Lesson 1. Simplified HCV Treatment for All HCV Genotypes

The advent of direct-acting antiviral (DAA) therapy has revolutionized the landscape of hepatitis C virus (HCV) therapy, allowing for shorter, safer, and more effective treatment of chronic HCV. This success has led to a paradigm shift in HCV treatment, with national and international guidelines calling for the treatment of all adults with HCV, regardless of fibrosis stage or active substance use.[1,2]

Owing to the success of DAA therapy, in 2016, the World Health Organization (WHO) released strategic targets to help achieve the elimination of viral hepatitis by 2030.[3] In addition, in 2017, the National Academies of Science, Engineering, and Medicine similarly released a strategy to eliminate viral hepatitis in the United States, calling for a 90% reduction in incident cases of HCV by 2030.[4] However, achieving these ambitious targets is predicated on expanding the availability of HCV treatment, a process that can be facilitated by simplified care pathways and treatment algorithms.

This lesson will review the hepatitis C simplified treatment approach for treatment-naïve adults (without cirrhosis or with compensated cirrhosis) based on guidance from the American Association for the Study of the Liver (AASLD) and Infectious Disease Society of America (IDSA).[5,6,7] As outlined in further detail below, the simplified treatment approach generated by the AASLD-IDSA HCV Guidance applies to most patients with chronic HCV, and it can help to streamline the pretreatment evaluation, treatment choices, and monitoring during and after treatment.[5,6,7]

Initial Assessment for HCV Treatment

The AASLD-IDSA HCV Guidance recommends treatment for all persons with chronic HCV, except for individuals who have a short (e.g., less than 12 months) life expectancy.[1] Therefore, all persons diagnosed with chronic HCV should be considered candidates for HCV treatment. Further, all persons with chronic HCV should be evaluated as potential candidates for the simplified treatment approach. As outlined below, it is important to assess liver fibrosis as part of the initial screening process. From a clinical standpoint, we have outlined the practical general flow of evaluating a person with chronic HCV who may be a candidate for the simplified treatment algorithm: this initial assessment should include initial laboratory studies, evaluation of fibrosis status, and screening for the simplified treatment criteria. All individuals with cirrhosis should have further evaluation for evidence of hepatic decompensation. Once a person has been determined to meet the criteria for the simplified treatment approach, they can be stratified into the evaluation and treatment categories for either (1) persons without cirrhosis or (2) persons with compensated cirrhosis.

Simplified Treatment Approach

The simplified treatment guidance primarily applies to adults with chronic HCV who are treatment naïve, including persons without cirrhosis and those with compensated cirrhosis.[5,6,7] Persons with decompensated cirrhosis are not eligible for the simplified treatment approach.[7] The simplified treatment approach utilizes the pangenotypic regimens glecaprevir-pibrentasvir and sofosbuvir-velpatasvir. Prior treatment experience excludes use of the simplified treatment approach because glecaprevir-pibrentasvir and sofosbuvir-velpatasvir are not uniformly appropriate for treatment-experienced patients.[7,8] Clinicians should follow the AASLD/IDSA guidance for treatment-experienced individuals, which is subdivided by the type of prior treatment.[8] Similarly, the simplified treatment guidelines are not intended for patients with chronic hepatitis B virus (HBV) coinfection due to the potential for HBV reactivation during treatment.[7,9] Further, the simplified algorithm should not be used to guide HCV treatment in pregnant people given limited data regarding use of DAAs in pregnancy.[7] Finally, any patient with known or suspected hepatocellular carcinoma (HCC) and those with a history of liver transplantation should not be treated under the simplified algorithm.[7] Patients with HCC have lower sustained virologic response (SVR12) rates when compared with patients without HCC, and they require additional evaluation by a liver tumor specialist prior to undergoing treatment.[10] Similarly, patients with a history of liver transplantation require careful evaluation for drug interactions that may impact the pharmacokinetics of DAAs and common post-transplant immunosuppressant medications.[11]

Authors Note: The above table was generated from several resources from the AASLD-IDSA HCV Guidance.[5,6,7,12] In this table, we have clarified which criteria can be used to determine cirrhosis status and which criteria are used to distinguish compensated cirrhosis or decompensated cirrhosis. See the Fibrosis-4 (FIB-4) and Child-Turcotte-Pugh (CTP) calculators on this website.

Assessing Liver Fibrosis Status

For all persons who have been diagnosed with HCV and are considering HCV treatment, it is essential to evaluate liver fibrosis status. We recommend evaluating liver fibrosis status as soon as possible after HCV diagnosis. For treatment-naïve adults under consideration for the simplified treatment approach, determining liver fibrosis status is extremely important to perform for the following four reasons:

1. Persons identified with cirrhosis need subsequent evaluation to determine whether they have compensated or decompensated cirrhosis, since persons with decompensated cirrhosis are not eligible for the simplified treatment approach, and they need a prompt referral to a liver specialist for expert management.
2. Once cirrhosis status is determined, the treatment-naïve patient with chronic HCV can be stratified into one of the simplified treatment algorithm categories: persons without cirrhosis or persons with compensated cirrhosis. The simplified treatment approach has a slightly different algorithm for persons without cirrhosis compared to those with compensated cirrhosis.
3. All persons identified with cirrhosis will need a liver ultrasound examination performed within 6 months prior to treatment to evaluate for hepatocellular carcinoma, as persons with hepatocellular carcinoma are not eligible for the simplified treatment approach and they need a referral to a liver cancer specialist.
4. All persons identified with cirrhosis need long-term, regular screening for hepatocellular carcinoma, typically every 6-month liver ultrasound, with or without alfa-fetoprotein.

For the purpose of the simplified treatment algorithm, the FIB-4 can be used to identify patients with or without cirrhosis. This simple, non-invasive test utilizes the patient’s age, aspartate aminotransferase (AST) level, alanine aminotransferase (ALT) level, and platelet count to calculate a score that is used to predict the degree of fibrosis. In clinical studies, a lower cutoff value of 1.45 (FIB-4 score <1.45) has been shown to have a negative predictive value of 90% for advanced fibrosis, while an upper cutoff value of 3.25 (FIB-4 score >3.25) has been shown to be 97% specific for advanced fibrosis with a positive predictive value of 65%. Patients with a FIB-4 score of >3.25 should be considered to have cirrhosis and follow the simplified treatment algorithm outlined in this section.[13] In addition, the AASLD-IDSA HCV Guidance provides additional methods, even if they were previously performed, that can be used to establish a presumptive diagnosis of cirrhosis:[5,6,7]

• FibroScan indicates liver stiffness with a score greater than 12.5 kPa
• Noninvasive serologic tests above proprietary cutoffs indicating cirrhosis (e.g., FibroSure, Enhanced Liver Fibrosis Test)
• Evidence of cirrhosis on imaging (e.g., liver nodularity and/or splenomegaly) or a platelet count less than 150,000/mm³, etc.)
• Prior liver biopsy showing cirrhosis

Evaluation for Decompensated Cirrhosis

All persons identified with cirrhosis should have a clinical and laboratory evaluation to determine whether the cirrhosis is compensated or decompensated. In the setting of presumptive or confirmed cirrhosis (or advanced fibrosis), clinicians should calculate a Child-Turcotte-Pugh (CTP) score. See the CTP Calculator on this website. This score, which is a proxy of overall liver function, takes into consideration both laboratory values (bilirubin, albumin, and international ionized ratio [INR]) and clinical manifestations (encephalopathy and ascites). A CTP score of 7 or greater (class B or C) is used to identify patients with decompensated cirrhosis.[6,14] Although studies indicate that most patients with decompensated cirrhosis experience improvement in clinical and laboratory markers of liver disease following treatment with DAAs, they remain at high risk for liver-related death and may progress to need transplantation regardless of HCV treatment.[15,16] Furthermore, DAA regimens containing a protease inhibitor as shown in bold (e.g., glecaprevir-pibrentasvir, sofosbuvir-velpatasvir-voxilaprevir, elbasvir-grazoprevir) are not recommended for use in patients with decompensated cirrhosis, because of limited data and the potential risk of causing hepatic decompensation.[17,18] As such, patients identified to have decompensated cirrhosis are not eligible for the simplified treatment approach, and they should be managed by a hepatologist (or another health professional who has expertise in liver disease), ideally at a liver transplantation center.[19]

As part of the initial assessment to determine eligibility for the simplified treatment algorithm, most pretreatment laboratory studies have already been conducted. Nevertheless, it is important to ensure all pretreatment laboratory studies and recommended education have been completed and reviewed prior to initiation of treatment. In addition, individuals who qualify for the simplified treatment algorithm should have a comprehensive medication reconciliation performed, which includes a review of over-the-counter medications.[5,12] This medication review serves to identify potential drug-drug interactions with commonly used DAA regimens. Resources to screen for drug interactions are available online, including in the Monitoring Section on the AASLD/IDSA guidance website and the University of Liverpool Hep Drug Interactions website, a resource that can also be downloaded as an app on mobile devices. The necessary pretreatment laboratory studies for persons without cirrhosis, as recommended in the AASLD-IDSA HCV Guidance, are listed in the table below.[5]

Authors Notes:

1. As noted in the table above, the AASLD/IDSA recommends checking hepatitis B surface antigen. In 2023, the Centers for Disease Control and Prevention (CDC) issued updated hepatitis B screening recommendations that included the recommendation that when screening, the following three tests should be ordered: hepatitis B surface antigen HBsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc).[20]

Routine genotype assessment is not part of the simplified HCV treatment algorithm for patients without cirrhosis, and as such, the AASLD-IDSA HCV Guidance recommends the following two pangenotypic regimens for persons without cirrhosis who have met eligibility for the simplified treatment approach.[5,7]

The glecaprevir-pibrentasvir and sofosbuvir-velpatasvir regimens have proven efficacy in treatment-naïve patients without cirrhosis, regardless of genotype. Below is a brief summary of the main registration trials of glecaprevir-pibrentasvir and sofosbuvir-velpatasvir in treatment-naïve patients without cirrhosis.

Glecaprevir-Pibrentasvir

• ENDURANCE-1: This phase 3, single-arm open-label trial evaluated the safety and efficacy of 8 versus 12 weeks of glecaprevir-pibrentasvir in 703 genotype 1 patients without cirrhosis, 62% of whom were treatment naïve.[21] Among the 336 patients enrolled in the 8-week arm, 99.1% achieved an SVR12, compared with 99.7% of the 334 patients enrolled in the 12-week arm.[21]
• SURVEYOR-II (Part 4): This phase-3, single-arm, open-label trial evaluated the safety and efficacy of 8 weeks of glecaprevir-pibrentasvir in 203 adults without cirrhosis and with genotype 2, 4, 5, or 6.[22] In the intention-to-treat analysis, the overall SVR12 rate was 96% across all genotypes.[22]
• ENDURANCE-3: This phase-3, randomized trial compared the safety and efficacy of 8 or 12 weeks of glecaprevir-pibrentasvir versus 12 weeks of sofosbuvir and daclatasvir in treatment-naïve adults without cirrhosis and with HCV genotype 3.[21] In total, 157 people were assigned to 8 weeks of glecaprevir-pibrentasvir, of whom 95% achieved an SVR12.[21] Similar results were observed in the 12-week arm.[21]

Sofosbuvir-Velpatasvir

• ASTRAL-1: This phase-3 trial randomized treatment-naïve and treatment-experienced adults with hepatitis C genotypes 1, 2, 4, 5, or 6 to receive 12 weeks of sofosbuvir-velpatasvir versus placebo.[23] Among the 624 people who received sofosbuvir-velpatasvir, 99% achieved an SVR12.[23]
• ASTRAL-3: This phase-3 randomized, open-label trial compared sofosbuvir-velpatasvir for 12 weeks versus sofosbuvir plus ribavirin for 24 weeks in adults with genotype 3.[24] Among the 206 treatment-naïve participants, 97% achieved an SVR12, which was significantly better than the 87% of treatment-naïve patients who received sofosbuvir plus ribavirin.[24]
• MINMON (ACTGA5360): This international phase 4 open-label, single-arm trial used a simplified treatment approach to provide a 12-week course of sofosbuvir-velpatasvir for 399 treatment-naïve adults with chronic HCV.[25] This trial allowed persons with HIV and/or compensated cirrhosis to participate; 42% of those enrolled had HIV and 9% had compensated cirrhosis. In this trial, the key elements of the simplified approach were: cirrhosis was determined by FIB-4, no pretreatment genotyping was performed, and the full course of sofosbuvir-velpatasvir was dispensed upon study entry, no scheduled on-treatment labs or in-person visits were performed, and investigators had remote contact (e.g., phone call) with participants at week 4 and week 22, with SVR12 labs being drawn at week 24.[25] Overall, 95% of study participants were cured of HCV, including 95% with HCV monoinfection and 95% with HCV and HIV coinfection.[25] Among the participants without cirrhosis, 96% were cured.[25] 

Monitoring Patients without Cirrhosis While On Treatment

Limited on-treatment monitoring is needed for treatment-naïve, noncirrhotic patients while on DAA therapy. Testing of HCV RNA level as well as hepatic enzymes/function is not necessary while on treatment as these results have not been shown to change management in patients without cirrhosis.[5] Treatment of HCV with DAAs has been shown to improve glycemic control in patients with chronic HCV, and, thus, patients undergoing treatment with DAAs who are concomitantly taking medications for diabetes should be informed about the potential for symptomatic hypoglycemia, and monitoring for hypoglycemia is recommended.[5,26] Although neither glecaprevir-pibrentasvir nor sofosbuvir-velpatasvir is likely to affect the pharmacokinetics of warfarin, close monitoring of INR is recommended for patients on warfarin therapy, given that it may change as the result of improved liver function.[27,28]

Post-Treatment Assessment of Cure in Patients without Cirrhosis

A follow-up HCV RNA level and repeat liver function testing are recommended 12 weeks following the completion of therapy to assess for cure and ongoing evidence of liver inflammation, respectively.[5,7] If the HCV RNA level is undetectable 12 or more weeks following the completion of therapy, this is considered a sustained virologic response or cure. If transaminase levels remain elevated despite the achievement of an SVR, further investigation is warranted to assess for other causes of liver disease.[5,7]

Monitoring Post-Treatment Patients who Achieve VIrologic Cure

Patients without cirrhosis who achieve a virologic cure do not require any screening or monitoring for hepatocellular carcinoma.[7,29] Patients should, however, be counseled that they are not immune to HCV following successful treatment and are susceptible to reinfection.[5,7] Patients with ongoing risk factors (e.g., people who inject drugs, men who have sex with men and engage in condomless anal intercourse) should be screened annually for reinfection using HCV RNA testing.[7,30]

Monitoring Post-Treatment Patients who Do Not Achieve Virologic Cure

If initial treatment fails to achieve a virologic cure, patients should be referred to a specialist who can evaluate them for repeat treatment.[7] In the setting of prior treatment experience, patients are not eligible for the simplified treatment algorithm, and the treatment plan should follow the AASLD-IDSA HCV Guidance for repeat treatment.[8] While a patient is awaiting repeat treatment, a CBC, hepatic function panel, and INR should be obtained every 6 to 12 months.[5,7]

As part of the initial assessment to determine eligibility for the simplified treatment algorithm, most pretreatment laboratory studies have already been conducted. Nevertheless, it is important to ensure all pretreatment laboratory studies and recommended education have been completed and reviewed prior to initiation of treatment. In addition, individuals who qualify for the simplified treatment algorithm should have a comprehensive medication reconciliation performed, which includes a review of over-the-counter medications.[6,12] This medication review serves to identify potential drug-drug interactions with commonly used DAA regimens. Resources to screen for drug-drug interactions are available online, including in the Monitoring Section on the AASLD/IDSA guidance website and the University of Liverpool Hep Drug Interactions website, a resource that can also be downloaded as an app on mobile devices. Note that for patients with compensated cirrhosis, a baseline HCV genotype is recommended if considering the use of sofosbuvir-velpatasvir, as resistance associated substitutions (RAS) can adversely impact SVR12 rates among genotype 3 patients with compensated cirrhosis.[24,31,32] The necessary pretreatment laboratory studies for persons without cirrhosis, as recommended in the AASLD-IDSA HCV Guidance, are listed in the table below.[5] 

Authors Notes:

1. For patients with cirrhosis, clinicians should calculate a Child-Turcotte-Pugh (CPT) score, which is the same as a Child’s Pugh score (see the CTP calculator on this website).[14] In the recommendations listed above in the table, the CTP calculation requires first obtaining several items listed later in table (total bilurubin, albumin, and INR). Although studies indicate that most patients with decompensated cirrhosis experience improvement in clinical and laboratory markers of liver disease following treatment with DAAs, they remain at high risk for liver-related death, and may progress to need transplantation regardless of HCV treatment.[15,16] Furthermore, DAA regimens containing a protease inhibitor (e.g. glecaprevir-pibrentasvir, sofosbuvir-velpatasvir-voxilaprevir, elbasvir-grazoprevir) are not recommended for use in patients with decompensated cirrhosis, owing to the potential risk of hepatic decompensation and overall limited data.[17,18] As such, patients identified to have decompensated cirrhosis should not be treated using the simplified algorithm and should be managed by a liver specialist and/or liver transplant center.[6,19]
2. As noted in the table above, the AASLD/IDSA recommended screening for hepatitis B is to check hepatitis B surface antigen. In 2023, the Centers for Disease Control and Prevention (CDC) issued updated hepatitis B screening recommendations that included the recommendation that when screening, hepatitis B testing should consist of the following three tests: hepatitis B surface antigen HBsAg), antibody to hepatitis B surface antigen (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc).[20]

The AASLD-IDSA HCV Guidance recommends the following two pangenotypic regimens for persons with compensated cirrhosis who have met eligibility for the simplified treatment approach: glecaprevir-pibrentasvir or sofosbuvir-velpatasvir.[6,7] If sofosbuvir-velpatasvir is planned for the treatment of a patient with compensated cirrhosis, an HCV genotype should be performed. If HCV genotype 3 is identified, then baseline resistance-associated substitution (RAS) testing is recommended. If the patient has compensated cirrhosis, HCV genotype 3 HCV, and a baseline Y93H mutation is present, sofosbuvir-velpatasvir should not be used, due to evidence of decreased efficacy in this specific setting.[6,24] If baseline NS5A resistance-associated substitution (RAS) testing is not sent or not available, then glecaprevir-pibrentasvir should be used.[6]

Both glecaprevir-pibrentasvir and sofosbuvir-velpatasvir have proven efficacy in treatment-naïve patients with cirrhosis. The following is a brief summary of the main registration trials of glecaprevir-pibrentasvir and sofosbuvir-velpatasvir in treatment-naïve patients with compensated cirrhosis.

Glecaprevir-Pibrentasvir

• EXPEDITION-8: This was a single-arm, multicenter, phase 3b trial evaluating the efficacy of glecaprevir-pibrentasvir for 8 weeks in treatment-naïve participants with compensated cirrhosis and genotypes 1-6.[33] Among the 343 people included in this trial, 97.7% achieved an SVR12 in the per protocol analysis.[33]

Sofosbuvir-Velpatasvir

• ASTRAL-1: This was a randomized, placebo-controlled, phase 3 trial using a fixed-dose combination of sofosbuvir-velpatasvir for 12 weeks in treatment-naïve and treatment-experienced patients with genotypes 1, 2, 4, 5, or 6.[23] Both patients without cirrhosis and those with compensated cirrhosis were included. Ninety-nine percent of patients with compensated cirrhosis achieved an SVR12, including 99% of those with baseline NS5A RASs.[23]
• ASTRAL-3: This randomized, placebo-controlled, open-label, phase 3 trial compared sofosbuvir-velpatasvir for 12 weeks to sofosbuvir plus ribavirin for 24 weeks in genotype 3 patients with and without compensated cirrhosis.[24] Ninety-three percent of treatment-naïve patients with compensated cirrhosis achieved an SVR12 in the sofosbuvir-velpatasvir arm, in comparison to 73% in the sofosbuvir plus ribavirin arm.[24] Among those who received sofosbuvir-velpatasvir and had baseline NS5A RASs, 88% achieved an SVR12, compared with 97% of those without baseline substitutions.[24]
• POLARIS-3 This open-label, randomized, phase 3 trial compared the efficacy of sofosbuvir-velpatasvir-voxilaprevir for 8 weeks versus sofosbuvir-velpatasvir for 12 weeks in patients with compensated cirrhosis and genotype 3.[34] Among treatment-naïve patients receiving sofosbuvir-velpatasvir, 99% achieved an SVR12. Four patients in the sofosbuvir-velpatasvir arm had a baseline Y93H mutation, all of whom achieved an SVR12.[34]
• Sofosbuvir-Velpatasvir in Patients with Compensated Cirrhosis and HCV Genotype 3 (Spain): This was a phase 2 trial of sofosbuvir-velpatasvir for 12 weeks versus sofosbuvir-velpatasvir plus ribavirin for 12 weeks in 204 patients with genotype 3 HCV and compensated cirrhosis.[31] Among the patients who received 12 weeks of sofosbuvir-velpatasvir, the SVR12 rate was 91%; participants who received sofosbuvir-velpatasvir and ribavirin had an SVR12 rate of 96%.[31] Among participants in the sofosbuvir-velpatasvir arm, 19 had NS5A RASs, 16 (84%) achieved an SVR12.[31]

Monitoring Patients with Compensated Cirrhosis While On Treatment

Due to the rare but potential risk for hepatic decompensation among patients with compensated cirrhosis on DAA therapy,[35] the AASLD/IDSA guidelines recommend providers consider monitoring for liver injury during treatment.[6] Many experts recommend monitoring a hepatic function panel monthly in patients with compensated cirrhosis who are on DAA therapy, with referral to a specialist if patients develop jaundice, ascites, encephalopathy, significant liver laboratory abnormalities, or other signs and symptoms of hepatic decompensation. Treatment with DAAs has been shown to improve glycemic control in patients with chronic HCV, and patients taking any medication for diabetes should be informed about the potential for symptomatic hypoglycemia, and monitoring of blood sugars is recommended.[6,26] Although neither glecaprevir-pibrentasvir nor sofosbuvir-velpatasvir is likely to affect the pharmacokinetics of warfarin, close monitoring of INR is recommended for patients on warfarin therapy, given that it may change as the result of improved liver function.[]

Post-Treatment Assessment of Cure in Patients with Compensated Cirrhosis

A follow-up HCV RNA level and liver function testing are recommended 12 weeks following the completion of therapy to assess for cure and ongoing evidence of liver inflammation, respectively. If the HCV RNA level is undetectable 12 or more weeks following the completion of therapy, this is considered a sustained virologic response or cure. If transaminase levels remain elevated despite the achievement of an SVR, further investigation is warranted to assess for other causes of liver disease.[6]

Monitoring After Achieving Virologic Cure (SVR)

Patients with cirrhosis require ongoing monitoring for hepatocellular carcinoma, even after achieving an SVR12.[29] This is done via a hepatic ultrasound every 6 months, with or without an alpha-fetoprotein level, in accordance with AASLD guidelines on screening for hepatocellular carcinoma.[29] Patients should also be counseled that they are not immune to HCV following successful treatment and are susceptible to reinfection. Individuals with ongoing risk factors (e.g., people who inject drugs, men who have sex with men and engage in condomless anal intercourse) should be screened annually for reinfection using HCV RNA.[30]

Monitoring Post-Treatment Patients who Do Not Achieve VIrologic Cure

If initial treatment fails to achieve a virologic cure, patients should be evaluated for repeat treatment. In the setting of prior treatment experience, patients with compensated cirrhosis are not eligible for the simplified treatment algorithm, and patients should be evaluated by a specialist in accordance with AASLD/IDSA guidance.[6] Similarly, as mentioned above, patients with cirrhosis should undergo ultrasound surveillance for hepatocellular carcinoma every six months, with or without the addition of an alpha-fetoprotein level.[29] This surveillance is done in all patients with advanced fibrosis, regardless of SVR12. While a patient is awaiting repeat treatment, a CBC, hepatic function panel, and INR should be obtained every 6 to 12 months.

Incomplete adherence to DAAs is relatively common among persons receiving treatment for HCV and has the potential to impact SVR12 rates.[37,38] Although short periods of nonadherence (e.g., 1-2 days) are very unlikely to affect treatment responses, longer periods of nonadherence can lead to virologic failure.[39,40]

AASLD/IDSA Recommendations for Management of Treatment Interruptions

Based on a review of the literature and expert consensus, the AASLD-IDSA HCV Guidance has addressed this important issue and developed recommendations for the management of nonadherence events, which considers the duration and timing of nonadherence.[7] This guidance is specific to whether the interruption occurred before the person received 28 days of DAA therapy or whether it occurred after they had received at least 28 days of DAA therapy.[7] In addition, this guidance is only applicable to DAA treatment-naïve individuals and is intended to reflect recommendations for management of nonadherence events in patients who qualify for the AASLD/IDSA simplified treatment algorithms (e.g., simplified HCV treatment for treatment-naïve individuals without cirrhosis and with compensated cirrhosis) who are receiving glecaprevir-pibrentasvir or sofosbuvir-velpatasvir.[7] Management of incomplete adherence in patients who fall outside of this guidance should be done in consultation with an HCV specialist. The following table summarizes the 2023 AASLD HCC Guidance for the management of treatment interruptions in persons while receiving glecaprevir-pibrentasvir or sofosbuvir-velpatasvir in the simplified treatment approach.[7]

• The AASLD/IDSA simplified HCV treatment algorithm can help streamline treatment initiation and on-treatment monitoring in select populations of treatment-naïve individuals.
• For the purposes of the simplified treatment assessment, a patient is presumed to have cirrhosis if their FIB-4 score is greater than 3.25.
• An HCV genotype is not necessary to obtain in noncirrhotic treatment-naïve patients eligible for the simplified HCV treatment algorithm.
• The use of 8 weeks of glecaprevir-pibrentasvir or 12 weeks of sofosbuvir-velpatasvir is recommended for treatment-naïve patients without cirrhosis as part of the AASLD/IDSA simplified HCV treatment algorithm.
• On-treatment monitoring of hepatic function tests is not necessary for treatment-naïve patients without cirrhosis who are eligible for the simplified treatment algorithm.
• Genotype 1, 2, 4, 5, or 6 cirrhotic patients on the simplified treatment algorithm can be treated with either 8 weeks of glecaprevir-pibrentasvir or 12 weeks of sofosbuvir-velpatasvir.
• For patients with genotype 3 HCV and compensated cirrhosis, sofosbuvir-velpatasvir should not be used if a baseline Y93H mutation is present. If baseline RAS testing is not sent, 8 weeks of glecaprevir-pibrentasvir should be used.
• Providers may elect to check on-treatment hepatic function tests for patients with compensated cirrhosis on the simplified treatment regimen, given that hepatic decompensation and liver injury rarely occur in cirrhotic patients during antiviral therapy.
• Patients with cirrhosis should undergo ongoing surveillance for HCC with liver ultrasound with or without the addition of a serum alpha-fetoprotein level every 6 months, regardless of HCV cure.