - with respect to SVR 24 - liver transplant patients suffering from HCV genotype 1 recurrence may benefit from a telaprevir-based triple therapy as this new regimen showed acceptable antiviral efficacy in this small cohort of mostly pre-treated patients. Management of drug-drug interactions is challenging, but feasible. In part severe side effects are frequent during treatment and require therapeutic interventions.
doi:10.1371/journal.pone.0080528
PMCID: PMC3827217  PMID: 24265827
11.  IL28B, HLA-C, and KIR Variants Additively Predict Response to Therapy in Chronic Hepatitis C Virus Infection in a European Cohort: A Cross-Sectional Study 
PLoS Medicine  2011;8(9):e1001092.
Vijayaprakash Suppiah and colleagues show that genotyping hepatitis C patients for the IL28B, HLA-C, and KIR genes improves the ability to predict whether or not patients will respond to antiviral treatment.
Background
To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%–50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control.
Methods and Findings
We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 “G” was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10−8, 1.67–2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10−14, 2.67–5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05–2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10−6, 2.03–7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B.
Conclusions
Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 170 million people harbor long-term (chronic) infections with the hepatitis C virus (HCV) and 3–4 million people are newly infected with the virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread though contact with infected blood. Transmission can occur during medical procedures (for example, transfusions with unscreened blood or reuse of inadequately sterilized medical instruments) but in developed countries, where donated blood is routinely screened for HCV, the most common transmission route is needle-sharing among intravenous drug users. HCV infection can cause a short-lived illness characterized by tiredness and jaundice (yellow skin and eyes) but 70%–80% of newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs—pegylated interferon-alpha and ribavirin (PegIFN/R). However, PegIFN/R is expensive, causes unpleasant side-effects, and is ineffective in about half of people infected with HCV genotype 1, the commonest HCV strain.
Why Was This Study Done?
It would be extremely helpful to be able to identify which patients will respond to PegIFN/R before starting treatment. An individual's genetic make-up plays a key role in the safety and effectiveness of drugs. Thus, pharmacogenomics—the study of how genetic variants affects the body's response to drugs—has the potential to alter the clinical management of many diseases by allowing clinicians to provide individually tailored drug treatments. In 2009, scientists reported that certain single nucleotide polymorphisms (SNPs, a type of genetic variant) lying near the IL28B gene (which encodes an immune system protein made in response to viral infections) strongly influence treatment outcomes and spontaneous clearance in HCV-infected people. This discovery is now being used to predict treatment responses to PegIFN/R in clinical practice but genotyping (analysis of variants of) IL28B only correctly predicts treatment failure two-thirds of the time. Here, the researchers investigate whether genotyping two additional regions of the genome—the HLA-C and KIR gene loci—can improve the predictive value of IL28B genotyping. Human leukocyte antigen C (HLA-C) and the killer immunoglobulin-like receptors (KIRs) are interacting proteins that have been implicated in HCV viral control.
What Did the Researchers Do and Find?
The researchers genotyped 417 patients chronically infected with HCV genotype 1 whose infection had been cleared by PegIFN/R treatment, 493 patients whose infection had not responded to treatment, and 234 patients whose infection had cleared spontaneously for two HLA-C variants (C1 and C2), the presence of several KIR genes (individuals carry different combinations of KIR genes), and two IL28B SNPs (rs8099917 and rs12979860). Carriage of “variants” of either IL28B SNP was associated with absence of treatment-induced clearance and absence of spontaneous clearance. That is, these variant SNPs were found more often in patients who did not respond to treatment than in those who did respond, and more often in patients who did not have spontaneous clearance of their infection than those who did. The HLA-C C2C2 genotype (there are two copies of most genes in the genome) was also more common in patients who failed treatment than in those who responded but was not associated with spontaneous clearance. The rate of correct prediction of treatment failure increased from 66% with IL28B genotyping alone to 80% with combined IL28B and HLA-C genotyping. Finally, carriage of specific KIR genes in combination with specific HLA-C and IL28B variants was also associated with an altered HCV treatment response.
What Do These Findings Mean?
These findings show that the addition of HCL-C and KIR genotyping to IL28B genotyping improved the prediction of HCV treatment response in the patients investigated in this study. Because all these patients were European or of European descent, these findings need confirming in people of other ethnic backgrounds. They also need confirming in other groups of Europeans before being used in a clinical setting. However, the discovery that the addition of HLA-C genotyping to IL28B genotyping raises the rate of correct prediction of PegIFN/R treatment failure to 80% is extremely promising and should improve the clinical management of patients infected with HCV genotype 1. In addition, these results provide new insights into how PegIFN/R clears HCV infections that may lead to improved therapies in the future.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001092.
The World Health Organization provides detailed information about hepatitis C (in several languages)
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
The Hepatitis C Trust is a patient-led, patient-run UK charity that provides detailed information about hepatitis C and support for patients and their families; a selection of personal stories about patients' experiences with hepatitis C is available, including Phil's treatment story, which details the ups and downs of treatment with PegIFN/R
MedlinePlus provides links to further resources on hepatitis C
The Human Genome Project provides information about medicine and the new genetics, including a primer on pharmacogenomics
doi:10.1371/journal.pmed.1001092
PMCID: PMC3172251  PMID: 21931540
12.  New Antiviral Agents for Hepatitis C 
Approximately 120-130 million individuals are chronically infected with hepatitis C virus (HCV) worldwide, although it is curable by therapy. Until recently, treatment of chronic hepatitis C was based on the combination of pegylated interferon-α and ribavirin. A number of models have been developed to study the HCV lifecycle and screen for potential HCV inhibitors. They led to the development of antiviral agents that specifically target a viral function (direct acting antivirals), and host-targeted agents that inhibit HCV replication. Direct acting antivirals in clinical development include NS3-4A protease inhibitors (two of which, telaprevir and boceprevir, have recently been approved for treatment of HCV genotype 1 infection in combination with pegylated interferon-α and ribavirin), nucleoside/nucleotide analogue and non-nucleoside inhibitors of HCV RNA-dependent RNA polymerase, and NS5A inhibitors. Host-targeted agents include cyclophilin inhibitors. This article describes the direct acting antivirals and host-targeted agents that have recently been approved or have been tested in HCV-infected patients and discusses their two current paths of clinical development: with or without interferon-α.
doi:10.3410/B4-5
PMCID: PMC3292288  PMID: 22403588
13.  A Multi-Variant, Viral Dynamic Model of Genotype 1 HCV to Assess the in vivo Evolution of Protease-Inhibitor Resistant Variants 
PLoS Computational Biology  2010;6(4):e1000745.
Variants resistant to compounds specifically targeting HCV are observed in clinical trials. A multi-variant viral dynamic model was developed to quantify the evolution and in vivo fitness of variants in subjects dosed with monotherapy of an HCV protease inhibitor, telaprevir. Variant fitness was estimated using a model in which variants were selected by competition for shared limited replication space. Fitness was represented in the absence of telaprevir by different variant production rate constants and in the presence of telaprevir by additional antiviral blockage by telaprevir. Model parameters, including rate constants for viral production, clearance, and effective telaprevir concentration, were estimated from 1) plasma HCV RNA levels of subjects before, during, and after dosing, 2) post-dosing prevalence of plasma variants from subjects, and 3) sensitivity of variants to telaprevir in the HCV replicon. The model provided a good fit to plasma HCV RNA levels observed both during and after telaprevir dosing, as well as to variant prevalence observed after telaprevir dosing. After an initial sharp decline in HCV RNA levels during dosing with telaprevir, HCV RNA levels increased in some subjects. The model predicted this increase to be caused by pre-existing variants with sufficient fitness to expand once available replication space increased due to rapid clearance of wild-type (WT) virus. The average replicative fitness estimates in the absence of telaprevir ranged from 1% to 68% of WT fitness. Compared to the relative fitness method, the in vivo estimates from the viral dynamic model corresponded more closely to in vitro replicon data, as well as to qualitative behaviors observed in both on-dosing and long-term post-dosing clinical data. The modeling fitness estimates were robust in sensitivity analyses in which the restoration dynamics of replication space and assumptions of HCV mutation rates were varied.
Author Summary
Hepatitis C virus (HCV) infects an estimated 170 million people worldwide. Current treatment for HCV is 48 weeks of peginterferon and ribavirin of which patient response has large variability. Recently, specifically targeted antiviral therapies for HCV (STAT-C) are under clinical development and have shown potentials to improve response. Within a patient, HCV exists as quasispecies consisting of multiple variants. Models of HCV dynamics in response to peginterferon and ribavirin treatment have been proposed elsewhere, with HCV quasispecies assumed to respond homogenously to treatment. However, some of the HCV variants possess different degrees of sensitivity to a STAT-C compound, and therefore, selections and competitions among variants have been observed in patients treated with STAT-C. We have developed a viral dynamic model that quantifies the evolution of multiple variants in patients dosed in monotherapy with telaprevir, a compound specifically designed to inhibit HCV NS3.4A protease. Our novel modeling approach integrated data from both in vitro and in patients, both during and after dosing with telaprevir. Our model quantified the antiviral response to telaprevir and the in vivo fitness of variants. The model provides a useful framework for the designs of STAT-C during clinical development and for understanding the consequences of failure to STAT-C.
doi:10.1371/journal.pcbi.1000745
PMCID: PMC2855330  PMID: 20419154
14.  Current Management of Hepatitis C Virus Infection in Patients With HIV Co-infection 
The Journal of Infectious Diseases  2013;207(Suppl 1):S26-S32.
As a result of shared routes of transmission, coinfection with hepatitis C virus (HCV) is common in human immunodeficiency virus (HIV)–infected patients. The prevalence of HIV/HCV coinfection is particularly high among persons who have used injection drugs; however, more recently, sexual transmission of HCV has been recognized among HIV-infected men who have sex with men (MSM). Over the past decade, the effectiveness of HIV treatment improved substantially, leading to a substantial reduction in HIV/AIDS-related deaths; in this context, liver disease due to HCV infection has emerged as major concern for co-infected patients. Over the same period, treatment of HCV remained stagnant, with pegylated interferon alfa (PegIFN) plus ribavirin (RBV; PegIFN/RBV) entrenched as the standard treatment for HCV infection for co-infected patients, who have the greatest risk for liver disease. However, the effectiveness of HCV treatment in this population has been disappointing because of low rates of treatment initiation and success. In 2011, novel HCV NS3/4A PIs (PIs), telaprevir and boceprevir, were approved for use in combination with PegIFN/RBV for the treatment of HCV genotype 1 infection; at the time of approval, important questions regarding the efficacy, safety, and potential for drug interactions with telaprevir and boceprevir had not been answered. More recently, data from drug-interaction studies and 2 small, phase II clinical trials indicate that these HCV treatment regimens may lead to higher rates of HCV eradication in HIV/HCV-coinfected patients, with manageable toxicity and pharmacologic interactions with antiretroviral drugs. As such, these HCV PI–based regimens have emerged as the standard for the treatment of HCV genotype 1 infection in carefully selected HIV-infected patients.
doi:10.1093/infdis/jis764
PMCID: PMC3565592  PMID: 23390302
hepatitis C; HCV; HIV; peginterferon; ribavirin; boceprevir; telaprevir
15.  Antiviral therapies for chronic hepatitis C virus infection with cirrhosis 
World Journal of Hepatology  2015;7(8):1133-1141.
Patients who are infected with hepatitis C virus (HCV) and also have advanced fibrosis or cirrhosis have been recognized as “difficult-to-treat” patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents (DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatment-naïve patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in null-responders and in patients with cirrhosis. Interferon-free regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-naïve, treatment-experienced and even for interferon-ineligible or interferon-intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferon is contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCV-infected patients with advanced liver diseases.
doi:10.4254/wjh.v7.i8.1133
PMCID: PMC4450190  PMID: 26052402
Hepatitis C virus; Hepatocellular carcinoma; Interferon-free regimen; Liver cirrhosis; Direct-acting antiviral agent
16.  A Novel Diagnostic Target in the Hepatitis C Virus Genome 
PLoS Medicine  2009;6(2):e1000031.
Background
Detection and quantification of hepatitis C virus (HCV) RNA is integral to diagnostic and therapeutic regimens. All molecular assays target the viral 5′-noncoding region (5′-NCR), and all show genotype-dependent variation of sensitivities and viral load results. Non-western HCV genotypes have been under-represented in evaluation studies. An alternative diagnostic target region within the HCV genome could facilitate a new generation of assays.
Methods and Findings
In this study we determined by de novo sequencing that the 3′-X-tail element, characterized significantly later than the rest of the genome, is highly conserved across genotypes. To prove its clinical utility as a molecular diagnostic target, a prototype qualitative and quantitative test was developed and evaluated multicentrically on a large and complete panel of 725 clinical plasma samples, covering HCV genotypes 1–6, from four continents (Germany, UK, Brazil, South Africa, Singapore). To our knowledge, this is the most diversified and comprehensive panel of clinical and genotype specimens used in HCV nucleic acid testing (NAT) validation to date. The lower limit of detection (LOD) was 18.4 IU/ml (95% confidence interval, 15.3–24.1 IU/ml), suggesting applicability in donor blood screening. The upper LOD exceeded 10−9 IU/ml, facilitating viral load monitoring within a wide dynamic range. In 598 genotyped samples, quantified by Bayer VERSANT 3.0 branched DNA (bDNA), X-tail-based viral loads were highly concordant with bDNA for all genotypes. Correlation coefficients between bDNA and X-tail NAT, for genotypes 1–6, were: 0.92, 0.85, 0.95, 0.91, 0.95, and 0.96, respectively; X-tail-based viral loads deviated by more than 0.5 log10 from 5′-NCR-based viral loads in only 12% of samples (maximum deviation, 0.85 log10). The successful introduction of X-tail NAT in a Brazilian laboratory confirmed the practical stability and robustness of the X-tail-based protocol. The assay was implemented at low reaction costs (US$8.70 per sample), short turnover times (2.5 h for up to 96 samples), and without technical difficulties.
Conclusion
This study indicates a way to fundamentally improve HCV viral load monitoring and infection screening. Our prototype assay can serve as a template for a new generation of viral load assays. Additionally, to our knowledge this study provides the first open protocol to permit industry-grade HCV detection and quantification in resource-limited settings.
Christian Drosten and colleagues develop, validate, and make openly available a prototype hepatitis C virus assay based on the conserved 3' X-tail element, with potential for clinical use in developing countries.
Editors' Summary
Background.
About 3% of the world's population (170 million people) harbor long-term (chronic) infections with the hepatitis C virus (HCV) and about 3–4 million people are newly infected with this virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread through contact with the blood of an infected person. Globally, the main routes of transmission are the use of unscreened blood for transfusions and the reuse of inadequately sterilized medical instruments, including needles. In affluent countries, where donated blood is routinely screened for the presence of HCV, most transmission is through needle sharing among drug users. The risk of sexual and mother-to-child transmission of HCV is low. Although HCV infection occasionally causes an acute (short-lived) illness characterized by tiredness and jaundice (yellow eyes and skin), most newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two drugs called interferon and ribavirin, but these drugs are expensive and are ineffective in many patients.
Why Was This Study Done?
An effective way to limit the global spread of HCV might be to introduce routine screening of the blood that is used for transfusions in developing countries. In developed countries, HCV screening of blood donors use expensive, commercial “RT-PCR” assays to detect small amounts of HCV ribonucleic acid (RNA; HCV stores the information it needs to replicate itself—its genome—as a sequence of “ribonucleotides”). All the current HCV assays, which can also quantify the amount of viral RNA in the blood (the viral load) during treatment, detect a target sequence in the viral genome called the 5′-noncoding region (5′-NCR). However, there are several different HCV “genotypes” (strains). These genotypes vary in their geographical distribution and, even though the 5′-NCR sequence is very similar (highly conserved) in the common genotypes (HCV genotypes 1–6), the existing assays do not detect all the variants equally well. This shortcoming, together with their high cost, means that 5′-NCR RT-PCR assays are not ideal for use in many developing countries. In this study, the researchers identify an alternative diagnostic target sequence in the HCV genome—the 3′-X-tail element—and ask whether this sequence can be used to develop a new generation of tests for HCV infection that might be more appropriate for use in developing countries.
What Did the Researchers Do and Find?
The researchers determined the RNA sequence of the 3′-X-tail element in reference samples of the major HCV genotypes and showed that this region of the HCV genome is as highly conserved as the 5′-NCR. They then developed a prototype X-tail RT-PCR assay and tested its ability to detect small amounts of HCV and to measure viral load in genotype reference samples and in a large panel of HCV-infected blood samples collected in Germany, the UK, Brazil, South Africa, and Singapore. The new assay detected low levels of HCV RNA in all of the genotype reference samples and was also able to quantify high RNA concentrations. The viral load estimates it provided for the clinical samples agreed well with those obtained using a commercial assay irrespective of the sample's HCV genotype. Finally, the X-tail RT-PCR assay gave similar results to a standard assay at a fraction of the cost when used to measure viral loads in a Brazilian laboratory in an independent group of 127 patient samples collected in Brazil.
What Do These Findings Mean?
These findings suggest that the HCV 3′-X-tail element could provide an alternative target for screening blood samples for HCV infection and for monitoring viral loads during treatment, irrespective of HCV genotype. In addition, they suggest that X-tail RT-PCR assays may be stable and robust enough for use in laboratories in emerging countries. Overall, these findings should stimulate the development of a new generation of clinical HCV assays that, because the protocol used in the X-tail assay is freely available, could improve blood safety in developing countries by providing a cheap and effective alternative to existing proprietary HCV assays.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000031.
The World Health Organization has a fact sheet about hepatitis C (in English and French)
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
The MedlinePlus Encyclopedia has a page on hepatitis C; MedlinePlus also provides links to further information on hepatitis C (in English and Spanish)
doi:10.1371/journal.pmed.1000031
PMCID: PMC2637920  PMID: 19209955
17.  Hepatitis C drugs: The end of the pegylated interferon era and the emergence of all-oral, interferon-free antiviral regimens: A concise review 
The increasing medical and economic burden of chronic hepatitis C virus (HCV) infection has rapidly prompted changes in the landscape of antiviral therapy in Canada, which has witnessed significant annual increases in morbidity and mortality due to HCV over the past two decades. The limited efficacy and tolerability of standard pegylated interferon and ribavirin therapy has prompted the development of direct-acting antiviral agents that target specific proteins involved in HCV replication. Although these agents have shown promise, issues regarding resistance testing, optimal follow-up and efficacy in difficult-to-cure populations require further research.
Between 2001 and 2011, the standard of care for chronic hepatitis C virus (HCV) infection was a combination of pegylated interferon (PEGIFN) and ribavirin (RBV). In May 2011, boceprevir and telaprevir, two first-generation NS3/4A protease inhibitors, were approved in combination with PEG-IFN and RBV for 24 to 48 weeks in hepatitis C virus genotype 1 infections. In December 2013, simeprevir, a second-generation NS3/4A protease inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotype 1, while sofosbuvir, a NS5B nucleotide polymerase inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotypes 1 and 4, as well as with RBV alone for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Sofosbuvir combined with simeprevir or an NS5A replication complex inhibitor (ledipasvir or daclatasvir) with or without RBV for 12 weeks in genotype 1 resulted in a sustained virological response >90%, irrespective of previous treatment history or presence of cirrhosis. Similarly impressive sustained virological response rates have been shown with ABT-450/r (ritonavir-boosted NS3/4A protease inhibitor)-based regimens in combination with other direct-acting antiviral agent(s) with or without RBV for 12 weeks in genotype 1. The optimal all-oral interferon-free antiviral regimen likely entails a combination of an NS5B nucleotide polymerase inhibitor with either a second-generation NS3/4A protease inhibitor or an NS5A replication complex inhibitor with or without RBV. Further research is needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and evaluate the antiviral efficacy and safety in difficult-to-cure patient populations.
PMCID: PMC4210236  PMID: 25229466
All-oral; Hepatitis C; Interferon-free; Simeprevir; Sofosbuvir
18.  Antiviral treatment of hepatitis C virus infection and factors affecting efficacy 
Hepatitis C virus (HCV) infection is the leading cause of chronic liver-related diseases, including cirrhosis, liver failure, and hepatocellular carcinoma. Currently, no effective vaccine is available for HCV infection. Polyethylene glycol interferon-α (PegIFN-α) in combination with ribavirin (RBV) is the standard of care (SOC) for chronic hepatitis C. However, the efficacy of PegIFN-α and RBV combination therapy is less than 50% for genotype 1 HCV, which is the dominant virus in humans. In addition, IFN and RBV have several severe side effects. Therefore, strategies to improve sustained virological response (SVR) rates have been an important focus for clinical physicians. The serine protease inhibitors telaprevir and boceprevir were approved by the United States Food and Drug Administration in 2011. The addition of HCV protease inhibitors to the SOC has significantly improved the efficacy of treatments for HCV infection. Several direct-acting antiviral drugs currently in late-stage clinical trials, both with and without peg-IFN and RBV, have several advantages over the previous SOC, including higher specificity and efficacy, fewer side effects, and the ability to be administered orally, and might be optimal regimens in the future. Factors affecting the efficacy of anti-HCV treatments based on IFN-α include the HCV genotype, baseline viral load, virological response during treatment, host IL28B gene polymorphisms and hepatic steatosis. However, determining the effect of the above factors on DAA therapy is necessary. In this review, we summarize the development of anti-HCV agents and assess the main factors affecting the efficacy of antiviral treatments.
doi:10.3748/wjg.v19.i47.8963
PMCID: PMC3870549  PMID: 24379621
Hepatitis C virus; Treatment; Interferon; Protease inhibitors; IL28B protein; Polymorphisms; Viral load; Genotype; Hepatic steatosis
19.  Hepatitis C (chronic) 
BMJ Clinical Evidence  2010;2010:0921.
Introduction
About 60% to 85% of people infected with hepatitis C virus will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions in treatment-naïve people with chronic hepatitis C infection, but without liver decompensation? What are the effects of interventions in people with chronic hepatitis C infection, but without liver decompensation, who have not responded to interferon treatment? What are the effects of interventions in people with chronic hepatitis C infection, but without liver decompensation, who relapse after interferon treatment? What are the effects of interventions in people with chronic hepatitis C infection who also have HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 35 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: interferon monotherapy; interferon alfa plus ribavirin; peginterferon monotherapy; and peginterferon plus ribavirin.
Key Points
Chronic hepatitis C virus (HCV) infection is defined as persistent, detectable serum HCV RNA for a period greater than 6 months, with or without derangement in liver function tests. About 60% to 85% of people infected with HCV will go on to develop chronic hepatitis C, which is now believed to affect 3% of the world's population.Complications of chronic HCV infection include cirrhosis, compensated and decompensated liver disease, and hepatocellular carcinoma.Many people chronically infected with HCV remain asymptomatic, including a significant proportion of those who progress to cirrhosis, so routine screening of people in high-risk groups is advisable.
Interferon monotherapy produces a sustained virological response in both treatment-naïve people and people with cirrhosis or advanced fibrosis compared with placebo or no treatment. Interferon also improves liver histology, although it may not be effective in preventing hepatocellular carcinoma in people with cirrhosis.Efficacy is dependent on duration of treatment, with treatment for 12 months seeming more effective than treatment for 6 months. However, treatment for 12 months is associated with an increase in adverse effects.A dose of 6 MU of interferon three times weekly seems no more effective at achieving sustained virological response than 3 MU three times weekly, and is associated with an increased risk of adverse effects.
Adding ribavirin to interferon regimens further increases the likelihood of achieving sustained virological response, but also increases the risk of anaemia. Efficacy of combination therapy depends on genotype, with genotype 1-infected people typically requiring longer duration of treatment compared with genotype 2- and genotype 3-infected people.
Peginterferon monotherapy increases the proportion of treatment-naïve people who achieve sustained virological response compared with standard interferon monotherapy.
Adding ribavirin to peginterferon increases the likelihood of achieving sustained virological response compared with either peginterferon alone or standard interferon plus ribavirin. This is currently the standard recommended therapeutic approach.
In people previously non-responsive to interferon monotherapy, treatment with interferon alfa plus ribavirin increases the likelihood of achieving sustained virological response compared with interferon alone. This effect seems greater when the interferon dose is higher than 3 MU three times weekly, or the duration of the treatment is 12 months or greater.We don't know whether peginterferon as a monotherapy, or in combination with ribavirin, is effective in non-responders to interferon monotherapy. We don't know whether peginterferon plus ribavirin is more effective than interferon alfa plus ribavirin.
In people who relapse after interferon monotherapy, treatment with interferon plus ribavirin is more likely than interferon treatment alone to achieve sustained virological response (SVR). There is general consensus that peginterferon plus ribavirin is likely to improve the probability of achieving SVR in people who relapse after interferon monotherapy.We don't know whether peginterferon alone is effective at achieving SVR in people who relapse after interferon monotherapy.
In people co-infected with HCV and HIV, peginterferon plus ribavirin seems more effective than standard interferon plus ribavirin treatment or peginterferon alone at achieving SVR. Although interferon plus ribavirin seems less effective than peginterferon plus ribavirin, the proportion of people achieving SVR suggests that interferon plus ribavirin may be effective in people with HCV and HIV. We don't know whether interferon alone is effective in people co-infected with HCV and HIV.
PMCID: PMC2907607  PMID: 21718581
20.  Boceprevir and personalized medicine in hepatitis C virus infection 
Boceprevir was the first agent, along with telaprevir, of a novel class of direct-acting antivirals that entered clinical practice for the treatment of chronic hepatitis C. Boceprevir is an antiprotease that directly blocks hepatitis C virus (HCV) replication. Two studies in patients with HCV genotype 1 infection have shown that addition of boceprevir to the standard of care, ie, pegylated interferon-alfa (PEG-IFN-α) and ribavirin, markedly increased the rate of sustained virological response. A sustained virological response was obtained in about 70% of patients who had never been treated, as well as in 69%–75% and 40% of previous relapsers and nonresponders to PEG-IFN-α-ribavirin, respectively. Side effects were observed in almost all treated patients. Anemia, the most frequent adverse event related to administration of boceprevir, occurred in about 50% of patients. The decision to add boceprevir to the standard of care is made on an individual basis, and takes into account the prognosis of the liver disease, the efficacy of therapy, as it could be at best predicted, and the side effects that may arise, taking into account the comorbidities of the patient. Ultimately, the treatment must be accepted by the patient, who should fully understand the benefits and risks. Boceprevir trials were designed with the concept of individualized and response-guided therapy which establishes treatment decisions on how rapidly patients respond to treatment. Individualized therapy for chronic hepatitis C is based on patient and viral characteristics to make the best choice about whether a person will benefit from therapy and to evaluate on-treatment predictors of response to shorten therapy in patients with a rapid response as well as in patients who did not respond sufficiently to expect HCV eradication. This review focuses on the main results obtained so far, their impact on the treatment of patients with chronic hepatitis C, and potential therapeutic perspectives.
doi:10.2147/PGPM.S24259
PMCID: PMC3513234  PMID: 23226068
boceprevir; antiviral therapy; hepatitis C virus
21.  The Global Spread of Hepatitis C Virus 1a and 1b: A Phylodynamic and Phylogeographic Analysis 
PLoS Medicine  2009;6(12):e1000198.
Using phylodynamic and phylogeographic methods, Angelos Hatzakis and colleagues find that the global spread of Hepatitis C virus coincided with widespread use of transfused blood and with the expansion of intravenous drug use.
Background
Hepatitis C virus (HCV) is estimated to affect 130–180 million people worldwide. Although its origin is unknown, patterns of viral diversity suggest that HCV genotype 1 probably originated from West Africa. Previous attempts to estimate the spatiotemporal parameters of the virus, both globally and regionally, have suggested that epidemic HCV transmission began in 1900 and grew steadily until the late 1980s. However, epidemiological data suggest that the expansion of HCV may have occurred after the Second World War. The aim of our study was to elucidate the timescale and route of the global spread of HCV.
Methods and Findings
We show that the rarely sequenced HCV region (E2P7NS2) is more informative for molecular epidemiology studies than the more commonly used NS5B region. We applied phylodynamic methods to a substantial set of new E2P7NS2 and NS5B sequences, together with all available global HCV sequences with information in both of these genomic regions, in order to estimate the timescale and nature of the global expansion of the most prevalent HCV subtypes, 1a and 1b. We showed that transmission of subtypes 1a and 1b “exploded” between 1940 and 1980, with the spread of 1b preceding that of 1a by at least 16 y (95% confidence interval 15–17). Phylogeographic analysis of all available NS5B sequences suggests that HCV subtypes 1a and 1b disseminated from the developed world to the developing countries.
Conclusions
The evolutionary rate of HCV appears faster than previously suggested. The global spread of HCV coincided with the widespread use of transfused blood and blood products and with the expansion of intravenous drug use but slowed prior to the wide implementation of anti-HCV screening. Differences in the transmission routes associated with subtypes 1a and 1b provide an explanation of the relatively earlier expansion of 1b. Our data show that the most plausible route of the HCV dispersal was from developed countries to the developing world.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 150 million people (3% of the world's population) harbor long-term (chronic) infections with the hepatitis C virus (HCV) and about 3–4 million people become infected with this virus every year. HCV—a leading cause of chronic hepatitis (inflammation of the liver)—is spread through contact with infected blood. Transmission routes include medical procedures (for example, transfusions with unscreened blood) and needle-sharing among intravenous drug users. This second transmission route is the most common one in developed countries where blood is now routinely screened before being used in transfusions. HCV infection can cause a short-lived illness characterized by tiredness and jaundice (yellow skin and eyes), but most newly infected people progress to a symptom-free, chronic infection that can eventually cause liver cirrhosis (scarring) and liver cancer. HCV infections can be treated with a combination of two expensive drugs called interferon and ribavirin, but these drugs are ineffective in many patients.
Why Was This Study Done?
Noone knows for sure where HCV originated although there is some evidence that it appeared first in West Africa or Southeast Asia. It is also unclear when the current HCV epidemic began. In this study, the researchers try to elucidate both the timescale and route of the global spread of the HCV epidemic by analyzing the genome sequence of HCV samples collected at different times and places. HCV is a ribonucleic acid (RNA) virus. That is, it stores the information it needs to replicate itself—its genome—as a series of “ribonucleotides.” Like other RNA viruses, the HCV genome continually accumulates small changes (mutations) and, over time, HCV has evolved into several different “genotypes,” each of which has several distinct subtypes. Furthermore, the viruses within a single subtype have subtly different genomes. By analyzing this viral diversity using complex “phylodynamic” and “phylogeographic” methods, scientists can build up a picture of how HCV has evolved in populations and how it has spread to reach its current geographical distribution.
What Did the Researchers Do and Find?
By examining the genomes of HCV samples collected between 1994 and 2006 at the Athens University Medical School (Greece), the researchers first defined a variable region of HCV called E2P7NS2 that is more informative for phylodynamic studies than the NS5B region that has been used in previous studies. They then retrieved the sequences of both regions for subtype 1a and 1b samples collected over the past 20–30 years in the Los Alamos HCV sequence database; HCV subtypes 1a and 1b cause 60% of global HCV infections. The researchers' phylodynamic analyses of these globally representative sequences (collected in the USA, Germany, Switzerland, and Greece) indicate that the transmission of HCV subtype 1a occurred at a low rate from 1906 until the 1960s, at which time there was an explosive increase in its transmission rate. Similarly, subtype 1b transmission occurred at a low rate from 1922 until the late 1940s but then increased exponentially. From 1980 onwards, the prevalence of both subtypes stabilized at a high level. The researchers' phylogeographic analyses (which considered 1a and1b NS5B sequences collected in 21 and 29 countries, respectively) suggest that HCV subtypes 1a and 1b may have spread from the developed to the developing world.
What Do These Findings Mean?
These findings indicate that the epidemic of HCV subtype 1b began in the 1940s when the use of transfused blood and blood products became widespread whereas the start of the subtype 1a epidemic coincided with the expansion of injected drug use that occurred in the 1960s. The findings also suggest that the transmission rates of both subtypes may have slowed before the widespread implementation of HCV screening in the early 1990s, possibly because the medical community was aware by then of the general risks associated with blood contamination. Finally, these findings provide new insights into how the HCV epidemic spread around the world and suggest that HCV may be evolving faster than previously thought. However, because this study relied on a small number of samples collected over a short time period, its findings need to be confirmed in larger studies.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000198.
The World Health Organization provides detailed information about hepatitis C and HCV
The US Centers for Disease Control and Prevention provides information on hepatitis C for the public and for health professionals (information is also available in Spanish)
The US National Institute of Diabetes and Digestive and Kidney Diseases provides basic information on hepatitis C (in English and Spanish)
MedlinePlus provides links to further resources on hepatitis C
The Los Alamos HCV database is available
The US National Center for Biotechnology Information provides a science primer on how scientists reconstruct evolutionary pathways from sequence information
doi:10.1371/journal.pmed.1000198
PMCID: PMC2795363  PMID: 20041120
22.  Faldaprevir for the Treatment of Hepatitis C 
The current treatments for chronic hepatitis C virus (HCV) genotype 1 infection are combinations of direct-acting antivirals, and faldaprevir is one of the new generation of HCV NS3/4A protease inhibitors. At the end of 2013, the US Food and Drug Administration (FDA) approved the HCV NS3/4A protease inhibitor simeprevir and the HCV NS5B polymerase inhibitor sofosbuvir. Simeprevir or sofosbuvir in combination with pegylated interferon and ribavirin are available for clinical use. Faldaprevir, another HCV NS3/4A protease inhibitor that also has fewer adverse events than telaprevir or boceprevir, is under development. Of interest, faldaprevir in combination with pegylated interferon and ribavirin, and interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin provides high sustained virological response rates for HCV genotype 1 infection. The aim of this article is to review these data concerning faldaprevir. Faldaprevir in combination with pegylated interferon and ribavirin treatment appears to be associated with fewer adverse events than telaprevir or boceprevir in combination with pegylated interferon and ribavirin, and may be one of the therapeutic options for treatment-naive patients with HCV genotype 1. The interferon-free combination of faldaprevir and deleobuvir with ribavirin was effective for HCV genotype 1 infection and may hold promise for interferon-ineligible and interferon-intolerant patients.
doi:10.3390/ijms16034985
PMCID: PMC4394460  PMID: 25749475
chronic hepatitis C; direct-acting antivirals; faldaprevir; genotype 1; protease inhibitor
23.  Advances in the Treatment of Hepatitis C Virus Infection 
Gastroenterology & Hepatology  2012;8(2):91-101.
Therapy for chronic hepatitis C virus (HCV) infection with pegylated interferon α and ribavirin leads to suboptimal rates of viral eradication in patients with genotype 1 HCV, the most common viral strain in the United States and many other countries. Recent advances in the study of viral kinetics, host factors that predict response to antiviral therapy, and viral protein structure have established the foundation of a new era in the treatment of HCV infection. The HCV NS3/4A protease inhibitors boceprevir and telaprevir, the first 2 agents in a new and promising generation of direct-acting antiviral agents to have completed phase III studies, were approved by the US Food and Drug Administration in May 2011. The addition of these HCV protease inhibitors to standard therapy has been demonstrated to dramatically improve sustained virologic response rates, both in treatment-naïve patients and in prior relapsers and nonresponders. These novel agents represent only the beginning of a revolution in HCV therapy, which will include additional protease inhibitors as well as other classes of drugs currently under investigation, such as polymerase inhibitors, NS5A inhibitors, and host factor inhibitors such as cyclophilin antagonists. The future of HCV therapy holds promise for significantly higher sustained virologic response rates with shorter treatment durations, as well as the intriguing potential to achieve virologic cure with interferon-free combination therapy regimens.
PMCID: PMC3317517  PMID: 22485076
Hepatitis C virus; genotype 1; boceprevir; telaprevir; direct-acting antiviral agents
24.  Impaired Hepatitis C Virus-Specific T Cell Responses and Recurrent Hepatitis C Virus in HIV Coinfection 
PLoS Medicine  2006;3(12):e492.
Background
Hepatitis C virus (HCV)-specific T cell responses are critical for spontaneous resolution of HCV viremia. Here we examined the effect of a lymphotropic virus, HIV-1, on the ability of coinfected patients to maintain spontaneous control of HCV infection.
Methods and Findings
We measured T cell responsiveness by lymphoproliferation and interferon-γ ELISPOT in a large cohort of HCV-infected individuals with and without HIV infection. Among 47 HCV/HIV-1-coinfected individuals, spontaneous control of HCV was associated with more frequent HCV-specific lymphoproliferative (LP) responses (35%) compared to coinfected persons who exhibited chronic HCV viremia (7%, p = 0.016), but less frequent compared to HCV controllers who were not HIV infected (86%, p = 0.003). Preservation of HCV-specific LP responses in coinfected individuals was associated with a higher nadir CD4 count (r2 = 0.45, p < 0.001) and the presence and magnitude of the HCV-specific CD8+ T cell interferon-γ response (p = 0.0014). During long-term follow-up, recurrence of HCV viremia occurred in six of 25 coinfected individuals with prior control of HCV, but in 0 of 16 HIV-1-negative HCV controllers (p = 0.03, log rank test). In these six individuals with recurrent HCV viremia, the magnitude of HCV viremia following recurrence inversely correlated with the CD4 count at time of breakthrough (r = −0.94, p = 0.017).
Conclusions
These results indicate that HIV infection impairs the immune response to HCV—including in persons who have cleared HCV infection—and that HIV-1-infected individuals with spontaneous control of HCV remain at significant risk for a second episode of HCV viremia. These findings highlight the need for repeat viral RNA testing of apparent controllers of HCV infection in the setting of HIV-1 coinfection and provide a possible explanation for the higher rate of HCV persistence observed in this population.
HIV infection impairs the immune response to HCV. Even individuals who have cleared HCV infection remain at significant risk for a second episode of HCV viremia.
Editors' Summary
Background.
Because of shared transmission routes (contaminated needles, contaminated blood products, and, to a lesser extent, unprotected sex), a large proportion of HIV-infected individuals (estimates range between 25% and 33%) are also infected with the hepatitis C virus (HCV). In most but not all individuals infected with HCV, the virus infection is chronic and causes liver disease that can eventually lead to liver failure. Disease progress is slow; it often takes decades until infected individuals develop serious liver disease. In people infected with both HCV and HIV, however, liver disease caused by HCV often appears sooner and progresses faster. As highly active antiretroviral therapy (HAART) and prophylaxis of opportunistic infections increase the life span of persons living with HIV, HCV-related liver disease has become a major cause of hospital admissions and deaths among HIV-infected persons.
Why Was This Study Done?
A sizable minority of people who are infected with HCV manage to control the virus and never get liver disease, and scientists have found that these people somehow mounted a strong immune response against the hepatitis C virus. CD4+ T cells, the very immune cells that are infected and destroyed by HIV, play an important role in this immune response. The goal of the present study was to better understand how infection with HIV compromises the specific immune response to HCV and thereby the control of HCV disease progression.
What Did the Researchers Do and Find?
The researchers recruited four groups of patients, 94 in total, all of whom were infected with HCV. Two groups comprised patients who were infected with HIV as well as HCV, with either high or undetectable levels of HCV (30 patients in each group). The two other groups included patients not infected with HIV, either with high or undetectable levels of HCV (17 patients in each group). The researchers focused on the individuals who, despite coinfection with HIV, were able to control their HCV infection. They found that those individuals managed to maintain relatively high levels of CD4+ T cells that specifically recognize HCV. However, a quarter of these patients (six out of 25) failed to keep HCV levels down for the entire observation period of up to 2.5 years; their blood levels of HCV rose substantially, most likely due to recurrence of the previously suppressed virus (the researchers could not be certain that none of the patients had become infected again after a new exposure to HCV-contaminated blood, but there was no evidence that they had engaged in risky behavior). The rise of HCV levels in the blood of the relapsed patients coincided with a drop in overall CD4+ T cell numbers. Following relapse in these individuals, HCV did not return to undetectable levels during the study. During the same period none of the 16 HIV-uninfected people with controlled HCV infection experienced a recurrence of detectable HCV.
What Do These Findings Mean?
Despite the relatively small numbers of patients, these results suggest that recurrence of HCV after initial control of the virus is more likely in people who are coinfected with HIV, and that HCV control is lost when CD4+ T cell counts fall. This is one more reason to test all HIV-positive patients for HCV coinfection. Coinfected patients, even those who seem to be controlling HCV and would not automatically receive HCV treatment, should be regularly tested for a rise of HCV levels. In addition, maintaining CD4+ T cells at a high level might be particularly important for those patients, which means that doctors might consider starting HAART therapy earlier than is generally recommended for HIV-infected individuals. Additional studies are needed to support these recommendations, however, especially as this study did not follow the patients long enough to determine the consequences of the observed loss of control of HCV.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030492.
AIDS Treatment Data Network factsheet on HIV/HCV coinfection
US CDC factsheet on HIV/HCV coinfection
American Liver Foundation, information on HIV and HCV
MedlinePlus pages on HCV
doi:10.1371/journal.pmed.0030492
PMCID: PMC1705826  PMID: 17194190
25.  Antiviral Lectins from Red and Blue-Green Algae Show Potent In Vitro and In Vivo Activity against Hepatitis C Virus 
PLoS ONE  2013;8(5):e64449.
Hepatitis C virus (HCV) infection is a significant public health problem with over 170,000,000 chronic carriers and infection rates increasing worldwide. Chronic HCV infection is one of the leading causes of hepatocellular carcinoma which was estimated to result in ∼10,000 deaths in the United States in the year 2011. Current treatment options for HCV infection are limited to PEG-ylated interferon alpha (IFN-α), the nucleoside ribavirin and the recently approved HCV protease inhibitors telaprevir and boceprevir. Although showing significantly improved efficacy over the previous therapies, treatment with protease inhibitors has been shown to result in the rapid emergence of drug-resistant virus. Here we report the activity of two proteins, originally isolated from natural product extracts, which demonstrate low or sub-nanomolar in vitro activity against both genotype I and genotype II HCV. These proteins inhibit viral infectivity, binding to the HCV envelope glycoproteins E1 and E2 and block viral entry into human hepatocytes. In addition, we demonstrate that the most potent of these agents, the protein griffithsin, is readily bioavailable after subcutaneous injection and shows significant in vivo efficacy in reducing HCV viral titers in a mouse model system with engrafted human hepatocytes. These results indicate that HCV viral entry inhibitors can be an effective component of anti-HCV therapy and that these proteins should be studied further for their therapeutic potential.
doi:10.1371/journal.pone.0064449
PMCID: PMC3660260  PMID: 23700478

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