Actualización en la terapia de la hepatitis C. Nuevos fármacos,monitorización de la respuesta y resistencias

The development of novel direct antiviral agents (DAAs) against hepatitis C virus (HCV) has represented a breakthrough in the treatment of chronic hepatitis C. Telaprevir and boceprevir are the first two protease inhibitor (PI) DAAs to be approved for combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). In genotype 1 monoinfected patients, triple PI therapy has increased sustained viral response (SVR) rates by approximately 30% compared with conventional combination therapy. The introduction of these drugs into clinical practice will modify the timing of monitoring parameters in diagnostic laboratories, especially with regard to stopping rules and to faster delivery of results. In the near future, new DAAs, directed against different targets of the HCV cycle (polymerase inhibitors, viral replication complex inhibitors and cyclophilin inhibitors), which are currently in various stages of clinical development, will be available. Some of these DAAs have already reached advanced phases of development, both in combination with PEG-IFN and RBV and in interferon-free therapy, with very high rates of SVR.     

Hepatitis C therapy in non-genotype 1 patients: the near future

Worldwide, 50-70 million subjects are infected with an hepatitis C virus (HCV) genotype 2, 3, 4, 5 or 6. In these patients, the combination of PEG-INF-α and ribavirin remains the currently approved standard-of-care treatment. The identification of different potential therapeutic targets in the HCV life cycle has led to the development of both direct antiviral agents (DAAs) and reagents targeting host functions essential for viral replication. DAAs comprise so far first-generation, second-wave and second-generation NS3/4A protease inhibitors (PIs), nucleos(t)ide (NIs) and non-nucleoside inhibitors of the NS5B RNA polymerase and NS5A complex inhibitors. The main host-protein-directed antiviral agents are cyclophilin inhibitors and silibinin. Whereas the launch of first-generation PIs was a major landmark in the management of genotype 1 (GT-1)-infected patients, these drugs are inactive in most non-GT-1-infected patients. Several of these and other drugs have now reached phase II and even phase III clinical stage development. The purpose of this article is to provide an overview of the clinical results recently reported for the treatment for non-GT-1 HCV infection with a focus on the most promising new compounds and combinations.     

Antiviral therapies for chronic hepatitis C virus infection with cirrhosis

Patients who are infected with hepatitis C virus(HCV) and also have advanced fibrosis or cirrhosis have beenrecognized 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 NS5 A inhibitors and HCV NS5 B 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 treatmentnave patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in nullresponders and in patients with cirrhosis. Interferonfree regimens in combination with ribavirin and/or two or more DAAs could be used for treatment-nave, 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. Interferonis 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 HCVinfected patients with advanced liver diseases.     

Antiviral activity of the new DAAs for the treatment of hepatitis C virus infection: virology and resistance

The treatment of chronic hepatitis C virus (HCV) infection has substantially evolved over the past decade, following the Consensus Conference organized by the European Association for the Study of the Liver in 1999. Since then, the standard of care (SoC) for patients with chronic hepatitis C has been the combination of pegylated interferon (pegIFN) alpha-2a or -2b and ribavirin. In patients infected with HCV genotype 1, by far the most frequent HCV genotype worldwide, such treatment leads to a cure of infection in only 40-50% of cases. After a decade in which pegIFN alpha and ribavirin therapy was the only available option, triple therapy with HCV protease inhibitors (PIs; boceprevir and telaprevir) in combination with pegIFN alpha and ribavirin has become the new SoC for genotype-1-infected patients. With PI therapy, higher cure rates can be achieved, but specific issues are also raised, such as the emergence of resistance to PIs. For this reason, the present report examines the antiviral activity of PIs and what is currently known about resistance to them, while focusing on telaprevir and boceprevir, two HCV PIs recently licensed for the treatment of treatment-na?ve and treatment-experienced genotype-1 patients with chronic hepatitis C. The clinical relevance of resistance testing is also discussed.     

Advances in hepatitis C therapy: What is the current state-what come's next?

Chronic hepatitis C virus (HCV) infection affects 80-160 million people worldwide and is one of the leading causes of chronic liver disease. It is only a few years ago that standard treatment regimes were based on pegylated interferon alpha and ribavirin. However, treatment of HCV has undergone a revolutionary change in recent years. The admission of the nucleotide polymerase inhibitor Sofosbuvir enabled an interferon-free regimen with direct antiviral agents (DAA). Meanwhile seven DAAs are available and can be applied in several combinations for 8 to 24 wk depending on HCV genotype and patient characteristics such as cirrhosis and chronic renal failure. High rates of sustained virological response (SVR) rates can be achieved with these novel drugs. Even in difficult to treat populations such as patients with liver cirrhosis, HCV-human immunodeficiency virus co-infections, after liver transplantion, or with chronic kidney disease comparable high rates of SVR can be achieved. The anticipated 2^nd generation DAAs are strikingly effective in patients so far classified as difficult to treat including decompensated liver cirrhosis or post-transplant patients. These 2^nd generations DAAs will have higher resistance barriers, higher antiviral effects and a pan-genotypic spectrum. This review highlights the current state of the art of antiviral treatment in hepatitis C and gives an outlook for upcoming therapies.     

The era of direct-acting antivirals has begun: the beginning of the end for HCV?

The year 2011 marks the dawn of the new era of direct-acting antivirals for hepatitis C. For the first time since 1998, the U.S. Food and Drug Administration approved two new antiviral drugs for the treatment of chronic hepatitis C virus genotype 1. Dual therapy with pegylated interferon and ribavirin is no longer the standard of care for genotype 1. The new treatment paradigm includes one direct-acting antiviral, a protease inhibitor, in combination with pegylated interferon and ribavirin. This combination nearly doubles the chances of response to treatment, but at the cost of increased toxicity. Many agents with different mechanisms of action and improved safety profiles are in clinical development. The holy grail of HCV treatment is an all oral, interferon-free treatment. The ideal regimen will be potent, well tolerated, with minimal drug-drug interactions and once daily. This article covers new concepts of treatment of hepatitis C with DAAs and gives an overview of the recent highlights in direct-acting antiviral development.     

Faldaprevir for the treatment of genotype-1 hepatitis C virus

Historically, pegylated interferon in combination with ribavirin was the standard of care in hepatitis C virus; however, this combination is often poorly tolerated, has a significant side-effect profile and is of limited efficacy in hepatitis C virus genotype-1. More recently, pegylated interferon/ribavirin has been combined with direct acting antiviral agents such as the first generation NS3/4A protease inhibitors. Faldaprevir, a first generation, second-wave protease inhibitor, when used with a pegylated interferon/ribavirin regimen, has also been shown to increase treatmentsuccess while shortening treatment duration; however, second generation direct acting antiviral agents offer even betterefficacy and tolerability. Various direct acting antiviral agent combinations in interferon-free regimens have been effective in over 95% of patients and are now in licensed use. While faldaprevir was a pioneering drug, by the time it reached late phase development it was superseded by newer agents.     

Treatment of Chronic Hepatitis C in the Age of Direct-Acting Antivirals with Emphasis on First Generation Inhibitors of HCV NS3/4A Protease

The past standard-of-care (SOC) for treatment of the chronic hepatitis C virus (HCV) was the combination of peginterferon with ribavirin (P + R). Sustained virologic response (SVR) for patients with HCV, genotype 1, was less than 50%. The new emerging SOC, Triple Therapy, using direct-acting antivirals (DAAs) with P + R will improve SVR for HCV genotype 1 infection to approximately 75%. Telaprevir and boceprevir are inhibitors of HCV NS3/4A serine protease and will be the first DAAs for treatment of patients with chronic hepatitis C. The treatment provider must effectively manage dosage and adherence to the regimen to avoid emergence of resistant variants of HCV. Close monitoring of patients, awareness of drug interactions, management of known telaprevir and boceprevir side effects, and strategies for reduction or discontinuation of individual drugs in the treatment regimen will be critical to ultimate success of triple therapy.     

Emerging Therapies for Hepatitis C

The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV), the current therapy for hepatitis C virus (HCV) infection, has saved the lives of many HCV-infected patients. Direct-acting antivirals (DAAs) target several sites of HCV nonstructural proteins, resulting in the cessation of viral replication. The first NS3/4A protease inhibitors consisted of boceprevir and telaprevir, which have shown superior efficacy against genotype 1 HCV infection when combined with PEG-IFN/RBV compared with the standard therapy in both treatment-naive and -experienced patients. Simeprevir, faldaprevir, and asunaprevir are second-wave, first-generation NS3/4A inhibitors that have already been or will soon be approved. Second-generation protease inhibitors are in clinical trials. Daclatasvir is the first approved DAA belonging to the class of NS5A replication complex inhibitors. The potency of daclatasvir is very high, and this drug is an important and essential component of combination regimens for all genotypes. Sofosbuvir, the first approved NS5B polymerase inhibitor, is characterized by high potency and genetic barriers to resistance. Sofosbuvir combined with RBV achieved an interferon-free regimen in genotype 2 or 3 patients with a reduced treatment duration. It can also be used in combination with PEG-IFN/RBV in genotype 1 patients for 12 weeks. DAAs have provided new hope for curing HCV infections with a short treatment duration and acceptable adverse events.     

Aktueller Stand der Hepatitis-C-Therapie

The approval of two NS3/4A protease inhibitors, boceprevir and telaprevir, as the first directly acting antiviral substances in combination with pegylated (PEG) interferon alfa and ribavirin, markedly changed the treatment of chronic hepatitis C genotype 1 infections. The pivotal studies showed significantly improved rates of sustained virologic response (SVR) of triple therapy combining a protease inhibitor with PEG interferon alfa and ribavirin in the range of 63–75 % in treatment-naïve patients and 59–65 % in treatment-experienced patients compared to 38–44 % and 17–21 %, respectively in the control groups without the protease inhibitor. The standard of care for all other HCV genotypes is still dual combination therapy with PEG interferon and ribavirin. Besides this considerable progress, HCV genotype 1 infected patients with previous null response and with liver cirrhosis showed limited response rates. In addition management of triple therapy is complicated by complex treatment schedules, drug-drug interactions and supplemental side effects, such as aggravation of anemia or a rash. The second generation of direct acting antiviral substances is currently in advanced stages of clinical development and will lead to a shortening and simplification of HCV therapy in addition to further improvement of efficiency including all HCV genotypes and interferon-free therapy.     

Sofosbuvir treatment and hepatitis C virus infection

Hepatitis C virus (HCV) infection is a serious problem worldwide. The use of interferon-based therapy has made HCV eradication challenging. The recent appearance of direct-acting antiviral agents (DAAs) has changed HCV therapy. Combining the use of DAAs with peginterferon and ribavirin has improved treatment efficacy. Furthermore, the combination of different orally administered DAAs has enabled interferon-free therapy with much higher efficacy and safety. In particular, sofosbuvir, a nucleotide-based NS5B inhibitor, prevents HCV RNA synthesis by acting as a “chain terminator”. Treatment with sofosbuvir has attained an extremely high rate of sustained virologic response. The current review summarizes the efficacy and safety of sofosbuvir therapy.     

Treatment of chronic genotype-3 hepatitis C virus infection using direct-acting antiviral agents: An Indian experience

Background

Direct-acting antiviral drugs (DAAs) are favored for the treatment of hepatitis C virus (HCV) infection. However, the experience with the DAAs currently available in India in the treatment of genotype-3 HCV is limited. We therefore reviewed our experience with these drugs in treating patients with chronic genotype-3 HCV infection, including those with cirrhosis.

Methods

We prospectively followed adult patients with genotype-3 HCV infection who had received treatment regimens containing sofosbuvir with/without daclatasvir. Patients were categorized as chronic hepatitis C (CHC), compensated cirrhosis (CC), and decompensated cirrhosis (DC). They received either (i) sofosbuvir and ribavirin, with or without pegylated interferon (Peg-IFN) for 12 or 24 weeks, or (ii) sofosbuvir and daclatasvir, with or without ribavirin for 12 or 24 weeks. Response was assessed using HCV RNA testing after 2 or 4 weeks of treatment (rapid virological response [RVR]), at treatment completion (end-of-treatment response [ETR]) or 12 weeks after treatment completion (sustained virological response [SVR12]).

Results

Of the 160 patients (90% treatment-naïve; CHC 49%, CC 32%, and DC 19%), 39 (24%) received Peg-IFN, sofosbuvir and ribavirin, 21 (13%) received sofosbuvir and ribavirin, and 100 (63%) received sofosbuvir and daclatasvir, with or without ribavirin. On intention-to-treat basis, RVR, ETR, and SVR12 in the entire cohort were 146/160 (91.3%), 151/160 (94.4%), and 147/160 (91.9%), respectively. Seven patients died (CC 2, DC 5) during treatment; four (2 CHC, 2 DC) patients discontinued treatment; and two patients with CC relapsed.

Conclusions

Dual-DAA-based regimens were safe and highly effective in treating genotype-3 HCV infection in CHC and CC patients.

     

Antiviral strategies in hepatitis C virus infection

Resolution of the three-dimensional structures of several hepatitis C virus (HCV) proteins, together with the development of replicative cell culture systems, has led to the identification of a number of potential targets for direct-acting antiviral (DAA) agents. Numerous families of drugs that potently inhibit the HCV lifecycle in vitro have been identified, and some of these molecules have reached early to late clinical development. Two NS3/4A protease inhibitors, telaprevir and boceprevir, were approved in Europe and the United States in 2011 in combination with pegylated interferon (IFN)-α and ribavirin for the treatment of chronic hepatitis C related to HCV genotype 1, in both treatment-na?ve and treatment-experienced patients. Sustained virological response rates in the range of 6675% and 5966% (2988% if the response to the first course of therapy is taken into account) have been achieved in these two patient populations, respectively, with treatment durations of 24 to 48 weeks. A number of other DAAs are at the clinical developmental stage in combination with pegylated IFN-α and ribavirin or with other DAAs in IFN-free regimens, with or without ribavirin. They include second-wave, first-generation, and second-generation NS3/4A protease inhibitors, nucleoside/nucleotide analogue inhibitors and non-nucleoside inhibitorsof HCVRNA-dependent RNA polymerase, inhibitors of nonstructural protein 5A (NS5A) and host-targeted compounds, such as cyclophilin inhibitors and silibinin. The proof of concept that IFN-free regimens may lead to HCV eradication has recently been brought. However, new drugs may be associated with troublesome side effects and drugdrug interactions, and the ideal IFN-free DAA combination remains to be found.     

Interferon-Free Hepatitis C Treatment before and after Liver Transplantation: The Role of HCV Drug Resistance

Hepatitis C virus (HCV) infection is one of the leading causes of end-stage liver disease and the main indication for liver transplantation (LT) in most countries. All patients who undergo LT with detectable serum HCV RNA experience graft reinfection progressing to cirrhosis within five years in 20% to 30% of them. Obtaining a sustained virological response (SVR) greatly improves overall and graft survival. Until 2011, standard antiviral therapy using PEGylated interferon (PEG-IFN) and ribavirin (RBV) was the only effective therapy, with an SVR rate around 30% in this setting. For patients infected with genotype 1, first generation NS3/4A protease inhibitors (PIs), boceprevir (BOC) or telaprevir (TVR), associated with PEG-IFN and RBV for 48 weeks have increased the SVR rates to 60% in non-transplant patients. However, tolerability and drug-drug interactions with calcineurin inhibitors (CNI) are both limiting factors of their use in the liver transplant setting. Over recent years, the efficacy of antiviral C therapy has improved dramatically using new direct-acting antiviral (DAA) agents without PEG-IFN and/or RBV, leading to SVR rates over 90% in non-transplant patients. Results available for transplant patients showed a better efficacy and tolerability and less drug-drug interactions than with first wave PIs. However, some infrequent cases of viral resistance have been reported using PIs or NS5A inhibitors pre- or post-LT that can lead to difficulties in the management of these patients.     

Ribavirin:Past,present and future

Before the advent of direct acting antiviral agents(DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5 A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-totreat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs.     

Hepatitis C-related liver cirrhosis-strategies for the prevention of hepatic decompensation,hepatocarcinogenesis,and mortality

Liver cirrhosis(LC)is a critical stage of chronic liver disease,including that caused by hepatitis C virus(HCV).In the absence of antiviral therapy,67%-91%of patients with HCV-related LC patients die of liver-related causes,including hepatocellular carcinoma(HCC)and liver failure.Among the therapeutic strategies used to prevent liver-related complications in these patients is standard therapy with pegylated interferon and ribavirin,which induces a sustained virological response(SVR)in 25%of HCV genotype 1-infected patients and in 69% of patients infected with genotypes 2 and 3.SVR in patients with HCV-related LC has been associated with reduced rates of hepatic decompensation,HCC,and mortality.More recently developed direct-acting antiviral agents have shown excellent antiviral efficacy,with preliminary data demonstrating that an interferon-free regimen that includes these direct-acting antiviral agents achieved SVR in more than 50%of patients with HCV genotype 1 LC.Branched-chain amino acid supplementation,improvement of insulin resistance,and the use ofβ-blockers for portal hypertension may also reduce liverrelated complications.Here,we review advances in antiviral and adjunctive therapies for improved outcomes in patients with HCV-associated LC.     

Direct-acting antiviral regimens in Egyptian patients with chronic hepatitis C virus infection: A real-world single-center experience

Background and study aims:Chronic hepatitis C virus (HCV) infection has always been identified as a major health threat and a potential cause of liver cirrhosis, portal hypertension, and other associated problems. The introduction of direct-acting antiviral agents (DAAs) has represented a paradigm shift in HCV management. In this study, we aim to observe the rate of sustained virologic response (SVR12) in a large scale of patients at a single center as well as record the post-treatment changes in the hematologic, hepatic, and renal biochemical profiles.Patients and methodsIn total, 1933 chronic HCV genotype 4 mono-infected non-HCC patients who completed the treatment with six different DAA regimens in the Faculty of Medicine, Ain Shams University Research Institute (MASRI), were retrospectively enrolled in this study. The rate of sustained virologic response after 12 weeks off-therapy (SVR12) was assessed. The baseline characteristics to predict the SVR12 were then analyzed. The post-treatment changes in many profiles were recorded and analyzed.ResultsThe overall SVR12 rate was 96.2% (after excluding 84 cases who were lost to follow-up). It was achieved in 346/375 patients (92.3%), 466/477 patients (97.7%), 60/62 patients (96.8%), 11/11 patients (100%), 532/545 patients (97.6%), and 445/463 patients (96.1%) who received sofosbuvir/daclatasvir (SOF/DCV), sofosbuvir/daclatasvir/ribavirin (SOF/DCV/RBV), sofosbuvir/ledipasvir (SOF/LDV), sofosbuvir/ledipasvir/ribavirin (SOF/LDV/RBV), sofosbuvir/simeprevir (SOF/SMV), and ombitasvir/paritaprevir/ritonavir/ribavirin (OBV/PTV/r + RBV), respectively. In total, 73 patients (3.8%) failed to achieve SVR12. The baseline aspartate aminotransferase (AST), cirrhotic status, and treatment regimen were determined to have a significant impact on SVR12. In the overall treated population, the levels of serum AST, alanine aminotransferase, albumin, creatinine, bilirubin, and hemoglobin and platelet count improved significantly after treatment. Furthermore, sustained virologic response was strongly related to cirrhosis and its degree.ConclusionThe interferon-free DAA regimens offered high SVR12 rates in Egyptian patients with chronic HCV infection. They were associated with a significant improvement in the hematologic, hepatic, and renal biochemical profiles. The baseline AST, liver cirrhosis, and treatment regimen might have an impact on achieving SVR.     

Treatment of Hepatitis C in the Patient with Decompensated Cirrhosis

Cirrhosis due to the hepatitis C virus (HCV) is increasing in prevalence and is the leading indication for liver transplantation in the United States. Current FDA-approved treatment for HCV includes peginterferon/ribavirin alone (all HCV genotypes (GT)) or with boceprevir or telaprevir (GT1). Decompensated patients tolerate interferon-based treatment poorly and only ~25 to 40 % with HCV GT1 and ~30 to 50 % with non-1 GTs achieve a sustained viral response. Emerging direct-acting antivirals (DAAs), which are more potent and have less toxicity, used in interferon-free multi-DAA combinations will enhance the tolerability of treatment and should improve outcomes for patients with decompensated cirrhosis.     

Papel de la ribavirina en la terapia libre de interferón frente al virus de la hepatitis C

Interferon-free regimens achieve sustained virologic response (SVR) rates of over 90%, have generally well-tolerated adverse effects and involve 12-week treatment durations for most patients with chronic hepatitis C, including naive or previously treated patients and patients with or without cirrhosis. However, some of the treatment options recommended by the guidelines require the addition of ribavirin (RBV) or extend the duration of treatment to increase efficacy. The use of RBV is a useful tool in those difficult-to-cure patients such as patients with decompensated or genotype-3-infected cirrhosis and those who have not achieved SVR after treatment with direct-acting antivirals (DAA). Overall, adding RBV to the different combinations causes adverse effects related to a decrease in haemoglobin and involves inconveniences such as its dosage, which requires patients to take several tablets twice daily. However, severe anaemia is rare and easily manageable with a dose reduction. In addition, RBV is teratogenic. In practice, because RBV is inexpensive and well tolerated when combined with an interferon-free regimen, it continues to be a useful tool to optimise the results of some HCV treatment regimens. RBV-free regimens eliminate RBV-related adverse effects related, resulting in better tolerability, improving patient adherence and quality of life and reducing the cost of treatment.     

A new era in the treatment of chronic hepatitis C infection

Treatment of chronic hepatitis C virus (HCV) infection has evolved over the past three decades. At the start, treatment involved interferon monotherapy followed by combination therapy using interferon and ribavirin, and subsequently evolved to pegylated interferon (Peg-IFN) and ribavirin. In genotype 1 infection, rates of sustained virological response (SVR) are approximately 45 % with Peg-IFN and ribavirin, whereas SVR rates in genotypes 2 and 3 infections are as high as 70 % to 80 %. Side effects and cost related to these drugs are important concerns, particularly in countries like India where patients have to bear their health expenses. In the recent past, there has been a significant change in course with the on-going search and the development of more effective drugs in the management of HCV infection. Telaprevir and Boceprevir are two new potent protease inhibitors (direct acting antiviral or DAA agents) which, when administered with Peg-IFN and ribavirin, have shown to result significantly higher SVR rates in phase 3 studies in patients with genotype 1 infection, both in treatment naïve patients (up to 75 %) and those with previously failed therapy. Several other new antiviral agents some in combination with Peg-IFN and ribavirin and some in combination without Peg-IFN (IFN-free regimens) are currently being tested in patients with genotype 1, 2 and 3 infections and are expected to dramatically change the armamentarium of HCV therapy in the coming years.