The treatment of hepatitis C should include a pre-treatment baseline evaluation, consideration of drug-drug interactions, evaluation of treatment response during and after therapy, and monitoring for safety. Although most currently recommended regimens do not include interferon or peginterferon, patients can develop side effects with direct-acting antivirals. A typical schedule for clinic visits related to a 12-week treatment course would consist of a baseline visit just prior to starting therapy, a follow-up visit at week 4 of therapy, an end-of-treatment visit, and a post-treatment visit 12 weeks after completing therapy. For longer courses of treatment, such as a 24-week treatment course, most clinicians would add one or more on-treatment visits. Patients with cirrhosis or other complicating conditions may require more frequent follow-up.
- Module 5 Overview
Treatment of Chronic Hepatitis C Infection
- 0%Lesson 1
Treatment of HCV Genotype 1Activities
- 1A.Core Concepts
- 1B.AASLD/IDSA Hepatitis C Guidance
- 1C.Initial Treatment of Chronic HCV Genotype 1
- 1D.Treatment of HCV Genotype 1 after Initial Treatment Failure
- 1E.Choices for Initial Treatment of Patients with Genotype 1a Chronic HCV
- Lesson 1 Quiz/CME/CNE
- 0%Lesson 2
Treatment of HCV Genotype 2Activities
- 2A.Core Concepts
- 2B.Treatment of Chronic HCV Genotype 2
- 2C.EASL 2015 HCV Treatment Recommendations
- Lesson 2 Quiz/CME/CNE
- 0%Lesson 3
Treatment of HCV Genotype 3Activities
- 3A.Core Concepts
- 3B.VA Treatment Considerations
- 3C.Treatment of Chronic HCV Genotype 3
- 3D.Choices for Initial Treatment of Patients with HCV Genotype 3
- Lesson 3 Quiz/CME/CNE
- 0%Lesson 4
Treatment of HCV Genotype 4Activities
- 4A.Core Concepts
- 4B.Hepatitis C Clinical Trials
- 4C.Treatment of Chronic HCV Genotype 4
- Lesson 4 Quiz/CME/CNE
- 0%Lesson 5
Treatment of HCV Genotype 5 or 6
Lesson 6. Monitoring During and After Treatment
- List the recommended monitoring for treatment efficacy and safety in patients receiving hepatitis C therapy.
- Summarize appropriate monitoring for patients after treatment for hepatitis C.
CNE/CME Continuing EducationThis lesson qualifies for 1 CME AMA PRA Category 1 Credit™ and 1 CNE contact hour. View CE Notices.
InstructionsTo complete this lesson you must work through all Lesson 6 Activities (listed below and on the left-hand navigation bar). After finishing the lesson activities, take the Lesson 6 Quiz. You can choose to obtain Continuing Medical Education (CME) or Continuing Nursing Education (CNE) credit at that point, but you must answer at least 80% of the questions correctly. After finishing the Lesson 6 Quiz, proceed to the next Lesson. After finishing all Module 5 lessons, you will be ready to take the Module 5 Self-Assessment.Last Updated: July 12th, 2016Table of Contents
Monitoring for Treatment Efficacy
Recommended Method for Monitoring of Treatment Efficacy: The optimal and standard approach to monitoring for treatment efficacy consists of repeated measurement of quantitative HCV RNA levels. Monitoring requires use of a highly sensitive quantitative HCV RNA assay, typically with a lower limit of quantification in the range of 15 to 25 IU/ml. In addition, to minimize interassay and interlaboratory variation, monitoring should utilize the same HCV RNA assay performed by the same laboratory. Three commercially available HCV RNA assays are widely used in the United States: Roche COBAS TaqMan Version 1.0, Roche COBAS TaqMan Version 2.0, and the Abbott RealTime HCV (ART) assay. The following definitions related to HCV RNA assay results are used in clinical practice and in research studies (Figure 1):
- Lower Limit of Quantification (LLOQ): This is the lowest HCV RNA concentration that the assay can accurately quantify by the assay. If HCV RNA is not quantifiable, the result is either HCV RNA detected but below the LLOQ or HCV RNA not detected. Note that the lower limit of quantification is not the same as the lower limit of detection.
- Limit of Detection (LOD): This value is the concentration of HCV RNA detectable at a rate of at least 95%. The ability of the assay to detect HCV RNA gradually decreases as the actual amount of HCV RNA in the sample approaches 0 IU/mL. The result below the limit of detection is referred to as undetectable.
- Target Detected (TD): The HCV RNA is detected.
- Target Not Detected (TND): The HCV RNA is not detected.
Recommended Scheduled HCV RNA Monitoring: For patients receiving hepatitis C therapy, the AASLD/IDSA guidance recommends obtaining a quantitative HCV RNA level at baseline, at 4 weeks after starting therapy and at 12 weeks after completing therapy; in addition, providers may consider obtaining HCV RNA levels at the end of treatment and 24 weeks after completing therapy (Figure 2). The European Association for the Study of the Liver (EASL) Clinical Practice Guidelines recommends obtaining a week 2 HCV RNA level as an early evaluation of adherence.
Approach to Patients with Detectable HCV RNA at Treatment Week 4: The role of week 4 HCV RNA testing with the use of DAA-based therapy is not completely clear at this time and recommendations will likely evolve as more data become available. The phase 3 trials of direct-acting antivirals demonstrated that nearly all non-cirrhotic patients achieved a week 4 viral level of undetectable or less than the LLOQ; cirrhotic patients may be more likely to have detectable HCV RNA at week 4. For patients who have low-level detectable HCV RNA at treatment week 4, the AASLD/IDSA guidance recommends performing a repeat quantitative HCV RNA level 2 weeks later (at treatment week 6) and if the HCV RNA has increased by more than 10-fold (1 log10 IU/mL) then HCV therapy should be stopped. Nevertheless, the significance of on-treatment persistent low-level viremia (that does not increase) is not known and there is no clear indication this represents lack of adherence or likelihood of virologic relapse. Indeed, recent data from Sidharthan and coworkers involving patients receiving DAA sofosbuvir-containing therapy has shown that low-level quantifiable HCV RNA levels at week 4 was not clinically useful in predicting SVR12; these findings contrast sharply with prior studies using interferon-based regimens. The AASLD/IDSA guidelines do not provide a recommendation regarding stopping or extending therapy in the setting of stable low-level viremia. In contrast with the AASLD/IDSA strategy, some experts do not routinely recheck the HCV RNA after a detectable level at week 4 in patients believed to have good adherence, since the vast majority of these patients go on to clear HCV. If, however, adherence is a concern, it is advised to recheck the HCV RNA in 2 weeks, and if there is a greater than 10-fold increase, then obtain expert consultation and consider stopping therapy.
Determining Sustained Virologic Response (SVR): The recommended testing to determine whether the patient has achieved an SVR is a quantitative HCV RNA level 12 weeks after completing therapy (Figure 3). An undetectable HCV RNA level 12 weeks after completing therapy is referred to as SVR12 and this generally translates into a long-term cure of HCV infection. Some experts will obtain an HCV RNA level 24 weeks after completing treatment in selected patients, such as those with cirrhosis. Research studies have utilized HCV RNA levels 4 weeks after completing therapy (SVR4), but the SVR4 is not considered as robust a marker for treatment response as an SVR12.
Monitoring for Safety During Treatment
Baseline Safety Laboratory Studies: The optimal and standard approach to monitoring for treatment safety depends on whether ribavirin and peginterferon are a component of the regimen. The following baseline safety laboratory studies are recommended in the AASLD/IDSA guidance:
- Complete blood count (CBC)
- International normalized ratio (INR)
- Hepatic function panel: albumin, total bilirubin, direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase
- Serum creatinine level (and calculated glomerular filtration rate)
- Thyroid stimulating hormone (TSH) if the patient will receive peginterferon
Safety Laboratory Studies at Week 4 of Therapy: For patients receiving hepatitis C therapy, the AASLD/IDSA guidance recommends obtaining the following safety laboratory studies 4 weeks after starting therapy:
- Complete blood count (CBC)
- Serum creatinine level (and calculated glomerular filtration rate)
- Hepatic function panel: albumin, total bilirubin, direct bilirubin, ALT, AST, and alkaline phosphatase
Management of Abnormal ALT at Week 4 of Therapy: For patients who have increases in ALT levels at week 4, the AASLD/IDSA guidance provides the recommendations outlined below. On October 22, 2015 the US FDA issued a Drug Safety Warning that treatment with ombitasvir-paritaprevir-ritonavir, with or without dasabuvir, can cause serious liver injury, mostly in patients with underlying advanced liver disease. In most of the reported cases, the liver injury occurred within 1 to 4 weeks of starting treatment. Until this recent announcement, the currently available DAAs had not associated with hepatotoxicity with the rare exception of paritaprevir-ritonavir-ombitasvir and dasabuvir when used in conjunction with medications containing ethinyl estradiol; this combination should not be used together.
- A 10-fold or Greater Increase in ALT Levels: Patients that have a 10-fold or greater increase in ALT levels, regardless of the presence of clinical symptoms, should have HCV therapy discontinued promptly and undergo close monitoring for liver toxicity.
- Symptomatic Increase in ALT Levels of Less than 10-Fold: If a patient has any increase in ALT levels less than 10-fold that is accompanied either by symptoms suggestive of acute hepatitis (weakness, nausea, vomiting, or jaundice) or increases in other hepatic function panel labs (bilirubin, alkaline phosphatase, or international ionized ratio), HCV therapy should promptly be discontinued and the patient should undergo close monitoring for liver toxicity. The guidelines do not specify what degree of change in bilirubin, alkaline phosphatase, or international ionized ratio would realistically be considered significant enough to warrant discontinuation of therapy. Most experts would use clinical judgment with this recommendation and not discontinue therapy with a very low level increase in ALT accompanied by a low-level increase in bilirubin or alkaline phosphatase.
- Asymptomatic Increases in ALT Levels Less than 10-Fold: Patients with an increase in ALT levels that is less than 10-fold, but without symptoms suggestive of acute hepatitis, should have close monitoring and repeat ALT levels checked at treatment week 6 and 8. If the ALT levels remain consistently elevated, discontinuation of therapy should be considered. Most experts in this situation would follow this general AASLD/IDSA recommendation but make a decision on a case-by-case basis, taking into account the degree of ALT elevation, the trend in ALT levels, and the presence or absence of underlying cirrhosis or acute hepatitis symptoms.
Monitoring After Receiving HCV Therapy
Approach to Monitoring After Receiving HCV Therapy: The approach to monitoring patients following completion of a course of HCV therapy depends entirely on the patient's response to therapy. Three main scenarios exist: (a) the patient achieved an SVR12, (b) the patient completed therapy but did not achieve an SVR12, or (c) the patient had an inadequate treatment course because of adherence problems, intolerance, or laboratory toxicity necessitating premature discontinuation of the treatment regimen.
Monitoring Patients who Achieved an SVR: Patients who have an undetectable HCV RNA at week 12 (or later) after completing HCV therapy are considered to have achieved an SVR. In a review by Welker of 44 studies involving more than 4,228 patients who achieved an SVR with an interferon-based regimen, 97% of patients maintained the SVR during the long-term follow-up period. Some experts will obtain an HCV RNA level 24 weeks after completing treatment in selected patients. In a more recent review by Manns, more than 99.2% of 1002 patients who achieved an SVR12 with interferon- or peginterferon-based therapy maintained undetectable HCV RNA levels for 5 years. Comparable data on the long-term durability of treatment response with all-oral DAA therapy is not yet available, but it is generally thought that SVR12 responses will represent sustained HCV clearance similar to that seen with interferon-based therapy. All patients who achieve an SVR should clearly understand they are not immune to HCV and can become reinfected with HCV. The AASLD/IDSA Guidance stratifies the follow-up for persons who achieve an SVR based on the degree of hepatic fibrosis and the risk of developing reinfection.
- Patients with Metavir Fibrosis (F0-F2): These patients do not need special monitoring or follow-up specifically for hepatitis C or liver care. This recommendation is based on data that show patients with SVR following hepatitis C treatment generally do not have further progression of HCV-related liver fibrosis.
- Patients with Advanced Fibrosis (F3-F4): Although fibrosis may improve in these patients, they are considered to have persistent risk, albeit lower than before achieving an SVR, for developing hepatocellular carcinoma. Accordingly, these patients should have surveillance for hepatocellular carcinoma (HCC) with hepatic ultrasound every 6 months. In addition, patients with cirrhosis (F4 fibrosis) should have a baseline upper endoscopy to screen for varices, unless this has previously been done. Patients identified with varices should receive appropriate management and follow-up.
- Patients with Ongoing Risk of HCV Reinfection: Regardless of the degree of hepatic fibrosis, all patients with ongoing risk for acquiring HCV should have periodic assessment for HCV reinfection and counseling on prevention of reinfection. Obtaining HCV antibody does not provide useful information in these individuals with known prior HCV infection since they are highly likely to remain antibody positive. Thus, reassessment should consist of a quantitative HCV RNA level. In addition, for these patients, any flare in liver enzyme tests should prompt evaluation for reinfection with a quantitative HCV RNA level.
- Patients with Persistently Abnormal Liver Tests: Any patient that develops persistently elevated liver tests should undergo evaluation for possible other causes of liver disease, such as alcohol use, iron overload, or fatty liver disease.
Monitoring for Patients who do not Achieve SVR: The AASLD/IDSA guidance recommends the following for patients who did not achieve an SVR with HCV therapy.
- All Patients: For all patients who did not achieve an SVR, follow-up laboratory testing should occur every 6 to 12 months with a hepatic function panel, complete blood count, and international normalized ratio. In addition, these patients should have periodic reevaluation for retreatment, especially as new options become available. It is important these patients receive counseling for alcohol abstinence (or safe use) and avoidance of hepatoxic medications.
- Patients with Advanced Fibrosis (F3-F4): These patients should have surveillance for hepatocellular carcinoma with hepatic ultrasound every 6 months. In addition, patients with cirrhosis (F4 fibrosis) should have a baseline upper endoscopy to screen for varices, unless this has previously been done. Patients identified with varices should receive appropriate management and follow-up.
- Patients undergoing treatment for hepatitis C need systematic monitoring before, during, and after therapy.
- Quantitative HCV RNA is the preferred test for monitoring response to therapy. Patients should have a quantitative HCV RNA obtained at baseline prior to starting therapy, 4 weeks after starting treatment, and 12 weeks after completion of treatment.
- The significance of low-level detectable HCV RNA values at treatment week 4 remains unclear; additional follow-up HCV RNA testing at treatment week 6 should be considered, especially if adherence or virologic breakthrough is a concern.
- An undetectable HCV RNA at 12 weeks after treatment is considered a sustained virologic response and translates into cure for nearly all patients.
- Monitoring safety laboratory labs should be obtained at baseline and after 4 weeks of treatment. Further safety laboratory monitoring may be required in circumstances with abnormal safety laboratory studies.
- Patients with a 10-fold or greater increase in ALT levels at treatment week 4 should have therapy promptly discontinued with close follow-up. In most circumstances, patients with lower-level increases in ALT and symptoms suggestive of acute hepatitis should discontinue therapy.
- Monitoring of patients after treatment depends on whether the patient achieved an SVR12 and whether they have advanced fibrosis (Metavir stage 3 or 4).
- Patients with an SVR12 should receive education and counseling on the risk of becoming reinfected with HCV.
- Patients with advanced fibrosis require long-term surveillance for HCC, regardless of whether they achieve an SVR12.
- Patients who do not achieve an SVR12 should continue to have regular follow-up and periodic reassessment for treatment, especially when additional new DAA medications become available.
- AASLD/IDSA. Recommendations for testing, management, and treating hepatitis C. Monitoring patients who are starting hepatitis C treatment, are on treatment, or have completed therapy.
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- Cloherty G, Cohen D, Sarrazin C, et al. HCV RNA assay sensitivity impacts the management of patients treated with direct-acting antivirals. Antivir Ther. 2014;20:177-83.
- Cobb B, Pockros PJ, Vilchez RA, Vierling JM. HCV RNA viral load assessments in the era of direct-acting antivirals. Am J Gastroenterol. 2013;108:471-5.
- European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2015.[EASL] -
- Harrington PR, Deming DJ, Komatsu TE, Naeger LK. Hepatitis C virus RNA levels during interferon-free combination direct-acting antiviral treatment in registrational trials. Clin Infect Dis. 2015;61:666-7.
- Manns MP, Pockros PJ, Norkrans G, et al. Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin. J Viral Hepat. 2013;20:524-9.
- Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158:329-37.
- Sarrazin C, Shiffman ML, Hadziyannis SJ, et al. Definition of rapid virologic response with a highly sensitive real-time PCR-based HCV RNA assay in peginterferon alfa-2a plus ribavirin response-guided therapy. J Hepatol. 2010;52:832-8.
- Sidharthan S, Kohli A, Sims Z, et al. Utility of hepatitis C viral load monitoring on direct-acting antiviral therapy. Clin Infect Dis. 2015;60:1743-51.
- Steinebrunner N, Sprinzl MF, Zimmermann T, et al. Early virological response may predict treatment response in sofosbuvir-based combination therapy of chronic hepatitis c in a multi-center "real-life" cohort. BMC Gastroenterol. 2015;15:97.
- Strassl R, Rutter K, Stättermayer AF, et al. Real-Time PCR Assays for the Quantification of HCV RNA: Concordance, Discrepancies and Implications for Response Guided Therapy. PLoS One. 2015;10:e0135963.
- Welker MW, Zeuzem S. Occult hepatitis C: how convincing are the current data? Hepatology. 2009;49:665-75.
- Yoshida EM, Sulkowski MS, Gane EJ, et al. Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus. Hepatology. 2014;61:41-5.
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- HCV Medications
- Daclatasvir (Daklinza)
- Elbasvir-Grazoprevir (Zepatier)
- Ledipasvir-Sofosbuvir (Harvoni)
- Ombitasvir-Paritaprevir-Ritonavir (Technivie)
- Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak)
- Peginterferon alfa-2a (Pegasys)
- Peginterferon alfa-2b (PegIntron)
- Ribavirin (Copegus, Rebetol, Ribasphere)
- Simeprevir (Olysio)
- Sofosbuvir (Sovaldi)
- Sofosbuvir-Velpatasvir (Epclusa)
- Boceprevir (Victrelis)
- Telaprevir (Incivek)
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- Evaluation, Staging, and Monitoring of Chronic Hepatitis C
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- Evaluation and Preparation for Hepatitis C Treatment
- Treatment of Chronic Hepatitis C Infection
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