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Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults
Author:
Andrew J Muir, MD, MHS
Section Editor:
Adrian M Di Bisceglie, MD
Deputy Editor:
Allyson Bloom, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Aug 23, 2017.

INTRODUCTION — Six major genotypes of the hepatitis C virus (HCV) have been discovered around the world. All HCV genotypes can cause both acute and chronic hepatitis. The acute process is self-limited, rarely causes hepatic failure, and usually leads to chronic infection. Chronic HCV infection often follows a progressive course over many years and can ultimately result in cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection".)

The goal of treatment is to eradicate HCV RNA, which is predicted by the achievement of a sustained virologic response (SVR), defined by the absence of HCV RNA by polymerase chain reaction 12 weeks after stopping treatment. An SVR is associated with a 99 percent chance of being HCV RNA negative during long-term follow-up and can therefore be considered cured of the HCV infection [1]. Achievement of an SVR has also been associated with improved clinical outcomes. (See "Overview of the management of chronic hepatitis C virus infection" and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Rationale for treatment'.)

HCV drug development has predominantly focused on genotypes 1, 2, and 3, which are the most common genotypes in Europe and North America. With the advent of direct-acting antiviral agents with broad coverage against all genotypes, patients with genotypes 4, 5, and 6 also have new treatment options.

This topic will review the antiviral treatment of patients with chronic HCV genotypes 4, 5, and 6 infections. General management of chronic HCV infection, evaluation and selection of patients for antiviral treatment, antiviral treatment of patients with other genotypes, and the treatment of acute HCV infection are discussed elsewhere:

(See "Overview of the management of chronic hepatitis C virus infection".)

(See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection".)

(See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults".)

(See "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults".)

(See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults".)

(See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

GUIDELINES — Guidelines for the diagnosis and management of HCV infection were released jointly by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in 2014, are updated on an ongoing basis, and can be accessed at www.hcvguidelines.org [2]. The discussion in this topic is generally consistent with those guidelines.

Other guidelines include treatment recommendations from the European Association for the Study of the Liver (EASL) [3]. World Health Organization (WHO) also released guidelines in 2014 on screening and treatment of HCV, intended primarily for clinicians and policy-makers in low- and middle-income countries [4].

Links to these and other guidelines can be found below. (See 'Society guideline links' below.)

DEFINITIONS — Specific terms have been used to define patient populations based on their exposure and prior response to therapy:

Treatment-naïve – Patients who have never received any treatment for HCV

Treatment-experienced – Patients who have failed prior treatment for HCV. This refers to:

Peginterferon and ribavirin failure – Patients who did not respond to or relapsed after treatment with peginterferon and ribavirin (without direct-acting antiviral exposure)

Protease inhibitor failures – Patients who did not respond to or relapsed after treatment with boceprevir, telaprevir, or simeprevir in combination with peginterferon and ribavirin

Sofosbuvir failures – Patients who did not respond to or relapsed after treatment with a regimen that contained sofosbuvir (but did not contain an NS5A inhibitor)

NS5A inhibitor failures – Patients who did not respond to or relapsed after treatment with a regimen containing an NS5A inhibitor (such as ledipasvir, daclatasvir, or ombitasvir)

Throughout this topic, peginterferon refers specifically to peginterferon-alfa.

EPIDEMIOLOGY OF GENOTYPES 4, 5, AND 6 — These genotypes tend to cluster in certain parts of the world and are also prevalent in other countries among immigrant populations from these regions (figure 1).

Egypt has the highest HCV prevalence in the world at approximately 15 percent, and more than 90 percent of cases are genotype 4 [5,6]. Genotype 4 is also the dominant strain in Central and West Africa, with increasing rates in European countries such as France, Spain, Greece, and Italy related to immigration [7].

Genotype 5 is most common in South Africa [8].

HCV genotype 6 has been found primarily in south China, Hong Kong, Taiwan, Macao, and southeast Asia, including Singapore, Malaysia, Vietnam, Thailand, and Burma [9].

DECIDING WHEN TO TREAT — With the proliferation of highly effective, interferon-free regimens and mounting data supporting the efficacy of some of these regimens for genotypes 4, 5, and 6 infection, a curative all-oral treatment is becoming a possibility for the vast majority of patients where these regimens are available. However, the cost of these new agents prevents universal delivery of antiviral therapy, particularly in resource-limited settings where these genotypes are prevalent. When resources are constrained, prioritizing patients who may benefit most from antiviral treatment may be warranted. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Deciding when to treat'.)

In locations where interferon-free regimens are unavailable, regimens for genotypes 4, 5, and 6 continue to include peginterferon and ribavirin, and it may be preferable to defer therapy to avoid the attendant side effects with such regimens.

The decision on whether to treat now with an interferon-based regimen or defer therapy to await more effective or better tolerated regimens should take into account the following factors:

Current liver disease stage – This is the main factor that informs the risk of morbidity from liver disease deferring therapy. If a patient has early stage liver fibrosis (none to portal or periportal fibrosis) and has no indications that there is rapidly progressive disease, it is unlikely that he will progress to clinically significant liver fibrosis over several years. In contrast, if the patient has bridging fibrosis or compensated cirrhosis, many clinicians favor initiating antiviral treatment given the risk of developing decompensated cirrhosis or hepatocellular carcinoma. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection", section on 'Factors associated with disease progression'.)

Extrahepatic manifestations – If serious extrahepatic manifestations of HCV infection, such as mixed cryoglobulinemia or glomerulonephritis are present, prompt antiviral therapy can improve these effects. However, in some cases, slightly delaying antiviral therapy to allow initiation of immunosuppressive therapy may be warranted. (See "Treatment of the mixed cryoglobulinemia syndrome", section on 'Initiation of HCV therapy'.)

Likely efficacy of therapy – Alternative interferon-containing regimens have suboptimal efficacy rates among certain patient populations, such as those with cirrhosis or with a history of prior partial or null response to antiviral therapy. Deferring interferon-based therapy may be particularly attractive for such patients.

Expected adverse effects of therapy – Deferring interferon-based therapy may be particularly attractive to individuals who have relative contraindications to peginterferon and ribavirin or would otherwise be more likely to suffer adverse effects. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

Patient preference and readiness – Some patients may feel strongly about being treated as soon as possible and are willing to tolerate the potential adverse effects of a peginterferon and ribavirin-containing regimen if that is the only option for them. In contrast, some patients may not be immediately appropriate for antiviral therapy because of adherence concerns or personal preference, even if an interferon-free regimen is available to them.

For patients who do defer antiviral treatment, liver wellness (eg, alcohol abstinence, maintaining a healthy weight, control of diabetes mellitus) and close monitoring of clinical status are warranted.

SELECTION OF TREATMENT REGIMENS

Genotype 4 — Several interferon-free regimens have high expected efficacy against genotype 4 infection. They are ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, glecaprevir-pibrentasvir, elbasvir-grazoprevir, ombitasvir-paritaprevir-ritonavir plus ribavirin, and sofosbuvir plus ribavirin. The choice between them depends primarily on potential for drug interactions, availability, and cost. If these are not an issue, we favor ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, or glecaprevir-pibrentasvir for the avoidance of ribavirin and ease of administration (once-daily dosing) with these regimens. If the only available option is sofosbuvir plus peginterferon and ribavirin, we favor deferring therapy until interferon-free regimens are available unless patient characteristics (such as advanced liver disease or severe extrahepatic manifestations) warrant earlier treatment. (See 'Deciding when to treat' above.)

The administration and efficacy of interferon free-regimens for genotype 4 are as follows. Adverse effects and drug interactions of these regimens are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

Ledipasvir-sofosbuvir – For genotype 4 infection, the fixed-dose combination pill ledipasvir-sofosbuvir is given once daily for 12 weeks, regardless of treatment history or the presence of cirrhosis. In a study of 21 genotype 4-infected patients, of whom 9 had advanced fibrosis or cirrhosis (METAVIR F3-4) and 8 had failed prior treatment with peginterferon and ribavirin, the sustained virologic response (SVR) rate was 95 percent after 12 weeks of ledipasvir-sofosbuvir [10]. In a similar study, the regimen resulted in a SVR in 96 percent of 22 treatment-naïve patients and in 91 percent of 22 treatment-experienced patients with genotype 4 infection [11].

Sofosbuvir-velpatasvir – For genotype 4 infection, the fixed-dose combination pill sofosbuvir-velpatasvir is given once daily for 12 weeks, regardless of treatment history or the presence of cirrhosis. In one study, this regimen resulted in SVR in 100 percent of 116 patients with genotype 4 infection, which included 27 patients with cirrhosis and 52 treatment-experienced patients [12].

Glecaprevir-pibrentasvir – For genotype 4 infection, the fixed-dose combination of glecaprevir-pibrentasvir (three pills once daily) is given for 8 weeks for patients without cirrhosis and 12 weeks for patients with cirrhosis. These regimens resulted in SVR rates of 93 percent in 46 patients without cirrhosis and 100 percent in 16 patients with cirrhosis [13,14]. All the individuals who did not achieve SVR with the 8 week regimen either discontinued therapy or had incomplete data. This regimen can be used in patients with any degree of renal impairment, including those on dialysis, but is contraindicated in patients with Child Pugh classes B and C cirrhosis.

Elbasvir-grazoprevir – For genotype 4 infection, the fixed-dose combination pill elbasvir-grazoprevir is given once daily for 12 weeks for treatment-naïve patients and once daily for 16 weeks with weight-based ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) for patients who had previously failed treatment with peginterferon and ribavirin. In an analysis of 56 treatment-naïve patients who received 12 weeks of elbasvir-grazoprevir, 96 percent achieved SVR [15]. In contrast, SVR rates were lower with only 12 weeks among a small number of treatment-experienced patients (78 percent in 9 patients), but were higher with the addition of ribavirin and treatment extension to 16 weeks (100 percent in 8 patients). SVR rates were similar in patients with and without cirrhosis. This regimen can be used in patients with any degree of renal impairment, including those on dialysis, but is contraindicated in patients with Child Pugh classes B and C cirrhosis.

Ombitasvir-paritaprevir-ritonavir plus weight-based ribavirin – For genotype 4 infection, the fixed-dose combination drug ombitasvir-paritaprevir-ritonavir is given as two pills once daily with ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) for 12 weeks, regardless of treatment history. Of note, dasabuvir is not included in this regimen for genotype 4, in contrast to genotype 1 infection. In a study of 135 genotype 4-infected patients without cirrhosis, the SVR rate was 100 percent among 42 treatment-naïve and 49 treatment-experienced patients who received 12 weeks of ombitasvir-paritaprevir-ritonavir with ribavirin for 12 weeks [16]. Among the 44 treatment-naïve patients who received the regimen without ribavirin, the SVR rate was lower, at 91 percent. This regimen has not been well studied in patients with genotype 4 and cirrhosis, but we generally administer the regimen for the same 12-week duration to such patients, with close monitoring for hepatic decompensation. The regimen is contraindicated in Child Pugh classes B and C cirrhosis.

Sofosbuvir plus weight-based ribavirin – For genotype 4 infection, sofosbuvir is given once daily with ribavirin (daily dose 1000 mg for those <75 kg and 1200 mg for those ≥75 kg) for 24 weeks, regardless of treatment history or the presence of cirrhosis. An open-label trial randomly assigned genotype 4-infected patients of Egyptian ancestry to 12 or 24 weeks of sofosbuvir and ribavirin [17]. Among the 14 treatment-naïve and 15 treatment-experienced patients who received the regimen for 24 weeks, SVR rates were 100 and 87 percent, respectively. All seven patients with cirrhosis who received 24 weeks of therapy experienced SVR. SVR rates were overall lower (at 79 and 59 percent, respectively) with 12 weeks of therapy.

The second generation protease inhibitor simeprevir has activity against genotype 4. In a study of 107 treatment-naïve and treatment-experienced patients, simeprevir for 12 weeks in combination with peginterferon and ribavirin for 24 to 48 weeks, depending on response to therapy, resulted in an overall 83 percent SVR rate [18]. Given that the responses to simeprevir- and sofosbuvir-based regimens in genotype 4 are similar to those seen with genotype 1, it is likely that the interferon-free regimen of simeprevir plus sofosbuvir for 12 to 24 weeks would be highly effective for genotype 4, as it is for genotype 1. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Simeprevir plus sofosbuvir'.)

If these interferon-free regimens are cost-prohibitive or otherwise unavailable, 12 weeks of sofosbuvir plus peginterferon and weight-based ribavirin is highly effective for treatment-naïve patients, but may not have high efficacy for prior partial and null responders. In an open label trial (NEUTRINO), which evaluated this regimen in treatment-naïve HCV-infected patients, 27 of the 28 genotype 4-infected patients achieved SVR12 (96 percent) [19]. No direct data are available to inform SVR rates with this regimen among treatment-experienced patients; however, based on response rates among genotype 1-infected patients with other characteristics that similarly portend lower response, one analysis estimated that 71 percent of genotype 1 treatment-experienced patients would achieve SVR with sofosbuvir plus peginterferon and ribavirin [20]. It is probable, but unconfirmed, that a similarly suboptimal response rate would be observed with genotype 4-infected treatment-experienced patients. Administration of interferon-containing regimens is discussed elsewhere. (See 'Administration of interferon containing regimens' below.)

In contrast to results with these regimens containing direct-acting antivirals, prior studies of 48 weeks of peginterferon and ribavirin alone for genotype 4 infection had demonstrated substantially lower SVR rates (approximately 30 percent) [21,22]. This regimen is not recommended for genotype 4 infection.

Genotype 5 — Data on treatment of genotype 5 infection are limited. The interferon-free options are the fixed-dose combination of ledipasvir-sofosbuvir or sofosbuvir-velpatasvir, each given once daily for 12 weeks, or glecaprevir-pibrentasvir (given for 8 weeks for those without cirrhosis and 12 weeks for those with compensated cirrhosis).

All appear highly effective based on studies with small numbers of genotype 5-infected patients. In a study that included 21 treatment-naïve and 20 treatment-experienced genotype 5-infected patients, ledipasvir-sofosbuvir for 12 weeks resulted in SVR rates of 95 percent for each group [11]. Similarly, in a trial that included 35 genotype 5-infected patients (5 and 11 of whom had cirrhosis and were treatment-experienced, respectively), sofosbuvir-velpatasvir for 12 weeks resulted in SVR in 97 percent [12]. In two studies of glecaprevir-pibrentasvir, 27 genotype 5-infected patients without cirrhosis who received eight weeks and two patients with cirrhosis who received 12 weeks all achieved SVR [13,14]. Adverse effects and drug interactions with these regimens are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection".)

If these interferon-free regimens are cost-prohibitive or otherwise unavailable, we favor deferring therapy unless patient characteristics (such as advanced liver disease or severe extrahepatic manifestations) warrant earlier treatment (see 'Deciding when to treat' above). For those who warrant earlier treatment, sofosbuvir plus peginterferon and weight-based ribavirin for 12 weeks is a potentially effective option. The NEUTRINO trial, which evaluated this regimen in treatment-naïve patients, only included one genotype 5-infected patient, who achieved SVR [19]. For patients who do not have access to sofosbuvir, the alternative regimen is 48 weeks of peginterferon and ribavirin. However, for patients with genotype 5 infection, this regimen is associated with lower response rates than would be expected with a sofosbuvir-containing regimen. In a meta-analysis of two trials from Belgium, the SVR rate was 55 percent among the 38 genotype 5-infected patients who received 48 weeks of peginterferon and ribavirin [23]. Administration of interferon-containing regimens is discussed elsewhere. (See 'Administration of interferon containing regimens' below.)

Genotype 6 — Data on treatment of genotype 6 are limited. The interferon-free options for genotype 6 infection are the fixed-dose combinations of ledipasvir-sofosbuvir or sofosbuvir-velpatasvir, each given once daily for 12 weeks, or glecaprevir-pibrentasvir (given for 8 weeks for those without cirrhosis and 12 weeks for those with compensated cirrhosis). All appear highly effective based on studies with small numbers of genotype 6-infected patients.

In a study of 25 genotype 6-infected patients, this regimen resulted in an SVR rate of 96 percent [24]. The one treatment failure was a relapse in a patient who discontinued the regimen after 8 weeks because of drug use. Similarly, in a trial that included 41 genotype 6-infected patients (6 and 3 of whom had cirrhosis and were treatment-experienced, respectively), sofosbuvir-velpatasvir for 12 weeks resulted in SVR in 100 percent [12]. In two studies of glecaprevir-pibrentasvir, 30 genotype 6-infected patients without cirrhosis who received eight weeks and seven patients with cirrhosis who received 12 weeks all achieved SVR [13,14]. Adverse effects and drug interactions with these regimens are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Ledipasvir-sofosbuvir'.)

If these interferon-free regimens are cost-prohibitive or otherwise unavailable, we favor deferring therapy unless patient characteristics (such as advanced liver disease or severe extrahepatic manifestations) warrant earlier treatment (see 'Deciding when to treat' above). For those who warrant earlier treatment, the 12 week regimen of sofosbuvir plus peginterferon and weight-based ribavirin is also expected to be highly effective in the treatment-naïve. The NEUTRINO trial, which evaluated this regimen in treatment-naïve patients, only included six genotype 6 patients, all of whom achieved SVR [19]. For patients who do not have access to sofosbuvir, the alternative regimen is 48 weeks of peginterferon and ribavirin. Patients with genotype 6 infection have been generally reported to have higher SVR rates with interferon-based regimens than genotype 1. The higher response observed with genotype 6 may be related to the increased prevalence of this viral genotype in Asia where patients are more likely to have the favorable IL28B genotype [25]. Given the excellent response rates in genotype 6 infection, a randomized controlled trial evaluated 24 versus 48 weeks of treatment with peginterferon and ribavirin [26]. The response rate in the 24-week group was 70 percent compared with 79 percent (P = 0.45) in the 48-week group. These results do not support a reduction in treatment duration, but might guide a decision to stop at 24 weeks in the patient struggling with side effects. Administration of interferon-containing regimens is discussed elsewhere. (See 'Administration of interferon containing regimens' below.)

TREATMENT CONSIDERATIONS IN SPECIFIC POPULATIONS

Patients with cirrhosis

Compensated — Regimen selection for cirrhotic patients with genotype 4, 5, or 6 infection is the same as for patients of the same genotype without cirrhosis (see 'Selection of treatment regimens' above). Adequate estimation of specific response rates for genotypes 4, 5, and 6 infections in the setting of cirrhosis are limited due to the small sample sizes of these genotypes in clinical trials.

Based on studies from all genotypes, interferon-free regimens are safe in patients with compensated cirrhosis.

If an interferon-free regimen is unavailable, the regimen of sofosbuvir plus peginterferon and ribavirin for 12 weeks does appear to be relatively well-tolerated among patients with compensated cirrhosis [19]. However, some studies have suggested an excess of serious adverse events, including decompensating events and death, among patients with cirrhosis when peginterferon and ribavirin were given with first-generation HCV protease inhibitors, particularly in those with a low platelet count or albumin level [27,28]. Although the limited data thus far do not suggest that a similarly high adverse effect rate would be observed among cirrhotics treated with peginterferon and ribavirin in combination with sofosbuvir, in light of this concern, we favor not using an interferon-based regimen for cirrhotic patients who have platelet counts <90,000/microL or albumin <3.5 g/dL. Other absolute and relative contraindications to interferon are discussed elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Bridging fibrosis and compensated cirrhosis' and "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Contraindications/precautions with anti-HCV agents'.)

Decompensated — Options are limited for patients with decompensated cirrhosis (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage), and antiviral treatment should only be undertaken by or in consultation with an expert in the management of such patients, preferably at a transplant center. Patients with decompensated cirrhosis or a MELD score greater than 10 should be evaluated for liver transplantation prior to initiation of HCV therapy. For genotypes 4, 5, and 6 infection, sofosbuvir-velpatasvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir plus ribavirin for 12 to 24 weeks are effective options [29,30]. Patients with decompensated cirrhosis who are undergoing HCV antiviral therapy should have frequent clinical and laboratory monitoring, including monitoring of liver synthetic function. General management issues for patients with decompensated cirrhosis are discussed elsewhere. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Major complications'.)

Of note, glecaprevir-pibrentasvir, elbasvir-grazoprevir, and sofosbuvir-velpatasvir-voxilaprevir are contraindicated in patients with Child B and C cirrhosis because of increased drug levels in the setting of such hepatic impairment. Ombitasvir-paritaprevir-ritonavir-based regimens are also contraindicated in patients with Child B or C cirrhosis because of the risk of worsened hepatic decompensation.

Prior failure of direct-acting antiviral regimens — For the rare patient with genotype 4, 5, or 6 infection who has failed prior therapy with a direct-acting antiviral (DAA) regimen, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks is a potential option for retreatment. As an example, among genotype 4-infected patients, this regimen resulted in sustained virologic response (SVR) rates of 92 percent for those with prior NS5A failure (n = 22) and 100 percent for those with prior non-NS5A DAA failure (n = 19) [31]. The few DAA-experienced genotype 5 and 6 patients included in this study all achieved SVR with this regimen.

Recurrence after liver transplantation — Recurrence of HCV occurs in more than 95 percent of patients after liver transplantation. Management of HCV recurrence post-transplant is discussed elsewhere. (See "Recurrence of hepatitis C virus infection following liver transplantation", section on 'Treatment of recurrence'.)

Patients with renal impairment — The selection of a HCV antiviral regimen for patients with renal disease depends upon the extent of renal impairment in addition to the genotype, extent of underlying liver disease, and history of past antiviral treatment. Antiviral treatment in such patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with renal impairment".)

HIV-HCV co-infection — Treatment with peginterferon and ribavirin resulted in lower SVR rates among coinfected compared with monoinfected patients [32,33], but studies of DAAs (either in interferon-based or interferon-free combinations) have demonstrated similar SVR rates among both groups [34-37]. However, drug-drug interactions between antiretroviral agents and HCV antiviral agents may be significant. These data suggest that patients with HIV infection and preserved immune function should not be thought of as a special population that has lower response rates compared with the monoinfected population, but instead as a group with particular drug-drug interaction concerns.

Treatment of HCV/HIV-infected patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C virus infection in the HIV-infected patient".)

MONITORING DURING INTERFERON-FREE REGIMENS — Monitoring during treatment is discussed in detail elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

ADMINISTRATION OF INTERFERON CONTAINING REGIMENS — If sofosbuvir is given with peginterferon and ribavirin, they are initiated together, without a lead-in period.

The two available peginterferons used in the treatment of HCV, peginterferon alfa-2a (Pegasys) and peginterferon alfa-2b (Peg-Intron), differ in their pharmacokinetics. We favor peginterferon alfa-2a for ease of administration.

Studies that have compared the two peginterferons in combination with ribavirin with or without the use of a direct-acting antiviral use have been mixed, with some, but not all, studies suggesting higher SVR rates with peginterferon alfa-2a. These are discussed in detail elsewhere. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Choice and dose of peginterferon and ribavirin'.)

The doses are different for the two formulations:

For peginterferon alfa-2a, the dose is 180 micrograms subcutaneously per week.

For peginterferon alfa-2b, the dose is 1.5 microgram/kg subcutaneously per week.

For patients with genotypes 4, 5, or 6, ribavirin dosing is weight-based. Ribavirin is given in divided daily doses (typically twice per day):

For patients receiving peginterferon alfa-2a, the total daily ribavirin dose is 1000 mg for patients who weigh <75 kg or 1200 mg for those who weigh ≥75 kg.

For patients receiving peginterferon alfa-2b, the total daily ribavirin dose is 800 mg for patients weighing <65 kg, 1000 mg for 65 to 85 kg, 1200 mg for >85 to 105 kg, and 1400 mg for >105 kg.

Ribavirin is potentially teratogenic, so two effective forms of contraception should be used by both men and women of child-conceiving potential during and six months after treatment with ribavirin-containing regimens. Monitoring and management of other adverse effects of interferon and ribavirin for the treatment of chronic HCV are discussed elsewhere. (See "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

FOLLOW-UP AFTER TREATMENT — Follow-up after treatment includes checking the viral load 12 weeks after the cessation of therapy to evaluate for a sustained virologic response. Patients with advanced fibrosis or cirrhosis also warrant ongoing screening for hepatocellular carcinoma, regardless of antiviral treatment outcome. These issues are discussed in detail elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Follow-up after antiviral therapy'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatitis C virus infection".)

SUMMARY AND RECOMMENDATIONS

The goal of treatment is to eradicate hepatitis C virus (HCV) RNA, which is predicted by the achievement of a sustained virologic response (SVR), defined by the absence of HCV RNA by polymerase chain reaction 12 weeks after stopping treatment. An SVR is associated with a 99 percent chance of being HCV RNA negative during long-term follow-up and can therefore be considered cure of the HCV infection. (See 'Introduction' above.)

Genotypes 4, 5, and 6 cluster in certain parts of the world and are prevalent in other countries among immigrant populations from these regions (figure 1). Genotype 4 is prevalent in Egypt and central and west Africa. Genotype 5 is most common in South Africa, and genotype 6 has primarily been identified in Asia. (See 'Epidemiology of genotypes 4, 5, and 6' above.)

Interferon-free regimens have demonstrated efficacy for genotypes 4, 5, and 6, but these may not be widely available because of cost or other issues. Other regimens for genotypes 4, 5, and 6 continue to include peginterferon and ribavirin. The decision to treat a patient at this time or await availability of interferon-free regimens should take into account the expected efficacy and adverse effects of available regimens, history of prior antiviral therapy, the current liver disease stage, extrahepatic manifestations, and patient preference. (See 'Deciding when to treat' above.)

Effective interferon-free regimens for genotype 4 infection include ledipasvir-sofosbuvir for 12 weeks, sofosbuvir-velpatasvir for 12 weeks, glecaprevir-pibrentasvir for 8 weeks (for patients without cirrhosis) or for 12 weeks (for patients with cirrhosis), elbasvir-grazoprevir for 12 weeks (for treatment-naïve) or for 16 weeks with ribavirin (for treatment-experienced), ombitasvir-paritaprevir-ritonavir plus weight-based ribavirin for 12 weeks, and sofosbuvir plus weight-based ribavirin for 24 weeks. The choice between them depends primarily on potential for drug interactions, availability, and cost. If these are not issues, we suggest ledipasvir-sofosbuvir, sofosbuvir-velpatasvir, or glecaprevir-pibrentasvir (Grade 2B). If interferon-free regimens are not available, 12 weeks of sofosbuvir plus peginterferon and weight-based ribavirin is also highly effective for treatment-naïve patients but has the added toxicity of peginterferon. Furthermore, the efficacy of this regimen is uncertain in treatment-experienced patients. (See 'Genotype 4' above.)

Data on treatment of genotype 5 and 6 infection are limited. For patients with genotype 5 or 6 infection, we recommend ledipasvir-sofosbuvir for 12 weeks, sofosbuvir-velpatasvir for 12 weeks, or glecaprevir-pibrentasvir for 8 weeks (for patients without cirrhosis) or for 12 weeks (for patients with cirrhosis) (Grade 1B). If these interferon-free regimens are cost-prohibitive or otherwise unavailable, the 12-week regimen of sofosbuvir plus peginterferon and weight-based ribavirin is also expected to be highly effective in the treatment-naïve. (See 'Genotype 5' above and 'Genotype 6' above.)

Interferon-free regimens are generally well tolerated, although the potential for drug interactions should be reviewed. Ribavirin is potentially teratogenic, so two effective forms of contraception should be used by both men and women of child-conceiving potential during and six months after treatment with ribavirin-containing regimens. Peginterferon and ribavirin are associated with a number of other side effects. These issues are discussed in detail elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection" and "Management of the side effects of peginterferon and ribavirin used for treatment of chronic hepatitis C virus infection".)

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