Management of chronic hepatitis C virus infection: Antiviral retreatment following relapse in adults

INTRODUCTION — Hepatitis C virus (HCV) 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".)

Successful antiviral treatment of chronic HCV infection halts the progression of liver disease and is associated with improvement in liver-related morbidity and mortality. Although contemporary antiviral regimens are highly effective, a small minority does not respond to initial treatment. In contrast to the limited evaluation needed prior to initial treatment, patients with relapse warrant more detailed assessment and monitoring to optimize the likelihood of cure with retreatment.

This topic will review the pretreatment evaluation, antiviral selection, and antiviral administration for chronic HCV infection that was not cured by initial treatment.

Our recommendations are generally consistent with joint guidelines on HCV management from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), which can be accessed at www.hcvguidelines.org [1].

Management issues other than antiviral retreatment for relapsed chronic 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 "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults".)

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

TREATMENT OBJECTIVE — The clinical objective of HCV treatment is cure of the infection. In the clinical setting and in HCV treatment trials, the marker for treatment success is a sustained virologic response (SVR), which is defined as an undetectable HCV viral level 12 weeks after the completion of therapy. An SVR at this time period has been associated with a >99 percent chance of sustained clearance of HCV, an effective cure of HCV infection [2]. SVR has also been associated with patient-important outcomes such as decreased mortality, decreased liver-related complications, and improved quality of life. These issues are discussed elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Benefits of treatment'.)

PRETREATMENT EVALUATION — The general approach to evaluation prior to HCV antiviral therapy is discussed in detail elsewhere. Issues specific to evaluation prior to retreatment are discussed here. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Evaluation'.)

Determining reasons for relapse — Our main objective in evaluating patients who experienced relapse following a contemporary direct-acting antiviral (DAA) regimen (eg, sofosbuvir-velpatasvir or glecaprevir-pibrentasvir) is to determine why treatment was not successful. If we identify a potential contributor to relapse, we address any modifiable factors with the patient prior to retreatment.

Such factors include:

●Adherence challenges – If patients missed more than several doses of the regimen or stopped it prematurely, we work with them to determine why they were unable to take the regimen as prescribed and identify ways to improve adherence. The proportion of the regimen completed may also impact selection of the retreatment regimen. (See 'Patients who did not finish a complete initial course' below.)

●Administration issues – If a patient took glecaprevir-pibrentasvir without food, that may have decreased absorption and thus efficacy of the regimen.

●Drug interactions – We re-evaluate for potential drug interactions that may have not initially been appreciated. In particular, for patients who used sofosbuvir-velpatasvir or ledipasvir-sofosbuvir for their initial regimen, we assess whether they took any antacids or acid-reducing medications (including over the counter medications), which could decrease absorption of these antivirals. Identifying and minimizing antacid use is especially important because the primary regimen for retreatment (ie, sofosbuvir-velpatasvir-voxilaprevir) is also acid dependent for absorption.

Laboratory testing — Pretreatment evaluation includes testing for HIV, hepatitis B virus (HBV) infection, and pregnancy, if not already performed. For patients with relapsed infection, we also evaluate for stage of fibrosis and check the genotype, even if they had a baseline genotype determined prior to initial therapy.

Although knowledge of the genotype is not always necessary for regimen selection, it may help distinguish relapse from reinfection, which has treatment implications, as discussed below. Additionally, identifying genotype 3 infection is important, as it is associated with lower response rates to retreatment and may warrant adjustment of the retreatment regimen.

These elements of the pretreatment evaluation are discussed in detail elsewhere. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'Evaluation'.)

Distinguishing relapse from reinfection — Patients identified as having recurrent HCV viremia following completion of initial antiviral therapy have either relapsed infection (nonresponse to antiviral therapy) or reinfection. Reinfection is treated with a regimen used for initial therapy (see "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults"). In contrast, relapsed infection usually warrants a different regimen for optimal retreatment. Overall, we have a low threshold to treat someone with a regimen used for relapsed infection if there is any uncertainty. (See 'Regimen selection for relapse after DAA therapy' below.)

In some cases, the distinction between reinfection and relapse is straightforward:

●Recurrent HCV viremia that is identified within 12 weeks of completing initial therapy and is with the same genotype as before therapy is relapse.

●Recurrent HCV viremia that is with a different genotype than before therapy is reinfection.

However, in patients who had a documented SVR and have the same genotype as before therapy (or had unknown genotype before therapy), the distinction is less clear and depends on the likelihood of repeat exposure. In such cases, we consider recurrent viremia to reflect reinfection if they have ongoing exposure (eg, injection drug use) and relapse if there is no clear exposure. If recurrent viremia is with a genotype that is rare in the area (eg, genotype 4 infection in the United States), relapse is also more likely. Although rare, late relapse after SVR is a possible explanation for recurrent HCV infection with the same genotype. As an example, in a study of 3000 patients who had participated in antiviral trials and achieved SVR, only 11 had subsequent recurrent viremia with the same genotype [3]. Phylogenetic analysis indicated that five represented relapse and the other six reinfection with a different virus.

In many cases, patients do not have a documented SVR (eg, because of loss to follow up) and are subsequently found to have HCV viremia. Unless we can document that the infecting genotype is different than in the original infection, we manage such patients as having relapsed infection. In some cases, resistance testing can help determine whether they can be treated with a regimen for initial therapy, although this is not generally necessary. (See 'Limited role for resistance testing' below.)

Limited role for resistance testing — We do not routinely check resistance testing prior to retreatment following relapse from initial antiviral therapy. This is because the primary regimen used for relapsed infection, sofosbuvir-velpatasvir-voxilaprevir, has such a high barrier to resistance that it remains active despite resistance-associated substitutions (RASs) [4].

The main exception is for patients with genotype 3 infection and relapse after interferon-based regimens. In such cases, resistance testing can help guide antiviral selection. (See 'Genotype 3' below.)

One of the authors of this topic also occasionally uses resistance testing when trying to distinguish between reinfection and relapse or when determining regimen options for someone who did not complete the initial course of therapy. In such cases, the absence of NS5A RASs suggests that one of the regimens used for initial therapy may be a reasonable option; in contrast, the presence of NS5A RASs would favor a regimen used for relapsed infection. Such resistance testing and analysis, however, should generally be done with guidance from an expert in HCV infection. Given the ambiguity in such situations, using a regimen recommended for relapsed infection without resistance testing is an appropriate approach that may be more straightforward. (See 'Regimen selection for relapse after DAA therapy' below.)

Overall, the clinical value of identifying RASs is limited. Although relapse is associated with selection of RASs, those RASs do not necessarily predict worse outcomes with regimens recommended for relapse. As an example, in a trial of 146 patients with genotype 1 infection who had previously failed an NS5A inhibitor-containing regimen (eg, sofosbuvir-velpatasvir), the majority had NS3/4A or NS5A RAS at baseline, but overall SVR rates were high (96 to 100 percent) with sofosbuvir-velpatasvir-voxilaprevir treatment, and RASs were not associated a lower likelihood of SVR [5].

REGIMEN SELECTION FOR RELAPSE AFTER DAA THERAPY

Patients who did not finish a complete initial course — Patients who started but did not complete a course of initial therapy for HCV infection should have the HCV viral level checked. In some cases, patients can achieve sustained virologic response (SVR) after abbreviated regimens, and no additional therapy is needed if the HCV viral level is undetectable >12 weeks after stopping therapy. For those with persistent infection (ie, a detectable viral level), our general approach to retreatment depends on how many weeks of the initial course they completed, the genotype, and the presence of cirrhosis. Overall, we have a low threshold to use a regimen for relapsed infection:

●For patients who completed more than four weeks of the initial antiviral course, have genotype 3 infection, or have advanced fibrosis or compensated cirrhosis, we suggest one of the treatment regimens preferred for relapsed infection, as outlined below. (See 'Relapse after sofosbuvir-velpatasvir (or other sofosbuvir-NS5A combination)' below and 'Relapse after glecaprevir-pibrentasvir' below.)

●For those who completed less than four weeks of the initial antiviral course, who do not have genotype 3 infection, and who have no cirrhosis, we suggest repeat treatment with one of the regimens preferred for initial therapy, as outlined elsewhere. (See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Our preferred regimens'.)

The ultimate decision on selecting a regimen for retreatment in such situations should be individualized. Repeating treatment with one of the regimens generally reserved for initial therapy could be useful for patients who have drug interactions that preclude use of a protease inhibitor (which is a component of regimens for relapsed infection). On the other hand, some patients may prefer to optimize the likelihood of response, even if that means using a regimen that includes a higher number of antiviral medications or has a longer duration, in which case we suggest a regimen for relapsed infection. In some cases, resistance testing can help determine whether patients who did not complete a full course can be retreated with a regimen for initial therapy, although this is not generally necessary. (See 'Limited role for resistance testing' above.)

Retreatment of certain patients with an initial therapy regimen is supported by limited data that demonstrate reasonably high SVR rates in patients retreated after short courses of investigational antiviral combinations. In a trial of 34 patients who had genotype 1 infection, early stage liver fibrosis, and relapse after a four- to six-week course of ledipasvir-sofosbuvir plus an investigational antiviral agent, 91 percent achieved SVR after retreatment with ledipasvir-sofosbuvir for 12 weeks [6]. Only one patient had virologic failure (relapse).

Because genotype 3 and cirrhosis have each been associated with lower SVR rates with certain regimens, we have a low threshold to treat patients who have either of these features with a regimen appropriate for relapse following an abbreviated initial antiviral course. Consulting with an expert in HCV management is useful when this decision is uncertain.

Relapse after sofosbuvir-velpatasvir (or other sofosbuvir-NS5A combination) — For patients with relapsed infection following sofosbuvir-velpatasvir (or ledipasvir-sofosbuvir), we suggest:

●Sofosbuvir-velpatasvir-voxilaprevir – Details on administration are discussed elsewhere (see 'Sofosbuvir-velpatasvir-voxilaprevir' below). Duration is as follows:

•For most patients, this regimen is given for 12 weeks.

•For patients with genotype 3 and compensated cirrhosis, we suggest extending the duration to 24 weeks or giving it with weight-based ribavirin for 12 weeks. If adherence was a major issue contributing to relapse, we generally try to avoid ribavirin, as that can exacerbate adherence difficulties. Dosing of ribavirin is discussed elsewhere. (See 'Weight-based ribavirin' below.)

Sofosbuvir-velpatasvir-voxilaprevir is highly effective in this setting [5,7,8]. In a trial that included 263 patients who had relapsed after a regimen containing an NS5A inhibitor (usually with sofosbuvir), the SVR rate after sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was 99 and 93 percent among those without and with cirrhosis, respectively [5]. Of the seven patients with virologic failure, all had cirrhosis, and four had genotype 3 infection. Thus, the regimen is extended or ribavirin is added in the setting of genotype 3 infection and compensated cirrhosis in an attempt to maximize SVR rates. For patients with compensated cirrhosis, seeking guidance from an expert is prudent, given the overall limited data in this population.

For patients who do not have genotype 3 infection, glecaprevir-pibrentasvir for 16 weeks is another potential option, although it does not offer a clear advantage over sofosbuvir-velpatasvir-voxilaprevir and is of longer duration [9-11]. In one study that evaluated this regimen among 49 patients without cirrhosis and 29 patients with compensated cirrhosis, all of whom had genotype 1 infection, the SVR rates were 94 and 97 percent, respectively [11].

Relapse after glecaprevir-pibrentasvir — For patients with relapsed infection following glecaprevir-pibrentasvir, we suggest:

●Sofosbuvir-velpatasvir-voxilaprevir – Details on administration are discussed elsewhere (see 'Sofosbuvir-velpatasvir-voxilaprevir' below). Duration is as follows:

•For patients without cirrhosis, this regimen is given for 12 weeks.

•For patients with compensated cirrhosis, we suggest extending the duration to 24 weeks or giving it with weight-based ribavirin for 12 weeks. If adherence was a major issue contributing to relapse, we generally try to avoid ribavirin, as that can exacerbate adherence difficulties. Dosing of ribavirin is discussed elsewhere. (See 'Weight-based ribavirin' below.)

Sofosbuvir-velpatasvir-voxilaprevir is highly effective in this setting. In a study of 31 patents (with genotypes 1a and 3 infection) who had relapsed after initial treatment with glecaprevir-pibrentasvir, retreatment with sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was associated with an SVR rate of 94 percent [12]. Although the addition of ribavirin or extending the course has not been systematically evaluated in this setting, we suggest it for patients with cirrhosis to optimize SVR rates based on indirect data with other regimens. For patients with compensated cirrhosis, seeking guidance from an expert is prudent, given the overall limited data in this population.

An alternative regimen is glecaprevir-pibrentasvir plus sofosbuvir plus weight-based ribavirin for 16 weeks. In a study of 23 patients, 96 percent achieved SVR with this combination of antivirals [13]. However, this regimen has a higher pill burden and payers may not provide coverage for it, making access challenging. Thus, we typically reserve it for patients who cannot take sofosbuvir-velpatasvir-voxilaprevir.

Relapse after sofosbuvir-velpatasvir-voxilaprevir — Patients who have had relapse following sofosbuvir-velpatasvir-voxilaprevir have generally had treatment failure with multiple antiviral regimens. Data on the management of such patients are limited to case reports or series [14-17].

Potential options include:

●Glecaprevir-pibrentasvir plus sofosbuvir plus weight-based ribavirin for 16 to 24 weeks; or

●Sofosbuvir-velpatasvir-voxilaprevir plus weight-based ribavirin for 24 weeks.

In a series of 40 patients with relapse following sofosbuvir-velpatasvir-voxilaprevir who were treated with various salvage regimens, including the two listed here, the overall SVR rate was 81 percent [14].

REGIMEN SELECTION FOR RELAPSE AFTER INTERFERON-BASED REGIMENS — The approach to patients with relapsed infection following treatment with peginterferon and ribavirin, with or without a protease inhibitor, regimen selection depends on the genotype.

Genotype 3 — For genotype 3-infected patients who have failed prior treatment with peginterferon and ribavirin, the preferred regimens include glecaprevir-pibrentasvir and sofosbuvir-velpatasvir-based regimens:

●Glecaprevir-pibrentasvir for 16 weeks – In a randomized trial of patients with genotype 3 infection who had failed peginterferon and ribavirin, SVR rates were 96 percent among the 44 patients without cirrhosis and the 47 patients with compensated cirrhosis [18]. Among those without cirrhosis, the SVR rate was higher than when given for only 12 weeks (91 percent).

●Sofosbuvir-velpatasvir-based regimens – Selecting among sofosbuvir-velpatasvir-based regimens depends on the presence of cirrhosis and the presence of the Y93H variant.

•For patients without cirrhosis who do not have a Y93H variant, sofosbuvir-velpatasvir is given for 12 weeks. Among 34 patients without cirrhosis who had failed peginterferon and ribavirin, sofosbuvir-velpatasvir for 12 weeks resulted in an SVR rate of 91 percent [19]. The presence of baseline NS5A resistance-associated substitutions (RASs; and particularly the Y93H variant) was associated with lower SVR rates.

•For patients who have either a Y93H variant or have compensated cirrhosis, we suggest sofosbuvir-velpatasvir-voxilaprevir for 12 weeks rather than sofosbuvir-velpatasvir. An alternative is to add weight-based ribavirin to sofosbuvir-velpatasvir for 12 weeks. Sofosbuvir-velpatasvir-voxilaprevir is highly effective for treatment-experienced patients [5]; adding ribavirin to sofosbuvir-velpatasvir has been associated with higher SVR rates in difficult-to-cure genotype 3-infected populations [20].

Administration of these regimens is discussed in detail elsewhere:

●(See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Glecaprevir-pibrentasvir'.)

●(See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Sofosbuvir-velpatasvir'.)

●(See 'Sofosbuvir-velpatasvir-voxilaprevir' below.)

Other genotypes — For patients who have genotype 1, 2, 4, 5, or 6 infection and relapsed after treatment with peginterferon and ribavirin, with or without a protease inhibitor, our preferred regimens include sofosbuvir-velpatasvir and glecaprevir-pibrentasvir:

●Sofosbuvir-velpatasvir – This regimen is given for 12 weeks, even in patients with compensated cirrhosis. SVR rates are approximately 98 to 99 percent [20,21].

●Glecaprevir-pibrentasvir – The duration of this regimen depends on the presence of cirrhosis and whether the patient also used a protease inhibitor (eg, simeprevir, telaprevir) with peginterferon and ribavirin.

•For patients without cirrhosis or protease inhibitor exposure, glecaprevir-pibrentasvir is given for eight weeks. SVR rates are approximately 99 percent [22-24].

•For patients with either cirrhosis or protease inhibitor exposure, glecaprevir-pibrentasvir is given for 12 weeks. SVR rates of 99 to 100 percent have been reported with this regimen among these patients [9,24]. A shorter course has not been evaluated in trials in these populations.

Administration of these regimens is discussed in detail elsewhere:

●(See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Sofosbuvir-velpatasvir'.)

●(See "Management of chronic hepatitis C virus infection: Initial antiviral therapy in adults", section on 'Glecaprevir-pibrentasvir'.)

SPECIAL PATIENT POPULATIONS

Patients with decompensated cirrhosis — Antiviral treatment should only be undertaken by or in close consultation with an expert in the management of patients with decompensated cirrhosis (eg, Child-Pugh class B or C, with ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage), preferably at a transplant center. The possibility of liver transplantation should be assessed for patients with decompensated cirrhosis or a MELD score greater than 10 prior to initiation of antiviral therapy.

For individuals who are transplant candidates, the timing of antiviral therapy depends on various factors, including the severity of disease and the expected wait time to transplant. These issues are discussed in detail elsewhere. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Deciding to treat before or after transplant'.)

If antiviral treatment is planned prior to transplant or for patients who are not transplant candidates, options are limited since certain antiviral agents (detailed below) are contraindicated in the setting of severe hepatic impairment.

Potential options may include sofosbuvir-velpatasvir or ledipasvir-sofosbuvir, each with ribavirin for a prolonged duration (eg, 24 weeks). However, there are very limited data informing retreatment of patients with decompensated cirrhosis and relapse following direct-acting antiviral therapy. All patients with decompensated cirrhosis who are undergoing HCV antiviral therapy should have frequent clinical and laboratory monitoring, including monitoring of liver synthetic function and hemoglobin (particularly if receiving ribavirin). 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'.)

Glecaprevir-pibrentasvir, elbasvir-grazoprevir, sofosbuvir-velpatasvir-voxilaprevir, and simeprevir are contraindicated in patients with Child-Pugh classes B and C cirrhosis because of increased drug levels in the setting of hepatic impairment. Although they are not available in the United States and of uncertain availability or utility elsewhere, ombitasvir-paritaprevir-ritonavir-based regimens are also contraindicated in patients with Child-Pugh classes B and C cirrhosis because of the risk of worsened hepatic decompensation.

Patients with renal impairment — The selection of HCV antiviral regimens for patients with renal disease is largely the same as that among patients without renal disease. Antiviral treatment in such patients is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)

Additional considerations for patients who are kidney transplant candidates or recipients, are also discussed elsewhere. (See "Hepatitis C infection in kidney transplant candidates and recipients".)

HIV-HCV coinfection — The selection of HCV antiviral regimens for patients with HIV and HCV coinfection is largely the same as that for patients without HIV infection, although potential interactions between antiretroviral agents and DAA agents must be taken into consideration. Treatment of HCV in patients with HIV is discussed in detail elsewhere. (See "Treatment of chronic hepatitis C virus infection in the patient with HIV".)

HCV following liver transplantation — Management of HCV infection in liver transplant recipients is discussed elsewhere. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Treatment approach for recipients of HCV-viremic donors' and "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Post-transplant antiviral therapy'.)

Pregnant individuals — The safety and efficacy of all HCV antiviral agents during pregnancy are unknown; thus, antiviral therapy of such patients should either be delayed until after delivery or administered within a clinical trial setting. (See "Vertical transmission of hepatitis C virus".)

ADMINISTRATION OF ANTIVIRAL AGENTS

Sofosbuvir-velpatasvir-voxilaprevir — Sofosbuvir-velpatasvir-voxilaprevir is a highly effective option for retreatment in certain patients. (See 'Regimen selection for relapse after DAA therapy' above.)

●Dose and administration – This is available as a fixed-dose combination of the NS5B inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor voxilaprevir. It is given once daily with food. We suggest that patients take it with a meal that contains a moderate amount of fat (eg, ≥11 g fat) to increase absorption.

Sofosbuvir-velpatasvir-voxilaprevir can be used in patients with any degree of renal impairment but should not be used in patients with decompensated cirrhosis (Child Pugh Class B or C).

●Adverse effects – Sofosbuvir-velpatasvir-voxilaprevir is well tolerated, with <1 percent of trial participants discontinuing a 12-week regimen for adverse events. The most common adverse events are headache, fatigue, diarrhea, and nausea [5].

●Drug interactions – Potential drug interactions should be evaluated prior to administration. Coadministration is contraindicated with rifampin and is not recommended with amiodarone, anticonvulsants, St. John's wort, certain antiretrovirals, and cyclosporine. Additionally, increased gastric pH levels decrease absorption of velpatasvir; thus, we recommend that patients use nonpharmacologic strategies only to manage their gastroesophageal reflux white taking sofosbuvir-velpatasvir-voxilaprevir and also counsel patients to avoid over-the-counter products that may contain stomach acid neutralizers. If they cannot forgo medications for acid reduction, we suggest famotidine 40 mg dosed simultaneously with sofosbuvir-velpatasvir-voxilaprevir or 12 hours later. Although the manufacturer recommendations allow for concurrent use of low-dose omeprazole dosed at least four hours after the sofosbuvir-velpatasvir-voxilaprevir dose, even with this adjustment, velpatasvir levels are reduced by 50 percent [25,26]. Thus, we favor avoiding proton pump inhibitors altogether to try to maximize the likelihood of response in patients who had not responded to prior treatment regimens.

For other specific drug interactions, refer to the drug interactions program included with UpToDate.

Additional details on dosing, adverse effects, and drug interactions for sofosbuvir-velpatasvir-voxilaprevir are discussed elsewhere. (See "Direct-acting antivirals for the treatment of hepatitis C virus infection", section on 'Sofosbuvir-velpatasvir-voxilaprevir'.)

Weight-based ribavirin — Ribavirin is sometimes added to certain antiviral regimens to improve the likelihood of sustained virologic response (SVR). (See 'Regimen selection for relapse after DAA therapy' above and 'Regimen selection for relapse after interferon-based regimens' above.)

When used for HCV treatment, ribavirin dosing is typically weight based, with a total daily dose of 1000 mg for those <75 kg and 1200 mg for those ≥75 kg, each divided into two daily doses. However, we generally start patients at a low dose (eg, 600 mg per day in divided doses), monitor tolerance and the hemoglobin level frequently (eg, every one to two weeks), and slowly increase, if tolerated, to the target dose.

The main adverse effect of ribavirin is hemolysis, which is clinically relevant mainly in patients with baseline anemia, kidney impairment, and coronary artery disease.

Ribavirin is teratogenic, so two effective forms of contraception should be used by all individuals of child-conceiving potential during and for six (for males) and nine (for females) months after treatment with ribavirin-containing regimens.

MONITORING DURING TREATMENT — Monitoring includes evaluation for rare adverse effects and adherence assessment throughout the treatment course. The latter is especially important during treatment for relapsed infection. Specifically, we check in with patients at one week on therapy then meet with them intermittently during the treatment course (either in person or virtually) to provide ongoing adherence support and ensure that they are not taking any medications that may interact with the antiviral regimen. One of the authors of this topic also checks HCV viral levels each month on treatment; a detectable viral level after week 4 suggests potential adherence or drug interaction issues and may warrant adjustment of the antiviral regimen. Such issues should be managed in consultation with an expert in HCV infection.

Aspects of monitoring during treatment are discussed in detail elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

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 (SVR). 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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Treatment for hepatitis C (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Benefits of HCV therapy – We recommend antiviral treatment for all patients with chronic HCV infection (Grade 1A). A sustained virologic response (SVR), or an undetectable HCV viral level 12 weeks after the completion of therapy, indicates effective cure of HCV infection. SVR has been associated with decreased mortality, decreased liver-related complications, and improved quality of life, regardless of liver disease stage. (See 'Treatment objective' above.)

●Evaluation of patients with relapse after treatment – Although contemporary antiviral regimens are highly effective, a small minority does not respond and has persistent or recurrent HCV viremia following the initial treatment course. In contrast to the limited evaluation needed prior to initial treatment, patients with relapse warrant more detailed assessment and monitoring to optimize the likelihood of cure with retreatment. (See 'Pretreatment evaluation' above.)

•Identifying and addressing potentially modifiable contributors to treatment failure (eg, adherence challenges or unappreciated drug interactions) are essential.

•We also assess fibrosis stage, if not recently done, and check a genotype (even if checked prior to initial therapy). Knowledge of the genotype may help distinguish relapse from reinfection in individuals with recurrent exposure, and in some cases (ie, with genotype 3) has treatment implications.

•Additional aspects of the pre-treatment evaluation are discussed elsewhere.

●Retreatment of relapse after DAA therapy – For patients with relapsed infection following direct-acting antiviral (DAA) therapy (ie, they did not achieve sustained virologic response [SVR] after an initial antiviral regimen), we suggest sofosbuvir-velpatasvir-voxilaprevir rather than other regimens (Grade 2B). This regimen results in SVR rates over 90 to 95 percent and is well tolerated. The most common adverse effects are mild headache, fatigue, diarrhea, and nausea. (See 'Relapse after sofosbuvir-velpatasvir (or other sofosbuvir-NS5A combination)' above and 'Relapse after glecaprevir-pibrentasvir' above.)

•For most patients, sofosbuvir-velpatasvir-voxilaprevir is given for 12 weeks.

•For patients who relapsed after sofosbuvir-velpatasvir or ledipasvir-sofosbuvir, have genotype 3 infection, and have compensated cirrhosis, we suggest giving sofosbuvir-velpatasvir-voxilaprevir either for 24 weeks or with ribavirin for 12 weeks (Grade 2C).

•For patients who relapsed after glecaprevir-pibrentasvir and have compensated cirrhosis, we suggest giving sofosbuvir-velpatasvir-voxilaprevir either for 24 weeks or with ribavirin for 12 weeks (Grade 2C).

●Retreatment when the diagnosis of relapse is uncertain – In patients with recurrent HCV viremia following an initial treatment course, relapse can sometimes be difficult to distinguish from reinfection or an insufficient, abbreviated course of therapy. When there is any uncertainty, we have a low threshold to treat as if they have relapsed infection (ie, with sofosbuvir-velpatasvir-voxilaprevir). However, for those who have clear reinfection (eg, a different genotype than in the initial infection) or for those who took less than four weeks of the initial antiviral regimen, have no cirrhosis, and have non-genotype 3 infection, a regimen used for initial therapy is reasonable. (See 'Distinguishing relapse from reinfection' above and 'Patients who did not finish a complete initial course' above.)

●Drug interactions with sofosbuvir-velpatasvir-voxilaprevir – Potential drug interactions should be evaluated prior to administration. Increased gastric pH levels decrease absorption of velpatasvir; thus, we avoid coadministration with proton pump inhibitors and other acid-reducing medications (including over-the-counter medications) when possible. (See 'Sofosbuvir-velpatasvir-voxilaprevir' above.)

●Monitoring – Monitoring includes evaluation for rare adverse effects and adherence assessment throughout the treatment course. The latter is especially important during treatment for relapsed infection. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

●Post-treatment follow-up – All patients should undergo HCV viral level testing at least 12 weeks after completing therapy to assess for treatment success. This and other aspects of follow-up are discussed in detail elsewhere. (See "Overview of the management of chronic hepatitis C virus infection", section on 'Follow-up after antiviral therapy'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Sanjiv Chopra, MD, MACP, who contributed to earlier versions of this topic review.