There are several strains, or genotypes, of hepatitis C virus (HCV) as follows—genotypes 1 through 6. These genotypes can be further divided into subgroups, such as genotype 1a, 1b and so on.

In Canada, Australia, the U.S., UK, Brazil and Scandinavia, genotype 1 is common, and genotype 1a is more common than genotype 1b. Furthermore, genotype 1a tends to respond less to therapy than 1b.

Researchers in several countries, along with the pharmaceutical company Merck (known as MSD outside of North America), pooled data from phase II and phase III trials of Zepatier (a fixed-dose combination of elbasvir and grazoprevir) taken with or without the broad-spectrum antiviral drug ribavirin in people with HCV genotype 1a. They then reviewed this data.

Key findings from the review were as follows:

When taken once daily for 12 consecutive weeks, Zepatier is highly effective among patients with genotype 1a who have not been previously treated or who were previously treated and experienced relapse.

Zepatier + ribavirin taken for 16 to 18 weeks is highly effective in patients with genotype 1a who have experienced virological failure with previous treatment.

The effectiveness of Zepatier was similar in participants whether or not they had cirrhosis (extensive scarring of the liver).

Study details

Researchers analysed data from 893 participants distributed as follows:

• no previous HCV treatment – 550 people
• previously treated  but subsequently relapsed– 343 people

The average profile of participants at the start of the study was as follows:

• 70% men, 30% women
• 92% were younger than 65 years
• main ethno-racial groups – 75% white, 20% black
• most (70%) participants did not have cirrhosis
• most (80%) participants had an HCV viral load of 6 million IU/mL or less

Among treatment-experienced participants, 76% had previously experienced virological failure, while the remaining 24% had relapsed.

Results

The effectiveness of Zepatier was high, ranging between 90% and 100% cure rates. Cure can also be expressed as a sustained virological response (SVR) 12 or 24 weeks after a course of treatment has ended, written as SVR₁₂ or SVR₂₄.

Here are the rates of cure for different groups of participants:

No previous treatment

• Zepatier for 12 weeks – 95% of participants were cured (402 out of 426 people)
• Zepatier + ribavirin for 12 weeks – 95% of participants were cured (71 out of 77 people)
• Zepatier for 16 to 18 weeks – 91% of participants were cured (21 out of 23 people)
• Zepatier + ribavirin for 16 to 18 weeks – 100% of participants were cured (23 out of 23 people)

Prior relapse

People in this group had previously been treated (with interferon and/or ribavirin). Although this prior treatment was able to greatly reduce the amount of HCV in their blood, once their course of treatment ended, HCV levels surged in their blood. Here is the distribution of cures in this group of participants by regimen:

• Zepatier for 12 weeks – 100% cured (22 out of 22 people)
• Zepatier + ribavirin for 12 weeks – 96% cured (25 out of 26 people)
• Zepatier for 16 to 18 weeks – 92% cured (12 out of 13 people)
• Zepatier + ribavirin for 16 to 18 weeks – 100% cured (21 out of 21 people)

Previous treatment failures

In this category, people had been previously treated but the amount of HCV in their blood was not significantly reduced. The proportions of participants achieving cure by regimen were as follows:

• Zepatier for 12 weeks – 90% cured (62 out of 69 people)
• Zepatier + ribavirin for 12 weeks – 94% cured (75 out of 80 people)
• Zepatier for 16 to 18 weeks – 94% cured (49 out of 52 people)
• Zepatier + ribavirin for 16 to 18 weeks – 100% cured (54 out of 54 people)

Cirrhosis

People who have extensive liver injury due to HCV do not generally respond as well to treatment as people without cirrhosis.

Overall, here are the results of Zepatier treatment for 12 weeks (with or without ribavirin), depending on cirrhosis status, in participants who either had not been previously treated or had been previously treated and experienced relapse:

• no cirrhosis – 95% cured (345 out of 362 people)
• cirrhosis – 98% cured (79 out of 81 people)

Here are the results among participants whose previous HCV therapy failed and who received Zepatier with or without ribavirin for 16 to 18 weeks:

• no cirrhosis – 100% cured (31 out of 31 people)
• cirrhosis – 100% cured (23 out of 23 people)

Resistance

Some participants had HCV that was somewhat resistant to the study drugs. Resistance could develop because HCV-infected cells produce a great deal of virus, and occasionally some of these viruses have changes (or mutations) that occur by chance. Some of these mutations could help HCV to partially or wholly resist the effect of treatment. Resistance also could have developed if some participants had been treated with therapies in the past that were similar in structure or shape to the medicines in Zepatier and such past therapy failed.

Resistance and past treatment relapse

In analyzing the blood samples of a sub-set of participants, here is how mutations associated with resistance to treatment were distributed and the result of Zepatier therapy:

• no resistance mutations present – 98% cured (284 out of 289 people)
• resistance mutations present – 91% cured (136 out of 150 people)

Resistance and past treatment failure

Among participants who experienced relapse when previously treated and who received Zepatier + ribavirin for 16 to 18 weeks, here are the rates of cure distributed by the presence of resistance mutations at the start of the study:

• no resistance mutations – 100% cured (38 out of 38 people)
• resistance mutations present – 100% cured (14 out of 14 people)

Note well

The present analysis found that, overall, 12 weeks of Zepatier with or without ribavirin is highly effective among treatment-naïve participants with the difficult-to-treat strain of HCV called genotype 1a.

Longer regimens—16 weeks—have been approved by regulatory authorities in Canada and the U.S. for use by patients with genotype 1 who have previously experienced virological failure on other regimens.

Safety analyses of Zepatier appear in other reports in this issue of TreatmentUpdate.

—Sean R. Hosein

REFERENCE:

Thompson A, Zeuzem S, Rockstroh J, et al. The combination of elbasvir and grazoprevir is highly effective for the treatment of genotype 1a-infected patients. American Association for the Study of Liver Diseases, 13-17 November 2015. Abstract 703.