The treatment strategy for hepatitis C virus (HCV) has been changing rapidly since the introduction of direct-acting antivirals such as daclatasvir (DCV) and asunaprevir (ASV). We evaluated the efficacy and safety of DCV and ASV for HCV in real-life practice.
Patients were treated with 60 mg of DCV once daily plus 200 mg of ASV twice daily for 24 weeks, and followed for 12 weeks. The primary endpoint was a sustained virological response at 12 weeks after treatment (SVR12) and safety.
This retrospective study included eight patients with chronic HCV genotype 1b infection. All of the enrolled patients were diagnosed with liver cirrhosis, and their mean age was 65.75 years. One patient was a nonresponder and two patients relapsed with previous pegylated interferon (PegIFN) and ribavirin (RBV) treatment. None of the patient showed NS5A mutation. An SVR12 was achieved in 88% of cases by the DCV and ASV combination therapy. The serum transaminase level and the aspartate-aminotransferase-to-platelet ratio were improved after the treatment. DCV and ASV were well tolerated in most of the patients, with treatment discontinuation due to adverse events (elevated liver enzyme and decompensation) occurring in two patients.
In this study, combination of DCV and ASV treatment achieved a high sustained virological response with few adverse events even in those with cirrhosis, advanced age, and nonresponse/relapse to previous interferon-based therapy. Close monitoring of safety issues may be necessary when treating chronic HCV patients receiving DCV and ASV, especially in older patient and those with cirrhosis.
Chronic hepatitis C virus (HCV) infection is affecting approximately 130 to 150 million individuals worldwide, and it is one of the leading causes of chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC) [
Until 2011, the combination of pegylated interferon (PegIFN) and ribavirin (RBV) was the only approved treatment for chronic hepatitis C. With this regimen, patients infected with HCV GT 1 had sustained virological response (SVR) rates of approximately 40% to 50% [
Recently, therapeutic regimens for patients with chronic HCV infection have been changed with the use of oral direct acting antivirals (DAAs) [
Although the efficacy of DCV and ASV has been assessed in various studies [
We included chronic hepatitis C patients who were treated with DCV and ASV in Daejeon St. Mary`s hospital, Daejeon, Korea form March 2015 to November 2015. The doses of medications were as follows: DCV 60 mg once daily plus ASV 200 mg twice daily. Patients were treated for 24 weeks and followed for 12 weeks.
The inclusion criteria for this study were age older than 20 years old, chronic HCV GT 1b infection for at least 6 months with detectable HCV RNA titer, and patients with liver cirrhosis. Liver cirrhosis was defined by documented imaging studies such as ultrasonography or computed tomography (CT) scan. Patients nonresponsive or relapsing to previous treatment with PegIFN/RBV were also included. Nonresponse was defined as failure to clear HCV RNA from serum after 24 weeks of therapy and relapse was defined as reappearance of HCV RNA in serum after cessation of the therapy [
The primary outcome measurement was SVR12, defined as undetectable HCV RNA (less than 15 IU/mL) at 12 weeks post-treatment. The baseline characteristics assessed included age, sex, BMI, HCV GT, HCV RNA titer, comorbidities (diabetes, hypertension), prior treatment history of HCV, and presence of cirrhosis or NS5A mutation. Clinical assessment of patients included complete blood cell counts, serum transaminase levels, serum creatinine levels, and HCV RNA titer. Clinical assessment was done at consecutive weeks of 4, 12, 24 and 36.
Eight patients were treated with DCV and ASV.
Seven patients (88%) completed 24 weeks of treatment. Serum HCV RNA levels decreased dramatically in all patients after the treatment initiation. After 4 weeks of treatment, all patients achieved undetectable HCV RNA levels below the lower limit of quantitation (15 IU/mL). Seven patients sustained undetectable HCV RNA levels until the end of the treatment and this was maintained throughout 12 weeks of post-treatment. SVR12 was achieved in 7 out of 8 patients (88%).
The most frequently reported adverse events were mild grade of nausea and dizziness, which were controlled by supportive management or medication. Two patients experienced treatment related serious adverse events (see below). None of the grade 3 or 4 laboratory abnormalities occurred in the rest of 6 patients. Most importantly, hemoglobin level was maintained consistently (
Two serious adverse events were reported along the treatment duration, including hepatic decompensation and AST flare up. A 68 year old female patient experienced hepatic decompensation. Her HCV RNA was undetectable at week 4 till week 12 and she did not complain of significant symptoms except for mild abdominal discomfort throughout the treatment. At week 15, she was hospitalized due to the development of jaundice and ascites. Laboratory findings revealed total bilirubin 7.8 mg/dL, AST 102 IU/L, ALT 179 U/L and Albumin 3.2 g/dL. Her liver dynamic CT scan showed moderate amount of ascites (
The other adverse event was associated with serum AST flare up (
This is the first report evaluating the efficacy of interferon and ribavirin free regimen composed only of oral agents including DCV and ASV in chronic HCV GT 1b patients in real-life practice in Korea. Patients with HCV GT 1b carried a higher risk for advanced liver disease such as cirrhosis or HCC than those with non-1b GTs (GTs 2, 3, 4, and 6) [
Patients who had no response or a partial response to previous therapy and those with liver cirrhosis are particularly difficult to cure [
In this study, serum AST, ALT levels and APRI decreased and the values were sustained during the treatment. These findings represent recovery of liver injury. Also, platelet count tends to increase with the treatment, which might be associated with improvement of portal hypertension. Successful treatment of HCV can provide prevention of the disease progression, cirrhosis regression and improvement of survival rates [
Few years ago, HCV protease inhibitors such as telaprevir, boceprevir were introduced for HCV treatment. HCV protease inhibitors in combination with PegIFN and RBV, achieved higher SVR rates than conventional PegIFN/RBV that 68% to 89% SVR rates in treatment-naïve patients with HCV GT 1 [
Patients with cirrhosis had more side effects related to interferon based therapy than in those without cirrhosis [
Limitations of this study include a relatively small number of patients enrolled and lack of NS5A mutation. In previous study, DCV/ASV therapy achieved 90% to 100% rates of SVR12 with the absence of NS5A resistance-associated variants (RAV) [
In conclusion, this all-oral, interferon and ribavirin free treatment of DCV and ASV is very effective and safe in real-life practice. DCV and ASV achieved SVR with low adverse events in patients with cirrhosis, previous nonresponsive to or relapsed after PegIFN/RBV. These results suggest that DCV and ASV combination therapy could be the effective treatment option in HCV genotype 1b patients, especially those ineligible or intolerant to interferon-based therapy.
Daclatasvir and Asunaprevir were supported by Bristol-Myers Squibb expanded access program.
hepatitis c virus
genotypes
daclatasvir
asunaprevir
pegylated interferon
ribavirin
sustained virological response
nonstructural protein 5A
aspartate aminotransferase
alanine aminotransferase
AST to platelet ratio index
resistance-associated variants
Serum HCV RNA levels of patients during 24 weeks of treatment and at 12 weeks posttreatment. (A) Treatment naïve patient. (B) Treatment naïve patient with advanced age. (C) Patient who relapsed after previous PegIFN/RBV therapy. (D) Patient who had nonresponsiveness to previous PegIFN/RBV therapy. HCV, hepatitis c virus; DCV, daclatasvir; ASV, asunaprevir; LLQ, lower limit of quantitation; PegIFN, pegylated interferon; RBV, ribavirin; EOT, end of treatment; SVR12, sustained virological response at 12 weeks after cessation of treatment.
Liver dynamic CT scan (A) and clinical course (B) of a patient who experienced hepatic decompensation during DCV and ASV treatment. HCV, hepatitis c virus; RNA, ribonucleic acid; DCV, daclatasvir; ASV, asunaprevir; LLQ, lower limit of quantitation; TB, total bilirubin.
Clinical course of a patient who showed AST flare up during DCV and ASV treatment. AST, aspartate aminotransferase; HCV, hepatitis c virus; RNA, ribonucleic acid; DCV, daclatasvir; ASV, asunaprevir; LLQ, lower limit of quantitation.
Demographics and baseline characteristics of the patients (n = 8).
Age, mean years (SD) | 65.75 (10.22) |
Sex (male/female) | 3/5 |
Liver status (chronic hepatitis/cirrhosis) | 0/8 |
HCV genotype 1b, n (%) | 8 (100) |
Prior treatment history of HCV (naïve/relapse/nonresponse) | 5/2/1 |
NS5A mutation, n (%) | 0 (0) |
HCV RNA, mean log IU/mL (SD) | 6.03 (0.45) |
ALT, mean U/L (SD) | 36.00 (12.66) |
Platelets x 109 cells/mL, median (min, max) | 84.50 (6, 133) |
Total bilirubin, mean mg/dL (SD) | 0.78 (0.21) |
Albumin, mean g/dL (SD) | 3.83 (0.53) |
INR, median (min, max) | 1.03 (0.97, 1.13) |
BMI, mean (SD) | 26.40 (3.58) |
Diabetes, n (%) | 3 (37.50) |
Hytertension, n (%) | 3 (37.50) |
HCV, hepatitis c virus; NS5A, nonstructural protein 5A; ALT, alanine aminotransferase; INR, international normalized ratio; BMI, body mass index.
Clinical laboratory data during treatment
Baseline | Week 4 |
Week 12 |
Week 24 |
Week 36 |
|
---|---|---|---|---|---|
Leukocyte count (/μL) | 3,975.00 (949.81) | 362.50 (261.14) | 197.14 (196.17) | 571.43 (350.32) | 1,583.33 (875.75) |
Neutrophil count (/μL) | 1,870.00 (621.43) | 81.25 (191.55) | 37.14 (156.02) | 277.14 (224.54) | 1,390.00 (855.05) |
Hemoglobin (g/dL) | 13.33 (3.05) | -0.48 (0.41) | -0.31 (0.41) | -0.30 (0.46) | 0.50 (0.58) |
Platelet count (/μL) | 76.38 (39.98) | 18.25 (15.48) | 15.71 (18.16) | 14.57 (11.01) | 10.17 (2.63) |
INR | 1.04 (0.06) | 0.01 (0.01) | 0.01 (0.01) | 0.06 (0.09) | -0.04 (0.02) |
Total bilirubin (mg/dL) | 0.78 (0.21) | 0.21 (0.11) | -0.03 (0.08) | 0.94 (0.98) | -0.03 (0.08) |
AST (IU/L) | 74.50 (42.52) | -31.50 (19.53) | -41.43 (16.44) | -34.29 (22.46) | -49.17 (17.63) |
ALT(IU/L) | 36.00 (12.66) | -20.63 (5.96) | -14.14 (7.62) | 5.71 (23.79) | -20.33 (6.82) |
Creatinine (mg/dL) | 0.74 (0.14) | 0.02 (0.03) | 0.02 (0.03) | 0.07 (0.04) | 0.13 (0.04) |
APRI | 4.32 (4.79) | -3.30 (1.72) | -3.74 (1.82) | -3.53 (1.59) | -2.27 (1.16) |
INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; APRI, AST to platelet ratio index.
Data are baseline mean value (standard deviation) or mean change from baseline (standard error).
Data are mean change from baseline to treatment weeks.