How to choose the right antiviral agent in HCV treatment

Significant advances in antiviral therapy with direct acting antivirals (DAAs) have transformed hepatitis C virus (HCV) treatment over the past four years (Table). We have achieved nearly every characteristic of an ideal regimen: pangenotypic, excellent safety and tolerability, high sustained virologic response (SVR), low pill burden, simplified dosing schedule, short treatment duration, and high genetic barrier to resistance. These regimens have proven to be effective in real-world settings, and even populations traditionally viewed as difficult to treat (HIV coinfection, opiate dependence, end-stage renal disease, post-transplantation) are no longer considered “special,” because SVR rates are generally equivalent. Furthermore, we have robust evidence that SVR is associated with significant improvement in clinical outcomes, including reduced risk of cirrhosis, hepatic decompensation, liver cancer, and both liver-related and all-cause mortality. In this context, HCV is now perceived as easy to treat, and many nonspecialists treat HCV in the context of primary care, clinics at correctional facilities, methadone clinics, and community health centers. Some have argued that we should bypass the usual formalities of an initial workup, and transition to a “test and treat” model in which patients are tested, diagnosed, and started on treatment in a single visit using point-of-care diagnostics, as well as without consideration of genotype or stage of liver disease. Although this has merit in a global context with an eye on large-scale HCV elimination, for routine care in a gastrointestinal/hepatology practice, there remains enough nuance in treatment that careful consideration should be given to several clinical factors to choose the “right” antiviral regimen.

Table. Current FDA Approved All-Oral DAA Regimens for Chronic Hepatitis C

Regimen Manufacturer FDA approval AASLD/IDSA


Gilead Oct. 10, 2014 Recommended for genotype 1 and 4




Nov. 5, 2014

Alternative for

genotype 1

Viekira Pak


AbbVie Dec. 19, 2014 Alternative for genotype 1

grazoprevir + elbasvir

Merck Jan. 28, 2016 Recommended for genotype 1 and 4



Bristol-Myers Squibb

Feb. 5, 2016 Alternative for genotype 1-3


Gilead June 28, 2016 Genotype 1-6


Gilead July 18, 2017 DAA-experienced genotype 1-6


AbbVie Aug. 3, 2017

Genotype 1-6 and

DAA-experienced genotype 1


Although the availability of three pangenotypic regimens such as sofosbuvir (SOF)/velpatasvir (VEL), glecaprevir/pibrentasvir, and SOF/VEL/voxilaprevir (VOX) may diminish the requirement for genotype testing, selection of antiviral regimen and treatment duration remains influenced by genotype and its subtypes. Whereas multiple nonpangenotypic regimens have excellent effectiveness exceeding 90% for genotype 1 HCV, including SOF/ledipasvir (LED), grazoprevir/elbasvir, and paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD), treatment is largely restricted to SOF/VEL and glecaprevir/pibrentasvir for genotypes 2 to 6. Of these, genotype 3 is established as the most challenging to eradicate and has been associated with higher risk of liver outcomes, including hepatocellular carcinoma (HCC) post-SVR.


The most important pretreatment clinical evaluation in patients with chronic HCV is assessment of liver fibrosis — specifically the identification of patients with cirrhosis. This is of high clinical importance and directly impacts management, including treatment duration, choice of antiviral regimen, need for variceal and HCC screening procedures, and post-SVR monitoring. In an era in which liver biopsies are rarely performed, clinicians largely rely on one or more noninvasive fibrosis tests such as Fibrosis-4 scoring system, commercial serum fibrosis assays, or imaging-based elastography. Due to the less-than-optimal reliability of any single test, and the clinical importance of identifying cirrhosis, consideration should be given for the use of two or more tests to provide greater confidence in the estimate of fibrosis stage, as well as to carefully interpret these test results in the context of all clinical data, particularly if there are examination, laboratory, or radiologic findings suggestive of advanced liver disease. If cirrhosis is suspected or confirmed, treatment duration should not be truncated to eight weeks to minimize virologic relapse (at a minimum, 12 weeks are required). Among patients with decompensated cirrhosis, protease inhibitor–based regimens (e.g., paritaprevir, grazoprevir, glecaprevir, VOX) should be avoided due to their risk for hepatic decompensation. Furthermore, a subset of patients with end-stage liver disease with high Model for End-Stage Liver Disease scores may reasonably consider treatment deferral to the post-transplant setting — a decision that should be made carefully in collaboration with a transplant hepatologist.

Treatment experience

Prior to treatment with an oral DAA regimen, the clinician should query patients regarding their prior treatment experience with historical interferon (IFN; or peg-IFN)–based regimens, IFN-based triple therapy regimens (telaprevir, boceprevir, simeprevir, sofosbuvir), or first-line oral DAA regimens (SOF/LED, PrOD, grazoprevir/elbasvir, SOF/VEL, glecaprevir/ pibrentasvir). For the purpose of treatment selection and duration, patients with prior exposure to IFN-based regimens without a DAA component are typically considered to be treatment naïve, with the exception of those with HCV genotype 3. In contrast, patients with prior DAA exposure may require a salvage regimen such as glecaprevir/pibrentasvir or SOF/VEL. Although it is not routinely required, some patients may benefit from formal resistance testing to identify the presence of resistance-associated substitutions, which may influence susceptibility to re-treatment, particularly among those with prior exposure to NS5A inhibitors.

Special populations

Despite excellent SVR rates across nearly every subgroup of patients with chronic hepatitis C, clinicians should continue to use special consideration in the selection of antiviral therapy in patients with HIV coinfection, opiate substitution, and post-transplant due to potential drug–drug interactions. In some cases, an alternative DAA regimen or an adjustment in the antiretroviral or post-transplant immunosuppressive drug regimen may be required. Among patients with chronic kidney disease, as well as those with a glomerular filtration rate below 30 mL/minute, clinicians should be mindful of the black box warning restricting the use of SOF-based regimens in this population, for whom grazoprevir/ elbasvir or glecaprevir/pibrentasvir are currently recommended as preferred regimens. All patients undergoing DAA therapy should be screened for current or prior hepatitis B virus (HBV) infection, because postmarketing reports have identified rare cases of HBV reactivation among patients who are hepatis B surface antigen (HBsAg) positive and those who are HBsAg negative/hepatitis B core antibody (HBcAb) positive.

Drug–drug interactions

In reaching a decision regarding an appropriate DAA regimen, clinicians should carefully review all prescribed and over-the-counter medications and supplements being taken by patients pursuing HCV therapy. If specific medications with known interactions to DAAs are medically necessary for the treatment of other conditions (e.g., proton pump inhibitors) and, thus, cannot be reasonably withheld or substituted with a medication without a potential interaction, then the selection of an alternate DAA regimen should be pursued. Due to its importance for patient safety, as well as treatment effectiveness, clinicians should routinely consult their local pharmacist as well as online resources such as the University of Liverpool website ( to guide DAA selection.

Patient preferences

Although the focus of gastroenterologists in the selection of DAA medications is generally centered on optimizing effectiveness, the wide selection of available regimens with similarly high SVR rates now permits the incorporation of patient choice into this decision. Patients often present to a clinician with specific preferences based on experiences of colleagues, friends, or family or with other patient-centered factors such as pill size and number, food interactions, adverse-event profile, and treatment duration.

Insurance coverage

Several factors can be used to guide the selection of the “right” antiviral regimen for the treatment of chronic HCV, but the ultimate choice of the exact therapy used is often driven by the formulary decisions of public or private insurers and their associated prescription drug benefit plans and specialty pharmacies. Although access to HCV therapy has improved since 2014, ongoing restriction persists in many states based on fibrosis stage, coexisting alcohol or substance use disorders, and medical comorbidities. In some cases, navigation of a challenging and lengthy appeals process may be required to successfully obtain authorization for nonpreferred regimens that are medically necessary and supported by best available evidence and guidelines from the American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA;

Concluding remarks

Oral DAA therapy for HCV infection is associated with excellent rates of safety and efficacy, and its use may result in significant improvement in clinical outcomes. The selection of the correct oral DAA regimen for patients with chronic HCV should incorporate consideration of HCV genotype, stage of liver fibrosis, prior treatment experience, special populations, drug interactions, and patient preferences. All patients with chronic HCV who desire antiviral therapy and do not have limited life expectancy should be offered the option of undergoing oral DAA therapy in accordance with AASLD/IDSA guidelines and the parameters of payor formularies.

Dr. Lim has received research grants from Allergan, AbbVie, Conatus, Genfit, Gilead, Intercept. He has consulted for Bristol-Myers Squibb. Dr. Lim is the chair of the AGA Institute Clinical Practice Updates Committee.

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