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Targeting the HCV Genome: A Four-Drug Fixed-Dose Regimen

Issue: March 2015

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The latest approval for a new fixed-dose regimen of ombitasvir, paritaprevir, dasabuvir and ritonavir indicated for the treatment of hepatitis C virus genotype 1, in combination with ribavirin for most patients, came to us in the form of Viekira Pak from AbbVie in December.

Leah Molloy

Clinical Pharmacology

Viekira Pak is the first available product to target three distinct nonstructural proteins of the HCV genome.

Ombitasvir is an NS5A inhibitor, paritaprevir is an NS3A/4A inhibitor and dasabuvir is an NS5B inhibitor. The potent CYP3A4 inhibitor ritonavir is co-formulated to enhance paritaprevir exposure, at a dose lower than typically used for this purpose in antiretroviral regimens for the treatment of HIV infection.

Viekira Pak is available as a fixed-dose, four-tablet package. The two tablets each containing ombitasvir (12.5 mg), paritaprevir (75 mg) and ritonavir (50 mg) are taken once daily in the morning, and the remaining two tablets containing dasabuvir (250 mg) should be taken separately, one in the morning and one in the evening. Owing to the higher maximum serum concentration and area under the concentration-time curve (88% and 56%, respectively) of all four drugs when taken with food compared with under fasting conditions, all tablets should be administered with a meal.

Both dasabuvir and paritaprevir undergo CYP450-dependent metabolism, and paritaprevir is more dependent on the ritonavir-inhibited CYP3A4 enzyme while dasabuvir is primarily metabolized by CYP2C8. All four components also are substrates of p-glycoprotein. Given extensive dependence and impact on the CYP450 and other enzymes, there is a high potential for drug-drug interactions and all concomitant therapies should be chosen carefully. All four agents are extensively (> 99%) protein bound, and all are primarily recovered in the feces with minimal urinary elimination. As such, no dose adjustment on the basis of renal function is required for patients with mild, moderate or severe renal impairment.

Indications and Regimens

Viekira Pak is indicated for the management of genotype 1 chronic HCV infection for treatment-naive or interferon-experienced patients with or without cirrhosis. Patients infected with HCV genotype 1a without cirrhosis must receive Viekira Pak in combination with ribavirin for 12 weeks, and 24 weeks is recommended for patients infected with HCV genotype 1a who do have cirrhosis. Patients infected with HCV genotype 1b without cirrhosis may take Viekira Pak alone without ribavirin for 12 weeks, whereas concomitant ribavirin is recommended for patients infected with HCV genotype 1a who do have cirrhosis.

The same dosing strategies are presented in the online working HCV treatment guidelines maintained by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America, where Viekira Pak is recommended with the same recommendation strength and evidence level (IA) as ledipasvir/sofosbuvir, (Harvoni, Gilead Sciences) compared with the IIaB rating awarded to the combination of sofosbuvir, (Sovaldi, Gilead Sciences) plus simeprevir (Olysio, Janssen Therapeutics).

Phase 3 Clinical Trial Data

Viekira Pak was approved after five phase 3 studies: SAPPHIRE-I, SAPPHIRE-II, TURQUOISE-II, PEARL-III and PEARL-IV. All studies had the same primary efficacy endpoint of sustained virologic response 12 weeks after completion of therapy, defined as an HCV RNA concentration below the lower limit of quantification, 25 IU/mL The placebo-controlled SAPPHIRE studies evaluated patients without cirrhosis; TURQUOISE-II studied patients with cirrhosis; and the PEARL studies evaluated Viekira Pak in the absence of concomitant ribavirin. Results are summarized in Table 1.

SAPPHIRE-I and SAPPHIRE-II both included patients with HCV genotype 1 without cirrhosis, and differed only on the basis of treatment history. SAPPHIRE-I included treatment-naive patients only, whereas all patients studied in SAPPHIRE-II had previously received pegylated interferon-alfa in addition to ribavirin, but had experienced relapse, partial response or null response. These were double blind, placebo-controlled studies that randomly assigned patients in a 3:1 ratio to receive 12 weeks of Viekira Pak plus ribavirin or placebo. Response was compared with a historical control of Incivek (telaprevir, Vertex Pharmaceuticals) in combination with PEG-IFN and ribavirin. Approximately 90% of participants in both studies were white, and genotype 1a was more common than genotype 1b (about 67% in SAPPHIRE-I and 58% in SAPPHIRE-II). Combined response rates for genotypes 1a and 1b were 96% among both treatment-naive and treatment-experienced patients.

The open-label TURQUOISE-II study administered Viekira Pak plus ribavirin to cirrhotic patients for either 12 or 24 weeks. Response rates were high (> 90%) for both the 12-week and 24-week groups, but differences were identified when patients were divided on the basis of subtype. Although response rates among patients infected with HCV genotype 1b were very similar after 12 weeks or 24 weeks of treatment (98.5% vs. 100%), SVR12 attainment by patients infected with HCV genotype 1a was lower in the 12-week group than in the 24-week group (88.6% vs. 94.2%). This finding is reflected in the product labeling recommending 24 weeks of treatment for genotype 1a patients with cirrhosis.

Finally, the PEARL-III and PEARL-IV studies compared a 12-week treatment course of Viekira Pak with or without ribavirin for treatment-naive patients without cirrhosis infected with HCV genotype 1. Although SVR12 attainment for genotype 1b patients was almost identical with or without ribavirin (99.5% vs. 99%), genotype 1a patients responded better when ribavirin was included compared with treatment with Viekira Pak alone (97% vs. 90.2%). Thus, Viekira Pak is given without ribavirin only to patients infected with HCV genotype 1b, without cirrhosis.

Cost and Acquisition

The price for a 12-week treatment course of Viekira Pak is $83,320, plus an additional cost of approximately $2,500 for 12 weeks of ribavirin for those who need both. This price is comparable to sofosbuvir and less than the cost of a 12-week course of ledipasvir/sofosbuvir, although the latter may be taken for only 8 weeks by some patients. AbbVie’s patient assistance program, Proceed, has been developed to assist a variety of eligible patients with copay costs.

Future Applications

Studies to describe the role of Viekira Pak in combination with sofosbuvir as well as the use of ombitasvir/paritaprevir/ritonavir with ribavirin for the treatment of HCV genotype 4 are actively recruiting. This newest all-oral anti-HCV regimen is the first to target three different nonstructural proteins of the HCV genome. Although most patients will still need to take concomitant ribavirin, the regimen appears to be well tolerated with high efficacy.