**8. Hepatitis C treatments**

The ultimate goal of treatment in patients with chronic HCV is to eradicate HCV RNA, which is associated with decreases in all-cause mortality, liver-related death, need for liver trans‐ plantation, hepatocellular carcinoma rates, and liver-related complications.

Since interferon-alpha (IFN-α) was first introduced for treatment of non-A, non-B hepatitis 1990, therapy for patients with chronic HCV has improved dramatically. Sustained virological response rates (SVRs) have increased from 5% to 10% with standard interferon therapy, to over 40% when standard interferon is combined with ribavirin. The modification of interferon (pegylation) to improve its pharmacokinetics has further increased rates of SVR. Two types of pegylated interferon, pegylated interferon α2a and pegylated interferon α2b,which differ in their pharmacokinetics and chemical properties, were approved by the FDA in 2001. Treatment with combined pegylated interferon and ribavirin may result in SVR in 42% to 52% of genotype 1 infected patients, 70% to 80% of genotype 2 or 3 infected patients, and 54-68% of genotype 4 infected patients [46,47].

The landscape of treatment for HCV infection has evolved substantially since the introduction of highly effective HCV protease inhibitor therapies, namely, boceprevir and telaprevir, in 2011. Both drugs were approved as directly acting antiviral treatments for use in HCV genotype 1 infection, in combination with pegylated interferon and ribavirin. These NS3/4A protease inhibitors have been shown to substantially increase rates of SVR to 59-75% in both treatment-naive and previously treated patients, compared with dual therapy [48-52]. Although their development was a major advance, both agents are associated with significant toxicity, numerous drug-drug interactions, and low response rates in those patients with cirrhosis and nonresponders to previous treatment. In addition, boceprevir and telaprevir required the addition of pegylated interferon and ribavirin for 24 to 48 weeks, which markedly increased the overall cost of therapy, and are associated with the emergence of resistanceassociated variants in the majority of patients who fail treatment [53].

In 2013 and 2014, the FDA approved new direct acting antiviral treatments, including second generation protease inhibitors, NS5A inhibitors, and NS5B RNA-dependent RNA polymerase inhibitors with HCV eradication rates of >95%.

The eradication of HCV RNA is predicted by the achievement of SVR and defined by the absence of HCV RNA by polymerase chain reaction three to 6 months after stopping treatment. An SVR is associated with a 99% chance of being HCV RNA negative during long-term followup and can therefore be considered an indication of a cure of the HCV infection. With the growing availability of highly effective interferon-free regimens for HCV infection, a curative all-oral treatment is becoming a possibility for the vast majority of patients. The secondgeneration protease inhibitors that have been approved for treatment of HCV and are available in the market are simeprevir, sofosbuvir, ledipasvir/sofosbuvir, daclatasvir, and the combi‐ nation of ombitasvir-paritaprevir-ritonavir and dasabuvir. Trials are still ongoing on other new products, many of which are expected to appear in the near future.

### **8.1. Simeprevir (Olysio®, Janssen Therapeutics)**

**8. Hepatitis C treatments**

86 Recent Advances in Liver Diseases and Surgery

infected patients [46,47].

The ultimate goal of treatment in patients with chronic HCV is to eradicate HCV RNA, which is associated with decreases in all-cause mortality, liver-related death, need for liver trans‐

Since interferon-alpha (IFN-α) was first introduced for treatment of non-A, non-B hepatitis 1990, therapy for patients with chronic HCV has improved dramatically. Sustained virological response rates (SVRs) have increased from 5% to 10% with standard interferon therapy, to over 40% when standard interferon is combined with ribavirin. The modification of interferon (pegylation) to improve its pharmacokinetics has further increased rates of SVR. Two types of pegylated interferon, pegylated interferon α2a and pegylated interferon α2b,which differ in their pharmacokinetics and chemical properties, were approved by the FDA in 2001. Treatment with combined pegylated interferon and ribavirin may result in SVR in 42% to 52% of genotype 1 infected patients, 70% to 80% of genotype 2 or 3 infected patients, and 54-68% of genotype 4

The landscape of treatment for HCV infection has evolved substantially since the introduction of highly effective HCV protease inhibitor therapies, namely, boceprevir and telaprevir, in 2011. Both drugs were approved as directly acting antiviral treatments for use in HCV genotype 1 infection, in combination with pegylated interferon and ribavirin. These NS3/4A protease inhibitors have been shown to substantially increase rates of SVR to 59-75% in both treatment-naive and previously treated patients, compared with dual therapy [48-52]. Although their development was a major advance, both agents are associated with significant toxicity, numerous drug-drug interactions, and low response rates in those patients with cirrhosis and nonresponders to previous treatment. In addition, boceprevir and telaprevir required the addition of pegylated interferon and ribavirin for 24 to 48 weeks, which markedly increased the overall cost of therapy, and are associated with the emergence of resistance-

In 2013 and 2014, the FDA approved new direct acting antiviral treatments, including second generation protease inhibitors, NS5A inhibitors, and NS5B RNA-dependent RNA polymerase

The eradication of HCV RNA is predicted by the achievement of SVR and defined by the absence of HCV RNA by polymerase chain reaction three to 6 months after stopping treatment. An SVR is associated with a 99% chance of being HCV RNA negative during long-term followup and can therefore be considered an indication of a cure of the HCV infection. With the growing availability of highly effective interferon-free regimens for HCV infection, a curative all-oral treatment is becoming a possibility for the vast majority of patients. The secondgeneration protease inhibitors that have been approved for treatment of HCV and are available in the market are simeprevir, sofosbuvir, ledipasvir/sofosbuvir, daclatasvir, and the combi‐ nation of ombitasvir-paritaprevir-ritonavir and dasabuvir. Trials are still ongoing on other

plantation, hepatocellular carcinoma rates, and liver-related complications.

associated variants in the majority of patients who fail treatment [53].

new products, many of which are expected to appear in the near future.

inhibitors with HCV eradication rates of >95%.

This is the first available second-generation protease inhibitor (NS3/4A protease inhibitor) indicated for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen [54]. Simeprevir is available in 150 mg capsules to be taken orally once daily with food. The elimination of simeprevir is by the liver, and no dose adjustment is required in the setting of renal impairment [55]. Simeprevir is not recommended in patients with hepatic impairment Child-Pugh Class B and C because of two- to five-fold increases in exposure. In general, simeprevir is well tolerated. Its most common adverse effects are rash (including a potentially serious photosensitivity reaction), pruritus, and nausea. The photo‐ sensitivity reaction that related to simeprevir usually occurs during the first 4 weeks of therapy but can develop at any time on treatment. Patients taking simeprevir may experience transient increases in serum bilirubin levels that peak at week 2 of treatment, but these are typically mild in severity and not associated with elevated hepatic aminotransferase levels [56,57]. The coadministration of simeprevir with substances that are moderate or strong inducers or inhibitors of cytochrome P450 3A (CYP3A) is not recommended, as this may lead to signifi‐ cantly lower or higher exposure of simeprevir, respectively, which may result in reduced therapeutic effect or adverse reactions. A number of compounds are contraindicated in patients receiving simeprevir, including the following:


Simeprevir is safe in patients using immunosuppressants, such as cyclosporine and tacrolimus, with no dose adjustment, and safe in those using lamivudine, emtricitabine, tenofovir, abacavir, raltegravir, maraviroc, and rilpivirine. The dose of simeprevir needs adjustment with some antiarrhythmics, warfarin, HMG Co-A reductase inhibitors, sedative/anxiolytics, and calcium channel blockers [58-64].

#### **8.2. Sofosbuvir (Sovaldi®, Gilead Sciences)**

This is an HCV nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C infection as a component of a combination antiviral treatment regimen. Sofosbuvir is available as a 400-mg tablet. The recommended dose of sofosbuvir is 400 mg taken orally once daily, with or without food, regardless of the patient's genotype or prior hepatitis C treatment experience. No dose adjustment is needed for mild-to-moderate renal impairment or with mild, moderate, or severe hepatic impairment. Currently, no dose recommendation can be given for patients with severe renal impairment (estimated glomer‐ ular filtration rate <30 ml/min) or with end-stage renal disease due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite. Sofosbuvir has pan-genotypic HCV activity and is effective in treatment-naive, treatment-experienced, and HIV-coinfected patients with compensated cirrhosis, and in patients with hepatocellular carcinoma meeting Milan criteria awaiting liver transplantation. Sofosbuvir has been very well tolerated in clinical trials. The most common adverse effects (≥20%) observed with sofosbuvir, when used in combination with ribavirin, have been fatigue and headaches. The most common adverse events (≥20%) observed in combination with pegylated IFN-α and ribavirin were fatigue, headaches, nausea, insomnia, and anemia. Drugs that are potent P-glycoprotein (P-gp) inducers significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect. Thus, sofosbuvir should not be administered with other known inducers of P-gp, such as rifampin, carbamazepine, phenytoin or St. John's wort [62,65-77].

#### **8.3. Ledipasvir-sofosbuvir (Harvoni®, Gilead Sciences)**

The nucleotide polymerase inhibitor sofosbuvir (400 mg) has been combined with the NS5A inhibitor ledipasvir (90 mg) in a single tablet regimen (SOF/LDV) administered once daily. The combination of ledipasvir-sofosbuvir has primarily been studied as an all-oral (interferon-free) combination regimen in treatment-naive and treatment-experienced patients with genotype 1 chronic HCV infection. For patients with mild to moderate renal impairment, no dosage adjustment of ledipasvir/sofosbuvir is recommended. Severe renal impairment (estimated glomerular filtration rate <30 mL/min) does not substantially affect the pharmacokinetics of ledipasvir, but because levels of sofosbuvir and its metabolite accumulate in the setting of severe renal impairment, the combination should not be used in such settings pending further data. Thus, no dosage recommendation has been given for patients with severe renal impair‐ ment or end-stage renal disease requiring dialysis. Available data from clinical trials have shown that the combination of ledipasvir and sofosbuvir has been very well tolerated. The most commonly reported adverse effects are fatigue and headaches. Ledipasvir, like sofosbu‐ vir, is a substrate of the P-gp drug transporter, so drugs that are potent intestinal P-gp inducers may decrease ledipasvir levels. Thus, the coadministration of ledipasvir-sofosbuvir is not recommended with rifampin, St. John's wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir. In addition, ledipasvir is an inhibitor of P-gp and may increase absorption of P-gp substrates. The coadministration of ledipasvir with tenofovir results in increased levels of tenofovir, particularly in the presence of other boosting agents. Until further data are available, ledipasvir-sofosbuvir should not be used with the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and should only be used cautiously with regimens that contain tenofovir and a ritonavir-boosted protease inhibitor [73,78-83].

#### **8.4. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®, AbbVie Inc)**

The Viekira Pak is an all-oral regimen comprised of four medications: ombitasvir, paritaprevir, ritonavir, and dasabuvir. This regimen can be used with or without ribavirin. In the Viekira Pak, ombitasvir, paritaprevir, and ritonavir (Viekirax®) are combined as a fixed-dose tablet and the dasabuvir (Exviera®) is a separate tablet. Ombitasvir, paritaprevir, and dasabuvir are direct-acting antivirals (DAAs) that directly interfere with HCV replication. Ombitasvir is an NS5A inhibitor with potent pan-genotypic picomolar antiviral activity, paritaprevir is an inhibitor of the NS3/4A serine protease, and dasabuvir is a nonnucleoside NS5B polymerase inhibitor. Ritonavir is a CYP3A inhibitor, and it boosts the blood levels of paritaprevir. Paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg) are coformulated in a single tablet taken as two tablets once daily. This tablet is combined with dasabuvir (250 mg) taken as one tablet twice daily. The regimen ombitasvir-paritaprevir-ritonavir plus dasabuvir is FDA approved for the treatment of chronic hepatitis C genotype 1, including those with compen‐ sated cirrhosis. The regimen ombitasvir-paritaprevir-ritonavir plus dasabuvir, with or without ribavirin, has primarily been studied as an all-oral (interferon-free) regimen in treatment-naive and treatment-experienced patients with genotype 1a or 1b chronic HCV infection, including those with compensated cirrhosis, HIV coinfection, and after receipt of liver transplantation. For patients with mild hepatic impairment (Child-Pugh A), no dosage adjustment is required for ombitasvir-paritaprevir-ritonavir and dasabuvir; however, this regimen is not recom‐ mended in patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated with severe hepatic impairment (Child-Pugh C). For patients with mild, moderate, or severe renal insufficiency, no dosing adjustment is required for the regimen ombitasvir-paritaprevirritonavir and dasabuvir; this regimen, however, has not been adequately studied in patients with end-stage renal disease on dialysis. Available data from clinical trials have demonstrated excellent tolerance with the ombitasvir-paritaprevir-ritonavir and dasabuvir regimen. The most common (greater than 10%) adverse effects observed in clinical trials when used without ribavirin have been fatigue, nausea, pruritus, other skin reactions, insomnia, and asthenia. The concomitant use of ombitasvir-paritaprevir-ritonavir and dasabuvir with ethinyl estradiolcontaining medications (e.g., oral contraceptives) can result in significant elevations in hepatic aminotransferase levels; accordingly, patients should discontinue any ethinyl estradiolcontaining medications prior to starting ombitasvir-paritaprevir-ritonavir and dasabuvir. The use of ombitasvir-paritaprevir-ritonavir plus dasabuvir can potentially cause significant drugdrug interactions, primarily because of the potent ritonavir inhibition of CYP3A4 enzyme. There are a number of medications contraindicated to use concomitantly with ombitasvirparitaprevir-ritonavir and dasabuvir, like carbamazepine, phenytoin, phenobarbital, gemfi‐ brozil, rifampin, ergotamine, oral contraceptives containing ethinyl estradiol, lovastatin, simvastatin, sildenafil, orally administered midazolam, and St. John's wort. The efficacy of ombitasvir-paritaprevir-ritonavir plus dasabuvir is not known for patients with prior virologic failure and resistance with treatment that included another NS3/4A inhibitor, NS5A inhibitor, or NS5B inhibitor [84-90].

#### **8.5. Daclatasvir (Daklinza®, Bristol-Myers Squibb)**

impairment or with mild, moderate, or severe hepatic impairment. Currently, no dose recommendation can be given for patients with severe renal impairment (estimated glomer‐ ular filtration rate <30 ml/min) or with end-stage renal disease due to higher exposures (up to 20-fold) of the predominant sofosbuvir metabolite. Sofosbuvir has pan-genotypic HCV activity and is effective in treatment-naive, treatment-experienced, and HIV-coinfected patients with compensated cirrhosis, and in patients with hepatocellular carcinoma meeting Milan criteria awaiting liver transplantation. Sofosbuvir has been very well tolerated in clinical trials. The most common adverse effects (≥20%) observed with sofosbuvir, when used in combination with ribavirin, have been fatigue and headaches. The most common adverse events (≥20%) observed in combination with pegylated IFN-α and ribavirin were fatigue, headaches, nausea, insomnia, and anemia. Drugs that are potent P-glycoprotein (P-gp) inducers significantly decrease sofosbuvir plasma concentrations and may lead to a reduced therapeutic effect. Thus, sofosbuvir should not be administered with other known inducers of P-gp, such as rifampin,

The nucleotide polymerase inhibitor sofosbuvir (400 mg) has been combined with the NS5A inhibitor ledipasvir (90 mg) in a single tablet regimen (SOF/LDV) administered once daily. The combination of ledipasvir-sofosbuvir has primarily been studied as an all-oral (interferon-free) combination regimen in treatment-naive and treatment-experienced patients with genotype 1 chronic HCV infection. For patients with mild to moderate renal impairment, no dosage adjustment of ledipasvir/sofosbuvir is recommended. Severe renal impairment (estimated glomerular filtration rate <30 mL/min) does not substantially affect the pharmacokinetics of ledipasvir, but because levels of sofosbuvir and its metabolite accumulate in the setting of severe renal impairment, the combination should not be used in such settings pending further data. Thus, no dosage recommendation has been given for patients with severe renal impair‐ ment or end-stage renal disease requiring dialysis. Available data from clinical trials have shown that the combination of ledipasvir and sofosbuvir has been very well tolerated. The most commonly reported adverse effects are fatigue and headaches. Ledipasvir, like sofosbu‐ vir, is a substrate of the P-gp drug transporter, so drugs that are potent intestinal P-gp inducers may decrease ledipasvir levels. Thus, the coadministration of ledipasvir-sofosbuvir is not recommended with rifampin, St. John's wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, or tipranavir/ritonavir. In addition, ledipasvir is an inhibitor of P-gp and may increase absorption of P-gp substrates. The coadministration of ledipasvir with tenofovir results in increased levels of tenofovir, particularly in the presence of other boosting agents. Until further data are available, ledipasvir-sofosbuvir should not be used with the combination of elvitegravir, cobicistat, emtricitabine, and tenofovir, and should only be used cautiously with regimens that contain tenofovir and a ritonavir-boosted protease inhibitor [73,78-83].

**8.4. Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak®, AbbVie Inc)**

The Viekira Pak is an all-oral regimen comprised of four medications: ombitasvir, paritaprevir, ritonavir, and dasabuvir. This regimen can be used with or without ribavirin. In the Viekira

carbamazepine, phenytoin or St. John's wort [62,65-77].

88 Recent Advances in Liver Diseases and Surgery

**8.3. Ledipasvir-sofosbuvir (Harvoni®, Gilead Sciences)**

The European Commission approved daclatasvir, a potent pan-genotypic NS5A replication complex inhibitor (in vitro), at the end of August 2014. Daclatasvir should be administered at the dose of 60 mg (one tablet) once per day. It is well tolerated overall. Dose adjustments are not needed in patients with Child B or C disease. Daclatasvir can be used in combination with other drugs for the treatment of chronic HCV infection genotypes 1, 2, 3, and 4 in adults. Daclatasvir*,* when used in combination with sofosbuvir, is an all-oral, interferon-free regimen that provided cure rates of more than 95% in clinical trials, including in patients with advanced liver disease, genotype 3, and those who have previously failed treatment with protease inhibitors. Across clinical studies, daclatasvir-based regimens have been generally well tolerated, with low discontinuation rates. The most common adverse effects with daclatasvir when used in combination with other drugs are fatigue, headaches, and nausea. Little information has been released on daclatasvir drug-drug interactions. Daclatasvir is a substrate of CYP34A and a substrate and inhibitor of P-gp. The daclatasvir dose should be adjusted to 30 mg daily in HIV-infected patients receiving atazanavir/ritonavir and to 90 mg daily in those receiving efavirenz. No dose adjustment is needed with tenofovir. No information on other antiretroviral drugs is available yet. No dose adjustments are required with cyclosporine or tacrolimus. Total daclatasvir AUC is decreased by 40% and 43% in patients with mild or moderate liver impairment, respectively. However, the unbound pharmacologically active fraction is unchanged; thus, dose adjustment is not needed in patients with liver impairment [77,91,92].

The direct acting antiviral treatment is usually used in combination for HCV treatment according to genotypes and stage of liver disease, and the patient is either naive or has previous experience of treatment.

The following recommendations can be used for treatment of HCV according to genotypes with a high response rate (>90%):

	- **a.** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.
	- **b.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis) for treatment of both naive and prior pegylated interferon and ribavirin treatment failure, in patients with HCV genotype 1a infection.
	- **c.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks for treatment-naive and prior pegylated interferon and ribavirin treatment failure, in patients with HCV genotype 1b infection. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis.
	- **d.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.

other drugs for the treatment of chronic HCV infection genotypes 1, 2, 3, and 4 in adults. Daclatasvir*,* when used in combination with sofosbuvir, is an all-oral, interferon-free regimen that provided cure rates of more than 95% in clinical trials, including in patients with advanced liver disease, genotype 3, and those who have previously failed treatment with protease inhibitors. Across clinical studies, daclatasvir-based regimens have been generally well tolerated, with low discontinuation rates. The most common adverse effects with daclatasvir when used in combination with other drugs are fatigue, headaches, and nausea. Little information has been released on daclatasvir drug-drug interactions. Daclatasvir is a substrate of CYP34A and a substrate and inhibitor of P-gp. The daclatasvir dose should be adjusted to 30 mg daily in HIV-infected patients receiving atazanavir/ritonavir and to 90 mg daily in those receiving efavirenz. No dose adjustment is needed with tenofovir. No information on other antiretroviral drugs is available yet. No dose adjustments are required with cyclosporine or tacrolimus. Total daclatasvir AUC is decreased by 40% and 43% in patients with mild or moderate liver impairment, respectively. However, the unbound pharmacologically active fraction is unchanged; thus, dose adjustment is not needed in patients with liver impairment

The direct acting antiviral treatment is usually used in combination for HCV treatment according to genotypes and stage of liver disease, and the patient is either naive or has previous

The following recommendations can be used for treatment of HCV according to genotypes

**a.** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24

**b.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks (no cirrhosis) or 24 weeks (cirrhosis) for treatment of both naive and prior pegylated interferon and ribavirin

**c.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks for treatment-naive and prior pegylated interferon and ribavirin treatment failure, in patients with HCV genotype 1b infection. The addition of daily weight-based ribavirin (1000 mg [<75 kg]

**d.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment

weeks in patients with contraindications to ribavirin.

treatment failure, in patients with HCV genotype 1a infection.

to 1200 mg [>75 kg]) is recommended in patients with cirrhosis.

extended to 24 weeks in patients with contraindications to ribavirin.

[77,91,92].

experience of treatment.

with a high response rate (>90%):

90 Recent Advances in Liver Diseases and Surgery

**1.** HCV genotype 1 [91,93]


When pegylated interferon and ribavirin was the treatment for HCV, the same regimen was administered to all subjects, and patients were defined as easy or difficult to treat according to viral genotype. HCV genotypes 1 and 4 were considered to be difficult to treat, and HCV genotypes 2 and 3 were considered to be easy to treat. The SVR rates in the latter group were above 80% with shorter treatment [94,95]. The availability of interferon-free regimens has confirmed that HCV genotype 2 patients are easy to treat, while the paradigm for HCV genotype 3 patients has been reversed compared to "older, difficult-to-treat" HCV genotype 1 patients. In fact, today, with available direct acting antiviral drugs, patients with HCV genotype 3 are the most difficult to treat patients. In large studies on HCV genotype 3 to assess the effectiveness of 12-16 weeks treatment with sofosbuvir and ribavirin, it has been shown that 12 weeks of therapy in treatment-naive patients resulted in an SVR in 61% and 34% of noncirrhotic and cirrhotic patients, respectively. Moreover, the SVR rates in experienced noncirrhotic patients were 37% at 12 weeks and were increased to 63% in patients with 16 weeks' course [70,67,95]. Extended treatments to 24 weeks of sofosbuvir and ribavirin were evaluated in the valence trial, resulting in an overall SVR rate of 83%. In particular, this was the result of higher SVR rates in treatment-naive (93% and 92% in patients without and with cirrhosis, respectively) and experienced patients without cirrhosis (87%), while rates were lower in experienced (61%) patients with cirrhosis [80,95,96]. The Lonestar-2 study tested treatment with pegylated interferon/sofosbuvir/ribavirin for 12 weeks in treatment-experi‐ enced HCV-2 and HCV-3 patients. The SVR in HCV genotype 3 patients was 83% with no difference in relation to baseline cirrhosis (SVR 83% vs. 83%, respectively) [69]. The second study tested a combination of daclatasvir/sofosbuvir, resulting in an SVR of 89% of 18 treatment-naive patients with HCV genotype 3 [97].

The following treatment options with similar efficacy can be used in genotype 3 naive patients and patients in whom prior pegylated interferon and ribavirin treatment has failed [91-93,97]:

	- **a.** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.
	- **b.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks for treatment of both naive and prior pegylated interferon and ribavirin treatment failure, and treatment can be extended to 24 weeks in patients with cirrhosis.
	- **c.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.
	- **d.** Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients with contraindications to ribavirin.
	- **e.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks.

A few data are available to help guide decision making for patients infected with HCV genotype 5 or 6, but currently the following are the recommendations until more data are available:

**a.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks


The following treatment options with similar efficacy can be used in genotype 3 naive patients and patients in whom prior pegylated interferon and ribavirin treatment has failed [91-93,97]: **a.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks in patients without cirrhosis. Daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is added to regimen to treat naive and treatment-experienced patients with cirrhosis

**b.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75

**c.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly pegylated interferon for 12 weeks is an acceptable regimen for interferon-

**a.** Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24

**b.** Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks for treatment of both naive and prior pegylated interferon and ribavirin treatment failure, and treatment can be extended to 24 weeks in patients with

**c.** Daily fixed-dose combination of daclatasvir 60 mg and sofosbuvir 400 mg for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment

**d.** Daily sofosbuvir (400 mg) plus simeprevir (150 mg) for 12 weeks. The addition of daily weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [>75 kg]) is recommended in patients with cirrhosis. The duration of treatment extended to 24 weeks in patients

**e.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg

A few data are available to help guide decision making for patients infected with HCV genotype 5 or 6, but currently the following are the recommendations until more data are

**a.** Daily sofosbuvir (400 mg) and weight-based ribavirin (1000 mg [<75 kg] to 1200 mg

extended to 24 weeks in patients with contraindications to ribavirin.

[>75 kg]) plus weekly pegylated interferon for 12 weeks.

[>75 kg]) plus weekly pegylated interferon for 12 weeks

eligible, treatment-naive patients with HCV genotype 3 infection.

weeks in patients with contraindications to ribavirin.

with contraindications to ribavirin.

for 24 weeks.

kg]) for 24 weeks.

92 Recent Advances in Liver Diseases and Surgery

cirrhosis.

**5.** HCV genotype 5 [91,93]

available:

**4.** HCV genotype 4 [70,91,93,98-101]


Due to the very high efficacy and the excellent tolerability of IFN-free regimens, responseguided shortening or prolongation of therapy have not been studied and, indeed, may not be needed to achieve high cure chances in the individual patient. However, given the high costs of direct antiviral drugs, HCV RNA testing during treatment may be helpful for surveillance of compliance and motivation of patients. HCV RNA should be measured at baseline, week 2 (assessment of adherence), week 4, week 12 or 24 (end of treatment), and 12 or 24 weeks after the end of therapy [102].
