The natural history of chronic hepatitis C is partly defined. The primary HCV infection is completely asymptomatic in 60%-70% of cases, but in 80% of patients the infection becomes chronic and is characterized by the persistence of the viral genome in the blood for at least 6 mo from the onset of acute infection. In a variable proportion of people carrying the virus, especially in the presence of strong necro-inflammation and/or co-factors of liver damage, the disease can evolve from the condition of chronic hepatitis to cirrhosis and HCC.

There are several factors that can change the course, severity and progression of the disease, including age at the time of infection, route of infection, viral load, co-infection with other hepatitis viruses or HIV, alterations of immune status, and the coexistence of other hepatolesive factors such as consumption of alcohol, iron overload, obesity, type 2 diabetes, resistance to insulin and genetic factors[12-14].

Chronic HCV infection in about 20% of cases progresses up to hepatic cirrhosis, end-stage liver disease and HCC, generally after 20-30 years from primary infection.

The progression of chronic disease leads, through a mechanism of chronic damage, to the loss of organ function, for progressive deposition of fibrotic tissue and disruption of the parenchymal structure, and results in liver fibrosis and cirrhosis.

Cirrhosis changes the normal liver architecture, and furthermore itself represents the most important risk factor for the development of HCC, in part by acting as a cofactor accelerating the process triggered by a primary carcinogen (HCV), and specially by increased hepatocyte regeneration. Once HCV infection progresses to cirrhosis, there is a 1%-5% annual risk of HCC[12].

The probability that a patient with compensated cirrhosis can evolve towards the decompensated form increases progressively over time.

Liver cirrhosis and its complications (portal hypertension and therefore esophageal varices, splenomegaly, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepato-pulmonary syndrome and HCC) are burdened with high morbidity and mortality.

It is also known that different variables influence the progression of the disease, for which the prognosis changes individually and is very hard to define[12-14].

Several studies have concluded that the eradication of HCV infection slows the progression of the disease, improves the survival, and reduces the incidence of liver failure and the risk of developing liver cancer[12-28]. The understanding of the natural history of chronic hepatitis C and its long-term consequences is essential to enable appropriate decisions on treatment, but unfortunately the natural history of HCV infection is still the subject of much controversy. In fact, according to some authors the disease is relentlessly progressive, with a high probability to evolve to cirrhosis and HCC, while according to others the course is variable, and most patients die as a consequence of co-morbidities, not the infection itself.

Because the infection has a significant role in causing chronic hepatitis, cirrhosis and HCC, the goal of treatment is to cure HCV infection, and consequently to prevent its complications.

Although the viral RNA genome does not integrate into the host genome, the infection becomes persistent in the majority of patients, and about 70%-90% of the infected people fail to clear the virus once acquired.

It is widely known that the antiviral treatment and the achievement of a sustained virological response (SVR - defined as an absence of detectable HCV-RNA 12 mo after therapy is complete) are associated with regression of fibrosis and clinical improvement. However, despite treatment, HCV may persist in liver tissue and extrahepatic locations like PBMCs, leading to late relapse, defined as reappearance of viremia after SVR has been achieved[29,30].

As mentioned above the primary goal of HCV therapy is the complete eradication of the virus, which is the SVR.

SVR was traditionally defined as HCV-RNA undetectable in serum for at least 24 wk after the end of treatment (SVR24); however, recent data suggest that the assessment at 12 wk after treatment (SVR12) is sufficient for defining this result.

Follow-up studies document that more than 99% of patients who achieve an SVR remain HCV-RNA negative 4-5 years after the end of treatment, and no signs of hepatitis have been documented.

SVR represents the main goal of antiviral therapy, indeed once achieved, the SVR is considered effective in the long term because late recurrences are rare; the SVR is associated with long-term health benefits, including improved quality of life.

SVR reduces risk for progression to cirrhosis, HCC, liver transplantation and liver-related mortality, and also decreases extra-hepatic manifestations of HCV infection (for example, cryoglobulinemic vasculitis).

Moreover it seems reasonable to assume that a lasting biochemical and virological response induced by treatment can also lead to improved liver fibrosis[31-39].

For decades the antiviral therapy of chronic HCV infection was based on the administration of interferon (IFN), initially as monotherapy and subsequently in combination with ribavirin (RBV). Dual therapy with “pegylated IFN (PEG-IFN) and RBV” achieves SVR rates of 40% to 50% in patients with genotype 1, and about 80% in those with genotypes 2, 3, 5 and 6; the results for genotype 4 are intermediates.

In 2011, the first direct-acting antivirals boceprevir and telaprevir have been approved in combination with PEG-IFN and RBV. These drugs are protease inhibitors (PIs) and increase SVR rates in both naive patients and in experienced patients, compared to dual therapy[40-46]; however, they were dropped due to their significant toxicity.

With the advent of new oral antiviral regimens, with better efficacy and tolerability, and a shorter treatment duration, the number of patients that can be treated is expected to increase significantly, and also the SVR rates will improve to approximately 95% or plus[47].

HCV is classified within the Flaviviridae family, as the only member of a distinct genus called Hepacivirus[48].

The lack of detailed information on the viral replication cycle has significantly prevented the development of direct acting antivirals.

For decades the antiviral therapy of chronic HCV infection was based on the administration of IFN, initially alone and then in combination with RBV, but this regimen was effective in only 50% of patients with genotype 1, with significant side effects[49-54].

In the last decade the development of in vitro models of viral replication has thus represented a turning point for the understanding of the different stages of the replication cycle, and quickly has led to the design and introduction of direct acting antivirals (DAAs)[55].

However, because of huge variability of the virus, new drugs cannot be administered as monotherapy because it would quickly lead to the selection of drug-resistant viral variants.

HCV indeed is characterized by an extremely high degree of variability. The genetic heterogeneity of HCV gives an adaptive advantage as the simultaneous presence of multiple genomic variants allows rapid selection of mutants that better adapt to environmental changes (for example resistance to drugs or the immune response); this genetic heterogeneity is the basis of chronic infection, and is probably involved in the phenomena of evasion of the immune response and in the limited efficacy of treatment[56-59].

The HCV replication cycle occurs in the cytoplasm, and can be summarized as follows: (1) entry into the host cell and release of viral genomic RNA into the cytoplasm; (2) translation of RNA, processing of the viral polyprotein and formation of a replication complex associated with intracellular membrane; (3) using positive RNA for the synthesis of an intermediate negative RNA for the production of new positive RNA molecules with different destination; and (4) release of viral progeny into circulation from infected cells. The infectious viral structure is comprised of envelope glycoproteins in a lipid bilayer, that contain the viral core protein and RNA[60-63].

After cell entry, the viral RNA is translated through the host machinery into a polyprotein, which is cleaved during and after translation by both host and viral-encoded proteases into 10 mature viral proteins, including several non-structural (NS) proteins. One of the viral proteases involved in this post-translational processing is a heterodimeric complex of the NS3 and NS4A proteins (NS3/NS4A). NS3 has the proteolytic activity and NS4 is a membrane protein that acts as a cofactor. Synthesis of new viral RNA occurs in a highly structured replication complex that consists of NS3, NS4A, NS4B, NS5A, and NS5B. NS5B is an RNA-dependent RNA polymerase that is essential for viral replication. NS5A has a presumptive role in the organization of the replication complex and in regulating replication. It is also involved in assembly of the viral particle that is released from the host cell (Figure 1)[64-69].

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Figure 1 Hepatitis C virus replicative cycle and main targets for direct acting antiviral agents. Modified from Manns and Cornberg. Lancet Infectious Diseases 2013. PIs: Protease inhibitors; NPIs: Nucleoside polymerase inhibitors; NNPIs: Non-nucleoside polymerase inhibitors.

Increased knowledge of the HCV replication cycle and genomic diversity has driven the development of antiviral agents specifically targeting well-conserved proteins required for efficient viral replication. Aside from PEG-IFN, HCV-specific therapeutic agents that have gained widespread use or reached late-stage clinical trials include NS3 PIs, nucleoside and nucleotide analogues, and other NS5B polymerase inhibitors.

After year of IFN-based therapy, the introduction of DAAs has increased the number of patients who respond to treatment, and has changed radically the treatment of chronic HCV genotype-1 infection[43,70-72].

Thanks to the discovery of key viral replication targets such as the NS3/4A protease, NS5A, and the NS5B RNA polymerase, other potent antiviral inhibitors were licensed in 2014.

These new regimens include the addition of simeprevir (SMV) (a second-generation PI), daclatasvir (an NS5A inhibitor), and sofosbuvir (an uridine nucleotide prodrug NS5B polymerase inhibitor), in combination with PEG-IFN and RBV for 12-24 wk[73,74].

The main targets of the DAAs are the HCV-encoded proteins that are vital to the viral replication. The DAAs have a high barrier to resistance and ideally, they should also be active against all HCV genotypes. Furthermore, these drugs are well tolerated and have few drug interactions.

There are four classes of DAAs, which are defined by their mechanism of action and therapeutic target[75] (Figure 2 and Table 1): (1) NS3/4A PIs; (2) NS5B nucleoside polymerase inhibitors (NPIs); (3) NS5B non-NPIs (NNPIs); and (4) NS5A inhibitors.

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Figure 2 Direct acting antiviral agents. Modified from Alexopoulou et al[121]. Interferon-based combination treatment for chronic hepatitis C in the era of direct acting antivirals. Annals of Gastroenterology 2015; 28: 55-65. NPIs: Nucleoside polymerase inhibitors; NNPIs: Non-nucleoside polymerase inhibitors; DAA: Direct acting antiviral.

The first-generation PIs telaprevir and boceprevir were the first DAAs available for the treatment of CHC[77].

The addition of PIs to PEG-IFN and RBV has become the new standard of care for the treatment of genotype 1 infection, and so, in 2011, has increased the efficacy of PEG-IFN and RBV in patients with chronic HCV genotype 1 infection.

Telaprevir and boceprevir were approved for the treatment of chronic HCV genotype 1 infection by the Food and Drug Administration (FDA) and European Medicines Agency in combination with PEG-IFN-α and RBV in adults with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous IFN and RBV therapy[78].

Telaprevir and boceprevir are NS3/4A PIs, and they both have the same molecular target: The HCV NS3/4A serine protease.

They have an high antiviral potency only against genotypes 1 and 2, but a low barrier to resistance[79].

Monotherapy with these agents resulted in the selection of drug resistant variants, so they should always be used in triple combinations together with PEG-IFN and RBV in a triple therapy regimen to reduce the frequencies of resistant mutants and viral breakthrough, and they can improve the SVR rates by 15% to 20% compared with PEG-IFN-α and RBV[42,43,80].

Viral resistance may develop even in triple combinations with PEG-IFN and RBV, and due to this problem strict stopping rules are applied in triple therapy-based regimens.

Response to HCV therapy in genotype 1 can be predicted by identifying the single nucleotide polymorphisms located in the region of interleukin-28B (IL-28B) gene through genome-wide association studies.

High response rates have been reported in patients with CC genotype of IL-28B as compared to CT or TT IL-28B-genotype (70% vs 25%-30%). Testing for IL-28B genotype is thus a useful tool in the management of patients[81].

First-generation PIs increase the number of patients with genotype 1 infection who respond to treatment, however, the side effect profiles of these triple combination therapies are not favourable, because it can cause clinically significant adverse events.

The most common side effects of telaprevir are anaemia, pruritis, nausea, diarrhoea, and anorectal discomfort. Around 4% of patients develop severe dermatitis, necessitating cessation of treatment.

Drug reactions like eosinophilia and systemic symptoms or Stevens-Johnson syndrome are rare, but have been reported. Boceprevir causes dysguesia and anaemia[43].

Several drug-drug interactions can occur, so the use of first-generation PIs has been significantly restricted[82].

Second-generation PIs offer several benefits, for example, few drug-drug interactions and less frequent and less severe side effects.

In addition, second-generation PIs also appear to have increased efficacy against genotype 1 HCV[83]; as treatment options have progressed and improved, HCV- 1, HCV-2 and HCV-4 are considered to be easy to treat[84] but HCV genotype 3 infection has become the most difficult to treat.

SMV: SMV was the first available second-generation PI with antiviral activity against genotypes 1, 2, 4, 5 and 6[85].

SMV is administered orally as a daily pill, and has limited drug-drug interactions.

No dose recommendation can be given for patients with Child-Pugh class B or C cirrhosis, because higher SMV exposure (particularly in Child-Pugh C patients) may be associated with increased frequency of adverse reactions. No dose adjustment is required in the setting of renal impairment, because SMV is eliminated by the liver[85]. SMV is well tolerated, and adverse reactions in patients receiving SMV in combination with PEG-IFN-α and RBV are rash, pruritus and nausea. Because SMV is an inhibitor of the transporters OATP1B1 and MRP2, mild, transient hyperbilirubinaemia not accompanied by changes in other liver parameters was observed in approximately 10% of cases. SMV is oxidatively metabolized by CYP3A subfamily, which consists mainly of hepatic and intestinal CYP3A4 metabolism[86]. Co-administration of SMV with inhibitors of cytochrome P450 3A (CYP3A) is not recommended.

In post-liver transplant patients with HCV infection, co-administration of SMV with cyclosporine resulted in significantly elevated SMV levels, so it is not recommended[87]. SMV can be safely administered with tacrolimus or sirolimus. SMV was approved by the FDA for genotype 1 treatment in November 2013 under the name of “OLYSIO”, in Japan it was licensed in September 2013, finally in Europe in May 2014 (European Medical Agency approval).

In phase II of COSMOS trial, sofosbuvir (SOF; 400 mg daily) was administered in combination with SMV (SMV 150 mg daily) with or without RBV for 12 wk or 24 wk in genotype 1 patients. SVR12 rates were not different between 12 or 24 wk of treatment, with or without RBV, and comparing naive patients to experienced (95% vs 91%)[87,88].

In this small study, the regimen SOF plus SMV with or without RBV was well tolerated; the most common side effects were headache, fatigue, and nausea, and only four (2%) patients discontinued treatment due to these events.

Although the results of this study are encouraging, due to the small number of patients and the future availability of other oral regimes with better antiviral efficacy and fewer side effects, this regimen should be considered as a second-line option.

Two phase III trials of SMV/SOF without RBV are ongoing (OPTIMIST-1 and -2)[89]. These studies provide us much bigger data about SOF/SIM regimen, and investigate the efficacy and safety of SMV 150 mg in combination with sofosbuvir 400 mg in HCV genotype 1 infected naïve or experienced patients, with and without cirrhosis.

SMV/SOF treatment led to high SVR12 rates in patients infected with HCV GT-1 subtype, regardless of treatment duration or the addition of RBV. SVR12 rates were high, regardless of baseline characteristics, including HCV GT-1 subtype, IL-28B allele, or Q80K polymorphism. On-treatment virologic response, including RVR, was not predictive of SVR. Two ongoing phase III trials are investigating SMV/SOF without RBV (OPTIMIST-1 and -2).

Baseline predictive factors significantly associated with virologic relapse were male sex, body weight ≥ 75 kg, IL-28B non-CC allele, cirrhosis, baseline HCV RNA ≥ 800000 IU/mL, and prior treatment failure. Current SOF regimens are highly efficacious, even in patients with multiple traditional negative predictors of diminished efficacy; SVR12 rates are comparatively lower in patients who have five or six negative predictors[90,91].

The approval of the treatment scheme “SMV plus PEG-IFN/RBV” is based on a clinical trial program comprising three phase III studies, with more than 1000 patients with genotype 1.

The studies, QUEST-1, QUEST-2 and PROMISE, have evaluated the use of SMV in combination with PEG-IFN/RBV in naive patients (Quest-1 and 2)[92,93] and relapsed patients (PROMISE[94]) after an IFN-based treatment. All three studies have shown that SMV, in combination with PEG-IFN/RBV, gets significant SVR rates when compared to PEG-IFN/RBV.

A triple therapy with SMV, PEG-IFN and RBV has been recommended for genotype 1 also after the data of other four phase III trials: CONCERTO-1, -2, -3 and -4[95-98].

Faldaprevir: Faldaprevir is one of the new-generation NS3/4A PIs in development. It is a pan-genotypic potent NS3/NS4 PI (antiviral activity against genotypes 1, 2, 4, 5 and 6 in vitro). It was used in genotype 1 infection in two combinations: (1) a triple regimen with faldaprevir, PEG-IFN and RBV for a total of 24 wk[98,99]; and (2) IFN-free regimens with faldaprevir and deleobuvir with or without RBV[100,101].

In both combinations faldaprevir provides high SVR rates, but IFN-containing regimens registered most cases of breakthrough and relapse, while with the IFN-free combination of faldaprevir and deleobuvir with RBV, very encouraging results were obtained[102].

Faldaprevir is administered orally, once a day. The most common adverse events are gastrointestinal dysfunction, rash and photosensitivity skin. Faldaprevir in combination with PEG-IFN and RBV appears to be associated with fewer adverse events than the first PIs telaprevir and boceprevir.

Paritaprevir and ritonavir: Paritaprevir is an HCV protease inhibitor that is given with low dose ritonavir for a pharmacologic boosting effect.

Ritonavir is a protease inhibitor that does not have anti-HCV activity but it is a pharmacoenhancer that is included to increase levels of paritaprevir through inhibition of CYP3A-mediated metabolism.

Paritaprevir and ritonavir are available as a fixed-dose combination with ombitasvir and given with the non-nucleoside NS5B inhibitor dasabuvir. This regimen is given with and without RBV for the treatment of HCV GT-1 subtype[103].

Daclatasvir is a pangenotypic NS5A inhibitor that is available for use in Europe. According to EASL guidelines daclatasvir should be administered orally (60 mg once daily) with low potential for drug-drug interactions. It is well tolerated. Dose adjustments are not needed in patients with Child B or C disease. Side effects with daclatasvir are fatigue, headache, and nausea. Little information has been released on daclatasvir drug-drug interactions.

In previously untreated patients infected with genotype 2 or 3, SVR was reported in 94%-100% of patients treated with the combination of daclatasvir plus sofosbuvir. In the ALLY-3 study[106], 133 patients with genotype 3 infection were treated for 12 wk with 400 mg of sofosbuvir and 60 mg of daclatasvir for 12 wk. Ninety-one percent of previously untreated patients had an SVR compared with 86% of treatment-experienced patients.

In the COMMAND GT2/3 study, Dore et al[107] compared the efficacy and safety of daclatasvir plus PEG-IFN-α-2a/RBV administered for either 12 or 16 wk with a standard 24-wk course of PEG-IFN-α-2a/RBV in HCV GT-2 or GT-3 subtype. Daclatasvir has been given with PEG-IFN-α-2a/RBV for 12 or 16 wk to previously untreated patients with genotype 2 or 3 infection. Around 83% of patients infected with genotype 2 and 70% of patients with genotype 3 infection have been reported to achieve SVR[107]. In another open-label study, the drug’s effectiveness has been demonstrated[108].

Other NS5A inhibitors available in the United States are ledipasvir and ombitasvir, and they are each available in fixed-dose combinations with other direct-acting antivirals.

Ledipasvir: Ledipasvir is the first NS5A inhibitor available in the United States. Ledipasvir and sofosbuvir are co-formulated in a single tablet in a fixed-dose combination (90 mg ledipasvir/400 mg sofosbuvir) that is administered once daily with or without food. This combination is well tolerated, and ledipasvir has the same drug interactions as sofosbuvir. This regimen is administered with or without RBV, depending on the patient population, in genotype 1 infection.

Ombitasvir: Ombitasvir (also known as ABT-267) is available as a fixed-dose combination with the PIs paritaprevir and ritonavir (12.5 mg ombitasvir/75 mg paritaprevir/50 mg ritonavir). This single tablet is administered orally with an additional drug: The non-nucleoside polymerase (NS5B) inhibitor dasabuvir[109,110]. This regimen is given with and without RBV in genotype 1 infection.

The combination ombitasvir-paritaprevir-ritonavir plus dasabuvir is generally well tolerated, and mild adverse effects are nausea, pruritus, insomnia, diarrhea, and asthenia[111,112]. Some of these symptoms may be attributable to RBV[113,114].

The most important studies that evaluated treatment duration of ledipasvir/sofosbuvir treatment and its safety and efficacy (SVR12) in naive and treatment-experienced patients are ION-1, LONESTAR, and ION-2[115-117] (Figure 3).

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Figure 3 ION-2 sub-analysis of cirrhosis vs without cirrhosis. Error bars represent 95%CIs. LDV: Ledipasvir; RBV: Ribavirin; SOF: Sofosbuvir; SVR12: Sustained virologic response at 12 wk post-treatment.

NPIs have high antiviral efficacy across all genotypes, although they have a very high barrier to resistance.

Sofosbuvir: Sofosbuvir is the first NS5B NPI available in the United States.

Sofosbuvir is a pangenotypic NS5B polymerase inhibitor with a high barrier to resistance and favorable clinical pharmacology profile. It is administered orally as a 400 mg pill once a day, and has no food effect. Sofosbuvir is well tolerated, and the most commonly reported side effects of sofosbuvir and RBV, with or without PEG-IFN, are fatigue, headache, nausea, insomnia, and anemia[74,119].

Although renal clearance is the major form of elimination, in patients with mild or moderate renal impairment (glomerular filtration rate greater than 30 mL/min)[120], any adjustment dose is not required.

No dose adjustment has been needed in patients with moderate (Child Pugh class B) or severe (Child Pugh class C) hepatic impairment.

Sofosbuvir has substantially less drug interactions than those observed with the HCV PIs. Sofosbuvir is a substrate of P-glycoprotein (P-gp), a drug transporter, so drugs that are potent intestinal P-gp inducers may decrease sofosbuvir levels. Thus, coadminstration of sofosbuvir is not recommended with rifampin, rifabutin, rifapentine, St. John’s wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir.

Sofosbuvir was approved by FDA for genotype 1 in combination with PR, and in genotypes 2 and 3 in IFN free regimens in December 2013, in Canada during the same month and in Europe in January 2014 (European Medical Agency approval).

In the NEUTRINO study (an open-label, single-arm phase III registration trial) 327 treatment-naive patients were treated with a regimen comprising sofosbuvir plus PR for 12 wk[119]. The overall patient population included mainly those infected with genotype 1 (89%) as well as a few patients infected with genotypes 4, 5 and 6; 17% of patients in this trial had cirrhosis. This sofosbuvir-based triple-therapy regimen resulted in a very high RVR, with the 4-wk RVR rate approaching 99%. The SVR rate for the entire trial population remained high at 90%, 12 wk after the end of treatment (with 99% of patients achieving virologic response at the end of treatment). Analyzing the groups based on viral genotype, patients with genotype 1 had an SVR rate of 89%, and the small number of patients with genotype 4, 5 and 6 had SVR rates between 96% and 100%. Overall, this sofosbuvir-based triple therapy regimen resulted in very high SVR rates across all genotypes that were evaluated. One important point from the NEUTRINO trial was the relative decrease in the overall response rate for patients with cirrhosis (SVR, 80%) compared with non-cirrhotics (SVR, 92%)[121].

Other representative studies on genotype 1 are ELECTRON, QUANTUM, VALENCE and LONESTAR-2[122-125].

Genotypes 2 and 3 have been studied together in three sofosbuvir phase III trials (FISSION, POSITRON, and FUSION)[119,122,126].

Therapy with sofosbuvir-RBV for 12 wk in patients with HCV genotype 2 infection and for 24 wk in patients with HCV genotype 3 infection resulted in high rates of SVR[127].

To date there are very few data on genotype 4 patients treated with sofosbuvir without PEG-IFN[128]. There are no data currently on treatment-experienced populations or any patients with genotypes 5 and 6[129].

Sofosbuvir is used in various combinations with other antivirals for different indications: (1) with ledipasvir for HCV GT-1; (2) with SMV (± RBV) for HCV GT-1; (3) with RBV for HCV GT-2, -3, -4, -5, and -6 infection (and among patients with any genotype awaiting liver transplant); and (4) with PEG-IFN and RBV for genotypes HCV GT-1 and -4.

NNPIs bind to one of four allosteric sites on the surface of NS5B and cause a conformational change, making the enzyme ineffective. Despite the active site of NS5B is well conserved across all genotypes, and they should have a pan-genotype antiviral activity, NNIs have a more limited spectrum of activity specifically targeting against GT-1 (all NNPIs in clinical development have been optimized for GT-1). They have a low to moderate barrier to resistance variable toxicity profiles[130]. Consequently, this class of drug has been studied primarily as an adjunct to more potent compounds with higher barriers to resistance.

Dasabuvir: Dasabuvir is a non-nucleoside polymerase (NS5B) inhibitor administered with the fixed-dose combination ombitasvir-paritaprevir-ritonavir (12.5 mg ombitasvir/75 mg paritaprevir/50 mg ritonavir).

ABT-450/ritonavir with ombitasvir (ABT-267) and dasabuvir (ABT-333): TURQUOISE-II is a global, multi-center, randomized, open-label study evaluating the efficacy and safety of 12 or 24 wk of treatment with ABT-450/ritonavir (150/100 mg) co-formulated with ombitasvir (ABT-267) 25 mg, dosed once daily, and dasabuvir (ABT-333) 250 mg with RBV in adult patients with GT-1 HCV infection with compensated liver cirrhosis. Patients achieved SVR₁₂ rates of 91.8% and 95.9% in the 12 and 24-wk treatment arms, respectively[131]. In TURQUOISE-II, both cirrhotic non-responders and treatment-naive cirrhotic subjects achieved higher SVR rates if they were genotype 1b-infected vs genotype 1a-infected. According to Asselah et al[132] we support the efficacy and safety profile in GT-1 HCV cirrhotic patients, and in some cases the efficacy was demonstrated also in borderline compensated cirrhosis. However, current data in patients with cirrhosis and other HCV genotypes, such as genotype 3 and 4, are clearly an unfulfilled need. Another significant study is the PEARL-II[133].

Cyclophilins (Cyp) are host proteins involved in the HCV lifecycle. CypA binds to the non-structural protein NS5A of HCV to promote replication of viral RNA, so molecules that are CypA antagonists, such as cyclosporines, are potent inhibitors of HCV replication. NS2, a non-structural protein of HCV involved in virus assembly, also plays an important role in the inhibitory effect of CypA inhibitors; NS2 modulates HCV sensitivity to cyclosporines and so NS2 may increase the inhibitory effect of cyclosporines on HCV replication[134,135].

Alisporivir, is the first Cyp A inhibitor in clinical development. It is a cyclosporine analog without immunosuppressive properties, and due to its mechanism of action, alisporivir is a pangenotypic antiviral, provides a high barrier for development of viral resistance, and does not permit cross-resistance to direct-acting antivirals.

This drug is also well tolerated. This drug has been used alone or in combination with PEG-IFN and RBV with very promising results[136,137].