Direct-Acting Antivirals for Patients with Hepatitis C Virus

 

Hepatitis C virus (HCV) is a ribonucleic acid (RNA) virus¹ with ≥6 known genotypes, and >50 subtypes.^2,3 Genotype 1 is the most common worldwide.⁴ HCV infection is prevalent, with an estimated 130 million to 175 million patients chronically infected worldwide^5,6; the disease affects approximately 4 million people in the United States.² Percutaneous exposure to blood is the main route of HCV transmission,⁷ and injection drug use is the most significant risk for HCV infection.⁸ Other risk factors include unsanitary tattooing,⁸ chronic hemodialysis,² human immunodeficiency virus infection, perinatal transmission,^2,9 occupational exposure,^2,9 and sexual transmission.^2,7,9 In 20 to 30 years, 25% to 30% of patients infected with chronic HCV will develop cirrhosis.⁵ Chronic HCV infection is the primary cause of cirrhosis, hepatocellular carcinoma, and end-stage liver disease.⁵ Complications, such as cirrhosis and hepatocellular carcinoma make HCV the leading indication for orthotopic liver transplantation.⁹

Treating Patients with HCV Infection

There is currently no vaccine available for HCV.² Treatment, however, is available, and is recommended for all patients chronically infected with HCV.⁹ Cure from HCV infection is measured by sustained virologic response (SVR), and defined as the sustained lack of detectable HCV RNA ≥12 weeks following therapy completion.⁸ Pegylated interferon (Peg-IFN) plus ribavirin, the previous standard treatment for patients with chronic HCV infection, had low success rates,⁵ and only achieved SVR in approximately 50% of patients with genotypes 1a and 1b.¹⁰ Telaprevir and boceprevir—first-generation direct-acting antivirals (DAAs)—were approved by the US Food and Drug Administration in 2011, but had a low barrier of resistance, many side effects, high pill burden, and needed to be administered with interferon and ribavirin.¹ They are no longer manufactured in the United States because of better alternative treatments and diminishing market demands.^11,12 Newer DAA medications—the majority of which are administered orally once daily and generally well-tolerated—have since been approved (Table),^13-19 contributing to greatly improved SVRs of 90%.¹

There are currently 3 classes of DAAs available: (1) nonstructural (NS) 3/4A protease inhibitors, (2) NS5A inhibitors, and (3) NS5B polymerase inhibitors.^4,9 NS5A inhibitors have fewer adverse drug events and drug–drug interactions (DDIs) compared with NS3/4A protease inhibitors,⁹ but similar to NS3/4A protease inhibitors, they still have a low barrier to resistance,²⁰ which require them to be taken with other DAAs.⁹ NS5B polymerase inhibitors are either nucleos(t)ide or nonnucleos(t)ide analogs.²⁰ The former has broad cross-genotypic activity, because of the NS5B active site’s highly preserved nature; emergence of resistance is also rare.²⁰

Olysio (simeprevir)

The HCV NS3/4A protease inhibitor Olysio (simeprevir) is indicated for patients with chronic HCV genotype 1 or 4, but must be given with other antiviral drugs.²¹ It may be given in combination with sofosbuvir or PegIFN-α and ribavirin. If given with sofosbuvir, the duration of therapy depends on cirrhosis status. Simeprevir is not recommended for patients with moderate or severe hepatic impairment, and with regard to DDIs, simeprevir is metabolized by the hepatic cytochrome P450 3A (CYP3A) enzyme; thus, coadministration with moderate or strong inducers or inhibitors of CYP3A may significantly alter simeprevir plasma exposure and not recommended.²¹

Sovaldi (sofosbuvir)

Indicated for patients with HCV genotype 1, 2, 3, or 4, Sovaldi (sofosbuvir) is an HCV nucleotide analog NS5B polymerase inhibitor that should be administered as part of a combination antiviral treatment regimen.²² Sofosbuvir should be given in combination with ribavirin, with or without PegIFN-α, and may be given with daclatasvir,²³ depending on the genotype being treated.²² Serious bradycardia may occur in patients taking sofosbuvir in combination with amiodarone and another DAA; therefore, such combinations are not recommended.²² Intestinal P-glycoprotein (P-gp) inducers (eg, rifampin, St. John’s wort) may significantly lower sofosbuvir levels, so concomitant use is not recommended.²²

Harvoni (ledipasvir/sofosbuvir)

Harvoni (ledipasvir/sofosbuvir), a fixed-dose combination tablet, is indicated for patients with chronic HCV genotype 1, 4, 5, or 6.²⁴ This drug may be given with or without ribavirin, depending on the genotype and subpopulation being treated. It has similar precautions as sofosbuvir regarding concomitant use with amio­darone and intestinal P-gp inducers.²⁴ In addition, acid-reducing agents can decrease the absorption of ledipasvir.

Viekira Pak (ombitasvir/paritaprevir/ritonavir; and dasabuvir)

Viekira Pak (ombitasvir/paritaprevir/ritonavir; and dasabuvir) is a fixed-dose, copackaged combination for patients with chronic HCV genotype 1.²⁵ It contains 2 different tablets: 1 comprising ombitasvir, paritaprevir, and ritonavir, given once in the morning; and 1 containing dasabuvir that is given twice daily. This combination may be used with or without ribavirin, depending on the patient’s cirrhosis status. Dasabuvir is metabolized by CYP2C8; paritaprevir and ritonavir are metabolized by CYP3A.²³ Viekira Pak use is contraindicated with strong CYP2C8 inducers and inhibitors, and with moderate or strong CYP3A inducers.²⁵ Rit­onavir, a strong CYP3A inhibitor, is used to boost the levels of paritaprevir.²⁵ Because Viekira Pak contains ritonavir, use of this drug is contraindicated with drugs that are metabolized by CYP3A, including alpha1-adrenoreceptor antagonists, ergot derivatives, and certain statin drugs (eg, lovastatin, simvastatin).

Daklinza (daclatasvir)

Daklinza (daclatasvir) is an NS5A inhibitor indicated for patients with chronic HCV genotype 1 or 3.²³ It is administered in combination with sofosbuvir, and simultaneous use of ribavirin depends on the patient’s cirrhosis and transplant status. Daclatasvir is a CYP3A4 substrate, and its use is contraindicated with strong CYP3A4 inducers; however, there are dose adjustments for concomitant use with strong CYP3A4 inhibitors and moderate CYP3A4 inducers.²³ Daclatasvir must be discontinued if the patient permanently stops taking sofosbuvir.

Technivie (ombitasvir/paritaprevir/ritonavir)

Technivie (ombitasvir/paritaprevir/ritonavir) is a fixed-dose combination tablet from the same manufacturer as Viekira Pak, and contains 3 of the 4 ingredients found in Viekira Pak.²⁶ This combination tablet is indicated for patients with chronic HCV genotype 4 who do not have cirrhosis. This combination drug contains similar DDIs to Viekira Pak, with regard to its paritaprevir and rit­onavir ingredients. Technivie use is contraindicated with strong and moderate CYP3A inducers.²⁶

Zepatier (elbasvir/grazoprevir)

Zepatier (elbasvir/grazoprevir) is the most recently FDA-approved combination DAA medication for patients with chronic HCV genotype 1 or 4.²⁷ It contains elbasvir, an NS5A inhibitor, and grazoprevir, an NS3/4A protease inhibitor. This drug may be used with or without ribavirin, depending on the patient’s baseline NS5A polymorphisms and treatment history.²⁷ It is contraindicated in patients with moderate or severe hepatic impairment, and because elbasvir and grazoprevir are both CYP3A substrates, is contraindicated with use of strong CYP3A inducers. Grazoprevir is also a substrate of the organic anion transporting polypeptides (OATPs) 1B1 and 1B3, and is contraindicated with all OATP1B1 and OATP1B3 inhibitors.²⁷

Issues with DAA Use

Although generally well-tolerated and a great improvement from the previous standard of treatment, DAAs are not without their own issues. Because of HCV’s intrinsically high error-prone replication property, it develops a resistance to antiviral treatments rather easily,³ and emergence of DAA resistance is a concern.⁶ DAAs also increase the risk for DDIs,⁷ as was briefly mentioned above. In October 2015, the FDA released a safety alert regarding Viekira Pak and Technivie, and risk of hepatic decompensation and failure in patients with cirrhosis taking these medications.²⁸ Viekira Pak and Technivie are now contraindicated in patients with moderate or severe hepatic impairment.^25,26

In addition, oral DAA therapies are associated with considerable treatment costs. For example, the cost of Harvoni (ledipasvir/sofosbuvir) is reported at $1125 per tablet²⁹; total cost of treatment can be more than $150,000 for some patients.³⁰ The newest FDA-approved DAA, Zepatier (elbasvir/grazoprevir), has a list price of $54,600 for a 12-week regimen.³¹ Because of the cost of DAAs, insurers and state and federal agencies have rationed their use to patients with advanced fibrotic liver disease, with the justification that many patients will experience disease progression slowly over many years, and not develop advanced liver disease.³² This approach ignores the long-term costs of HCV treatment as it relates to treatment of cirrhosis, decompensated cirrhosis, as well as hepa­to­cellular carcinoma, and liver transplantation. Some data even suggest that treatment regimens without any restrictions would result in substantially reduced healthcare costs. More analyses are needed to evaluate the real-world cost-effectiveness of DAAs, taking into consideration the benefits of HCV treatment in preventing transmission, in addition to extrahepatic and indirect economic benefits of HCV treatment.³⁰

Conclusion

The ever-changing landscape of HCV treatment provides promising advances toward eradication of HCV infection. DAA medications will likely continue to play an important role in HCV treatment. Future advances in HCV treatment may reveal other potential mechanisms, such as entry inhibitors.⁶ A new HCV vaccine developed by GlaxoSmithKline plc has shown promise, and is currently the focus of phase 2 efficacy studies.^33,34 A big challenge continues to be cost, but hopefully with more options, this will become less of an issue.

 

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References

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