Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis

Chisom Anosike, LECOM school of pharmacy

Hepatitis C virus (HCV) infection has been considered to be one of the key causes of end-stage liver disease and indications for liver transplant. Recently, the effectiveness of treatment has drastically improved based on newly suggested direct acting antiviral agents that treat all genotypes of HCV, sofosbuvir and velpatasvir. Sofosbuvir is a HCV nucleotide analog of non-structural 5B (NS5B) polymerase inhibitor indicated for the treatment of genotype 1, 2, 3 or 4 chronic HCV infections as a component of a combination antiviral treatment regimen. Velpatasvir on the other hand, is an investigational inhibitor of the HCV NS5A protein with antiviral activity against all HCV genotypes. [1]

Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis
Design Multicenter Open- label trial; N= 438
Objective To assess the efficacy and safety of a fixed dose of sofosbuvir–velpatasvir with or without ribavirin for 12 weeks or sofosbuvir–velpatasvir for 24 weeks in patients infected with HCV genotypes 1 through 6 and with decompensated cirrhosis
Study Groups Patients were divided into three groups:

First group to receive a fixed-dose combination tablet of sofosbuvir 400mg and velpatasvir 100mg for 12 weeks (n= 90)

Second group to receive sofosbuvir–velpatasvir plus ribavirin for 12 weeks (n= 87)

Third group to receive sofosbuvir–velpatasvir for 24 weeks (n= 90)

Methods Patients were randomly assigned in a 1:1:1 ratio. Ribavirin was given orally with food twice daily, with the dose determined according to each patient’s body weight (1000 mg daily in patients with a body weight of <75 kg and 1,200 mg daily in patients with a body weight ≥75 kg). Random assignation was done according to HCV genotype. Inclusion Criteria: Patients 18 years of age or older with chronic HCV infection of any genotype and decompensated cirrhosis. Exclusion Criteria: Patients who had undergone liver transplantation, patients who had received previous treatment with any nonstructural 5A (NS5A) inhibitor or nucleotide analogue nonstructural 5B (NS5B) inhibitor, patients with a platelet count of 30,000 per cubic millimeter or less or a creatinine clearance of less than 50 ml per minute.
Duration 24 weeks
Primary Outcome Measure Rates of sustained virologic response
Baseline Characteristics Characteristic Sofosbuvir-velpatasvir for 12 wk (n= 90) Sofosbuvir-velpatasvir plus ribavirin for 12 wk (n= 87) Sofosbuvir-velpatasvir for 24 wk (n= 90)
Mean age (range) 58 (42-73) 58 (40-71) 58( 46-72)
Male sex, no. (%) 57 (63) 66 (76) 63 (70)
HCV genotype no. (%)      
1a 50 (56) 54 (62) 55 (61)
1b 18 (20) 14 (16) 16 (18)
2 4 (4) 4 (5) 4 (4)
3 13 (15) 13 (15) 12 (13)
4 2 (2) 2 (2) 2 (2)
6 0 0 1 (1)
IL28B genotype – no. (%)      
CC 20 (22) 22 (25) 20 (22)
CT 51 (57) 46 (53) 49 (50)
TT 19(21) 19 (22) 19 (21)
Missing data 0 0 2 (2)
Previous HCV treatment –no./total no. (%)      
No 32/90 (36) 40/87 (46) 48/90 (53)
Yes 58/90 (64) 47/87 (54) 2/90 (47)
 Protease inhibitor regimen 9/58 (16) 12/47 (26) 7/42 (17)
 Peginterferon-   ribavirin 48/58 (83) 5/47 (74) 35/42 (83)
Results Outcome Sofosbuvir-velpatasvir for 24 wk (n= 90) Sofosbuvir-velpatasvir plus ribavirin for 12 wk (n= 87) Sofosbuvir-velpatasvir for 24 wk (n= 90)
no. % 95% CI no. % 95% CI no. % 95% Cl
Sustained virologic response            
All genotype 83 74- 90 94 87- 98 86 77- 92
Genotype 1a 88 76-96 94 85- 99 93 82- 98
Genotype 1b 89 65-99 100 77-100 88 62- 98
Genotype 2 100 40-100 100 40-100 75 19- 99
Genotype 3 50 23-77 85 55- 98 50 21- 79
Genotype 4 100 40-100 100 16-100 100 16-100
Genotype 6 0 NA 0 NA 100 3- 100
Virologic failure      
All genotype 12 3 9
Genotype 1a 6 2 4
Genotype 1b 11 0 6
Genotype 3 43 15 42
Other outcome      
Death 3 2 2
Loss to follow-up 1 0 3
Adverse Events Common Adverse Events: fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in patients taking ribavirin.
Serious Adverse Events: The most serious adverse events were hepatic encephalopathy and sepsis and occurred in 19% of patients who received 12 weeks of sofosbuvir–velpatasvir, 16% of those who received 12 weeks of sofosbuvir–velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir–velpatasvir
Percentage that Discontinued due to Adverse Events: sofosbuvir–velpatasvir for 12 weeks, 1% discontinued; sofosbuvir–velpatasvir plus ribavirin for 12 weeks, 5% discontinued; and for sofosbuvir–velpatasvir for 24 weeks, 4% discontinued.
Study Author Conclusions In conclusion, treatment with the fixed-dose combination tablet of sofosbuvir–velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir–velpatasvir for 24 weeks resulted in a high rate of sustained virologic response and early improvements in hepatic function in patients with decompensated cirrhosis caused by HCV of all genotypes. Whether the early improvements in liver function translate to long-term clinical benefits remains to be determined, and future trials are required to assess this regimen in patients with more severe degrees of liver decompensation.

In this study, patients with HCV genotype 3 had lower rates of sustained virologic response than patients with other HCV genotypes. The rate of 85% among patients with HCV genotype 3 who received sofosbuvir–velpatasvir plus ribavirin was higher than the 71% response rate previously reported among patients with HCV genotype 3 and decompensated had a sustained virologic response, which suggests that the contribution of ribavirin may be particularly important in patients with HCV genotype 3. This study has the following limitations: it was not focused to identify significant differences among the three treatment groups and only patients with moderate hepatic decompensation were enrolled, so the results cannot be generalized to patients with more severe liver disease.

References

  1. Curry MP, O’leary JG, Bzowej N, et al. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015;373(27):2618-28.
  2. Coilly A, Roche B, Duclos-vallée JC, Samuel D. News and challenges in the treatment of hepatitis C in liver transplantation. Liver Int. 2016;36 Suppl 1:34-42.

 

 

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