Pan-Genotypic Direct-Acting Antiviral Combination Therapy for Chronic HCV Infection

By Clinical Content Hub

Treatment with direct-acting antivirals (DAAs) has transformed the landscape of hepatitis C virus (HCV) infection management, and changes in HCV epidemiology were reported worldwide during the first several years after these agents became available.1

Approximately 58 million people worldwide have chronic HCV infection (Figure).2 In the United States, an estimated 2 million adults are infected with HCV3 and most have nonspecific symptoms such as chronic fatigue and depression.4 More than 39% of US individuals with chronic HCV  may not be aware that they have the infection.5 Research conducted in the southern United States indicates that the prevalence of HCV infection is rapidly increasing among the following populations: individuals who are 20 to 29 years of age; those who are White; those who live in rural areas; and injection drug users.6
The success of DAAs has been highlighted by studies reporting sustained virologic response rates 12 weeks following treatment (SVR12) greater than 85%, with negligible side effects (Table).7,8 Although the availability of DAAs has eliminated the demand for new HCV therapies, certain genotype-specific and HCV disease-specific challenges remain, and customized treatment may be the solution, especially for patients who have difficult-to-treat HCV. The introduction of oral, interferon-free, pan-genotypic DAAs for the management of chronic HCV infection is anticipated to simplify therapy and increase treatment uptake on a global scale.

Glecaprevir/pibrentasvir (GLE/PIB) was approved by the US Food and Drug Administration (FDA) as a fixed-dose combination of 2 DAAs for the treatment of chronic HCV genotypes (GTs) 1, 2, 3, 4, 5, or 6 in adult patients.7 The approval of GLE/PIB dual-combination therapy marked an important milestone in the treatment of HCV infection and addressed the need for development of all-oral combination therapies with activity against HCV GTs 1 through 6.
GLE/PIB has proven to be a highly effective pan-genotypic treatment for HCV in patients without cirrhosis and those with compensated cirrhosis.9 It is safe and effective in patients with HCV and advanced kidney disease, solid organ transplants, and coinfection with HIV.10 Newer-generation inhibitors exhibit a high barrier to treatment resistance and when administered in various combinations, they provide additional treatment options and improved SVR rates across all HCV GTs.

Glecaprevir/ pibrentasvir adverse effects
Adverse effects most commonly reported for glecaprevir/pibrentasvir include headache and fatigue.

HCV Genotypic-Related Treatment Challenges

HCV exhibits a substantially higher degree of genetic diversity than that observed in HIV. Pan-genotypic DAA therapy targets HCV GTs 1 through 6 in patients without cirrhosis and with compensated cirrhosis. The HCV GTs demonstrate an approximately 30% divergence in their nucleotide sites. Treatment responses can vary due to differences in the natural course of infection. In some cases, HCV has been shown to develop treatment-resistant mutations in patients who experience relapse following treatment with nonstructural protein 5A (NS5A) inhibitor-containing regimens.11 GT1 and 3 account for 46% and 30% of all infections, respectively, and are the most prevalent GTs worldwide. Comparatively, GTs 2, 4, 5, and 6 are less prevalent and globally account for 9%, 8%, less than 1%, and 5% of cases, respectively.12
Although SVR rates are sustained with GLE/PIB across all HCV subtypes, HCV GT3 remains challenging to treat, especially in patients with cirrhosis.13 Infection with HCV GT3 has been associated with clinical phenotypes, such as increased rates of liver fibrosis, hepatic steatosis, and an increased chance of progression to hepatocellular carcinoma, all of which have been linked to poor outcomes after DAA therapy.14 In patients with HCV without cirrhosis, both GLE/PIB and sofosbuvir/velpatasvir (SOF/VEL) treatment yielded 95% SVR12 in participants with GT3 infection.15,16
A real-world study recruited 723 patients with chronic HCV and administered GLE/PIB up to 8, 12, and 16 weeks. The overall SVR rate was 99.3%, although SVR rates were notably lower among patients with HCV GT3 treated for 8 weeks.17 A 16-week course of GLE/PIB is recommended for treatment-experienced patients with HCV GT3 infection, irrespective of the presence of cirrhosis.7 For patients with HCV GT3 who are treatment-naive and have difficult-to-treat characteristics, such as progressive fibrosis or pre-existing mutations, 12 weeks of treatment may be more effective than 8 weeks.7

Sofosbuvir, Velpatasvir, and Voxilaprevir Combination: A Treatment Option for the Most Difficult-to-Cure Patients?

The pan-genotypic HCV NS3/4A protease inhibitor, voxilaprevir, has recently been approved as a component of a pan-genotypic, single-tablet regimen containing sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX). This combination therapy offers potent pan-genotypic activity in the setting of failed prior DAA therapies.11 Additionally, for some patients who are DAA-naive, SOF/VEL/VOX provides an option for a shortened treatment duration of 8 weeks.11 Although multiple HCV treatment options are available for patients, these regimens can still fail to generate a response due to the presence of viral resistance-associated substitutions (RAS, also referred to as variants) that have decreased susceptibility to DAAs. Voxilaprevir addresses this issue and has the added advantage of improved antiviral activity against common RAS.
POLARIS-1 ( Identifier: NCT02607735) and POLARIS-4 ( Identifier: NCT02639247) are phase 3 trials that assessed the efficacy, safety, and tolerability of SOF/VEL/VOX administered for 12 weeks in DAA-experienced patients with or without compensated cirrhosis. POLARIS-1 was a placebo-controlled trial that investigated the use of SOF/VEL/VOX in NS5A inhibitor-experienced patients with HCV GTs 1 through 6. POLARIS-4 was an open-label study that assessed the use of SOF/VEL/VOX in GTs 1 through 4 and SOF/VEL in GTs 1 through 3 in DAA-experienced patients who had not previously undergone treatment with an NS5A inhibitor. The combined results revealed an overall SVR rate of 97% in DAA-experienced patients treated with SOF/VEL/VOX, with high SVR rates observed irrespective of the presence of pre-existing RAS, genotype, or prior DAA regimen.18

HCV Special Population Treatment Strategies

Special populations are patients who have HCV and HIV coinfection, chronic kidney disease (CKD), HCV and hepatitis B virus (HBV) coinfection, and/or an unsuccessful prior DAA regimen. The efficacy and safety of GLE/PIB were assessed by EXPEDITION-4 ( Identifier: NCT02651194), an open-label, single-arm trial consisting of patients with HCV GT1-6, CKD stages 4 or 5, and either without cirrhosis or with compensated cirrhosis.9 After 12 weeks of treatment, the SVR was found to be 98% and clinical and biological tolerance were satisfactory, with all recorded side effects being unrelated to treatment.
The GLE/PIB combination is currently the first-line therapy in patients with CKD and has also been shown to be effective in patients with HCV who are coinfected with HIV or HBV, although careful analysis of drug-drug interactions is required in this population.10 The concept of special populations is no longer pertinent with pan-genotypic DAA combination therapy and this is reinforced by international guidelines recommending that all patients with HCV be treated.1

Potential Drug-Drug Interactions With DAAs

The risk of drug-drug interactions should be considered for all interferon-free DAA treatment regimens. Rifampin, efavirenz, carbamazepine, phenytoin, and St John’s wort may significantly decrease plasma concentrations of GLE/PIB and therefore are not recommended for concurrent use. GLE/PIB may also increase plasma levels of statins, digoxin, and dabigatran.
There is a lack of safety data to support the use of GLE/PIB in pregnancy and children younger than 18 years. Under international guidelines, no dosage adjustment is required in patients with CKD, including those undergoing dialysis, although use of GLE/PIB is contraindicated in patients with severe hepatic impairment.19

DAA Treatment Failures

The risk of virologic failure with a first DAA treatment is approximately 4% and corresponds to either a viral breakthrough or virologic relapse in a patient with undetectable HCV RNA during therapy.10

Patients who previously experienced treatment failure with NS5A inhibitors may develop RAS that decreases the efficacy of retreatment. Empirical recommendations for retreatment include ribavirin or an array of other DAAs, including sofosbuvir. In patients with CKD or decompensated cirrhosis, retreatment regimens cannot contain sofosbuvir.10

Side Effect Mitigation and Treatment Monitoring

All DAA therapies for HCV infection have been shown to be well tolerated. The most frequently reported side effects are headache, fatigue, nausea, and diarrhea. During treatment, patients need to be monitored for possible increases in levels of alanine aminotransferase and bilirubin.20 Severe side effects of DAA therapy, while rare, have been found to occur, especially in patients with advanced liver disease, for whom treatment with RBV is still recommended.21


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Posted by Haymarket’s Clinical Content Hub. The editorial staff of Gastroenterology Advisor had no role in this content’s preparation.

Reviewed January 2022