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SVR of 8-Weeks Ledipasvir/Sofosbuvir Therapy

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Name of journal: World Journal of Gastroenterology

ESPS Manuscript NO:32607

Manuscript type:Retrospective study

Eight-week Ledipasvir/Sofosbuvir Therapy in Non-Cirrhotic, Treatment-naïve Hepatitis C Genotype-1 Patients with HCV-RNA < 6 million IU/mL: Real World Effectiveness and Safety

Latt et al. 8-weel LED/SOF therapy for non-cirrhotic, treatment-naïve Hepatitis C genotype-1 Patients

Nyan L. Latt, Beshoy T. Yanny, Derenik Gharibian, Rita Gevorkyan, Amandeep K. Sahota

Nyan L. Latt, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, FL 32224, United States.

Beshoy T. Yanny, Amandeep K. Sahota, Division of Gastroenterology and Hepatology, Kaiser Permanente, Los Angeles Medical Center, Los Angeles, CA 90027, United States.

Derenik Gharibian, Pharmacy Operations Office, Kaiser Permanente, Los Angeles Medical Center, Los Angeles, CA 90027, United States.

Rita Gevorkyan, Department of Clinical Operations, Kaiser Permanente Southern California, CA 91107, United States.

Author contributions: Latt N designed the research, performed the data abstraction, contributed to the analysis and wrote the paper; Yanny B performed the data abstraction and contributed to the analysis; Gharibian D provided clinical advice and supervised the report; Gevorkyan R helped with the data abstraction and provided clinical advice; Amandeep S designed the research, provided clinical advice and supervised the report.

Institutional review board statement: This study was reviewed and approved by Kaiser Permanente Southern California Institutional Review Board.

Informed consent statement: Patients were not required to give informed consent to the study. The study was qualified for an 'exempt status' by the Institutional Review Board due to its retrospective nature. We collected only the existing data from electronic medical records, the date were stored without any patient identifiers.

Biostatistics statement: The analysis of this study was performed using IBM SPSS Statistics 20 (IBM, Armonk, NY).

Conflict-of-interest statement: We have no financial relationships to disclose.

Data sharing statement: No additional data are available.

 

Abstract

AIM: To evaluate SVR of 8-weeks ledipasvir/sofosbuvir therapy among non-cirrhotic, genotype-1 HCV patients with RNA <6 million IU/mL

METHODS: We performed a retrospective cohort study to examine SVR rates, predictors of treatment failure and safety analysis of 8-weeks LDV/SOF therapy among non-cirrhotic, genotype 1 HCV patients with viral load < 6 million IU/mL. Primary outcome of our study was achievement of SVR at 12 weeks after treatment. Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment.

RESULTS: Total 736 patients: 55% males, 51% Caucasians and 65% were genotype 1a. Non-cirrhotic state of 53% was determined by clinical judgment (imaging, AST, platelet count) and 47% had documented liver fibrosis testing. Overall SVR12 was 96%. No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. Age groups, gender, ethnicity and genotype 1 subtype did not predict SVR. Non-cirrhotic state determined by clinical judgment based on simple, non-invasive tests were not associated with lower SVR [OR: 1.02, CI: 0.48-2.17, p=0.962]. No death or morbidities were reported.

CONCLUSION: Our outcomes validate high SVR rates in non-cirrhotic, treatment-naïve HCV genotype 1 patients with HCV RNA < 6 million IU/mL who received 8-week LDV/SOF therapy.

Key words: Hepatitis C, cirrhosis, sustained viral response, ledipasvir, sofosbuvir

Core tip:This is a retrospective study to evaluate the real-world efficacy and safety of 8-week ledipasvir/sofosbuvir therapy in hepatitis C virus (HCV) genotype-1 patients with RNA < 6 million IU/mL. Currently, the HCV treatment guidelines differ in recommendation of the duration 8 week versus 12 week for this population. We validate high sustained viral response (SVR) in this subset of patients in a large real-world cohort. We also highlight SVRs in patients whose non-cirrhotic state determined by clinical judgment using simple, cheap, non-invasive tests are comparable with those who had liver biopsy, vibration-controlled transient elastography or specialized FIBROSPECT II test.

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Latt NL, Yanny BT, Gharibian D, Gevorkyan R, Sahota AK. 8-week Ledipasvir/Sofosbuvir Therapy in Non-Cirrhotic, Treatment-naïve Hepatitis C Genotype-1 Patients with HCV-RNA < 6 million IU/mL: Single Center, Real World Effectiveness and Safety. World J Gastroenterol 2017; In press

Introduction

Hepatitis C virus (HCV) infection is a major cause of cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality [1]. Recent studies estimate the prevalence of HCV to be between 1.2-1.5% in the United States, which is approximately 4.5-5 million. This population is composed of 1 million incarcerated/homeless individuals, hospitalized patients, and people living on Indian reservations, and also includes 3.6 million from the 2003-2010 National Health and Nutrition Examination Survey (NHANES) [2, 3]. The prevalence of HCV is declining, but HCV-related cirrhosis is still expected to peak in the year 2020 [4]. Therefore, effective, safe and well-tolerated treatment regimens with shorter duration are urgently needed.

Hepatitis C treatment has evolved from a 78-week interferon monotherapy to 48-week pegylated interferon plus ribavirin therapy and now 12-week therapy with newer direct-acting antiviral (DAA) agents. DAA regimens have revolutionized the treatment of hepatitis C with their excellent sustained virologic response (SVR), tolerable side effect profiles and shorter duration of therapy. Despite the high cost of newer DAAs, a cost-effective analysis has demonstrated that ledipasvir/sofosbuvir (LDV/SOF)-based regimens will reduce long-term HCV-related complications and are cost-effective in the majority of chronic HCV patients [5].

ION-3 trial demonstrated that an 8-week LDV/SOF therapy in non-cirrhotic, treatment naïve genotype 1 HCV patients with HCV RNA < 6 million IU/mL is non-inferior to 12-week LDV/SOF therapy [SVR: 94% vs 95%] [6]. The shorter duration of treatment can remarkably increase patient compliance and substantially reduce treatment cost. Real-world studies have reported that SVR rates are comparable to those observed in ION-3 trial [7-10]. However, conflicting data has been reported by a large real-world cohort from Veteran's Affairs (VA) in which researchers found that non-cirrhotic patients with HCV-RNA < 6 million IU/mL were less likely to achieve SVR with 8-week LDV/SOF treatment compared to 12-week treatment [9].

8-week LDV/SOF therapy for non-cirrhotic, genotype 1 HCV patients is not included in HCV guidelines by American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA) due to lack of real-world validation for comparable SVR with 12-week therapy (11). European Association for the Study of the Liver (EASL) and U.S. Food and Drug Administration (FDA) recommend considering 8-week therapy with caution in treatment-naïve genotype-1 HCV patients without cirrhosis who have pre-treatment viral load < 6 million IU/mL (12, 13). We performed a retrospective cohort study to examine the SVR rates, the predictors of treatment failure and the safety analysis of 8-weeks LDV/SOF therapy among non-cirrhotic, genotype-1 HCV patients with viral load < 6 million IU/mL.

Methods

Study population

Kaiser Permanente Southern California (KPSC) is a large, integrated healthcare system with over 4 million members. Integrated healthcare is delivered to members at 14 medical centers throughout the region. All interactions with the healthcare system, such as clinic/emergency department/urgent care visits, hospital admissions and outpatient laboratory tests are captured in an integrated electronic medical record (EMR) system and the data is available for research purposes. Emergency care delivered at outside facilities is captured in a claims system that is also available. The KPSC Regional guidelines for 8-week LDV/SOF therapy were developed and all providers were notified for eligibility criteria: genotype-1, non-cirrhotic, HCV-RNA < 6 million IU/ml and no prior treatment failure. Cirrhotic status was confirmed by liver biopsy or other non-invasive testing such as vibration-controlled transient elastography (VCTE) or FIBROSPECT II test in some KPSC centers. However, non-cirrhotic status was determined by clinical judgement of treating healthcare providers by using sonographic morphology of the liver, the spleen size and the platelet count (cut off value >150,000) in other KPSC centers. Every patient had hepatic sonography and baseline laboratory testing prior to hepatitis C treatment.  We developed a protocol for KPSC nurse practitioners, physician assistants and pharmacists, who specialized in hepatitis C treatment, to document intended treatment duration and rationales, pre-treatment testing and close monitoring of patients during treatment such as laboratory testing every 2 weeks, calling/messaging to identify any barriers/adverse events and providing coping mechanisms/strategies if any event occurred.

Inclusion criteria: patients with age ≥ 18 years, HCV viral load < 6 million IU/mL, no cirrhosis or prior treatment failure and who had received 8-week LDV/SOF therapy for chronic HCV genotype-1 infection. Exclusion criteria: patients without SVR12 (SVR at 12 weeks after end of treatment) data, patients who did not complete the intended therapy and patients who missed doses for more than seven consecutive days.  Individuals who fulfilled above criteria were included in the final study analysis.

Study design

We conducted a retrospective cohort study from December 2015 to December 2016, of all patients who had completed 8-week LDV/SOF therapy. Patient's clinical and demographic information was captured from KPSC-EMR system. We developed a standardized protocol with explicit criteria for data abstraction including pre- and post-treatment laboratory results, co-morbid medical conditions, liver biopsy (Metavir fibrosis staging), VCTE (kilopascal), FIBROSPECT II test (serum biomarkers), adverse events, clinic/urgent care/emergency department visits and hospitalizations during treatment. Two data abstractors, who are familiar with the EMR system, collected the data according to the protocol criteria to maximize the inter-rater reliability of data abstraction.

Safety analysis

Patient reported side effects such as fatigue, headache, insomnia, arthralgia/myalgia, nausea, cough, rash, dizziness, diarrhea, pruritus, irritability and edema, were recorded. Serious adverse events were defined as any event requiring care at the emergency department or hospital admission.

Study outcome

Primary outcome of our study was achievement of SVR at 12 weeks after treatment. Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment. SVR was defined as non-detectable level of HCV-RNA test.

Statistical analysis

For the primary endpoint evaluating SVR12 and for the evaluation of adherence, the final analysis was restricted to per-protocol fashion of those patients who completed therapy and returned for follow-up HCV-RNA testing 3 months after the end of treatment. The rationale to exclude patients who were lost to follow-up was to counter artificial lowering of the calculated SVR rates. Descriptive statistics were used to compare the baseline differences between those individuals who did or did not achieve SVR12. We used cross-tabulation with Pearson Chi-square test to determine the significant difference between categorical variables and 2-tailed Independent-samples T-test to determine the significant difference between 1 categorical variable and 1 quantitative variable. We used multivariate logistic regression to estimate odds ratio (OR) and 95% confidence intervals (CI) to identify predictors of treatment failure while adjusting for confounding variables. All data were entered into and analyzed using IBM SPSS Statistics 20 (IBM, Armonk, NY).

Results

We identified total of 775 non-cirrhotic, genotype 1 HCV patients with HCV-RNA < 6 million IU/mL who received 8-week LDV/SOF treatment. 736 patients were included in the final analysis after exclusion of patients who reported missing doses, discontinued treatment due to adverse events and patients who did not follow up for SVR12. Fig 1 demonstrates the flow chart of patient selection process.

The demographic and clinical characteristics of patients are outlined in Table 1. The mean age of 58 years, 55% males, 51% Caucasian and 65% with genotype 1a. 53% of patients considered to be non-cirrhotic state was determined by providers based on clinical judgement and 47% had documented liver fibrosis testing (43% liver biopsy, 3% VCTE and 0.4% FIBROSPECT II). Mean HCV-RNA log10 was 6.2.

Table 2 demonstrates study outcomes (SVR). Overall SVR12 was 96%. None of the patients who achieved SVR12 had viral relapse at 24-week post treatment. 59% patients had SVR24 data at the time of analysis. We found no difference in SVR12 between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. No significant difference in SVR12 was seen among gender, genotype 1 subtype, ethnicity, type of fibrosis tests and fibrosis stages. Special populations; those co-infected with HIV and HBV achieved 100% SVR12. When reviewed by age groups, patients with age > 65 years had lower SVR compared to age groups 55-65 and < 55 years but no statistical significance was observed. We found significantly lower SVR in patients whose HCV-RNA were more than 2,200,000 IU/mL [91% vs 98%, p<0.001].

Table 3 exhibits the odds ratios for SVR12 in multivariate logistic regression. We found that patients with HCV-RNA < 800,000 IU/mL were more likely to achieve SVR compared to those with more than 800,000 IU/mL [OR: 7.91, CI: 1.86-33.63, p=0.005].  Age groups, gender, ethnicity and genotype 1 subtype did not predict SVR. Non-cirrhotic state determined by clinical judgment based on simple, non-invasive tests was not associated with lower SVR [OR: 1.02, CI: 0.48-2.17, p=0.962].

Table 4 reveals the safety analysis of the patients who received 8-week LDV/SOF therapy. 4 (0.5%) patients discontinued treatment due to intolerable adverse events. 1 patient who discontinued treatment developed drug-induced liver injury (DILI) with positive biopsy findings. No death or significant morbidities were reported. 4 (0.5%) patients experienced serious adverse events during therapy: 2 were hospitalized for observation to evaluate non-cardiac chest pain, 1 was hospitalized for DILI and 1 was due to emergency department admission for pneumonia. The most common minor adverse events were fatigue (14%), headache (13%), insomnia (5%), arthralgia/myalgia (4%) and nausea (4%).

Discussion

Our findings have validated that SVR rate of 8-week LDV/SOF therapy in treatment naïve, non-cirrhotic, genotype 1 HCV patients with RNA < 6 million IU/mL is comparable with clinical trials and preliminary outcomes from small real-world studies [7-9]. We demonstrated that there is no difference in SVR between patients whose cirrhosis state was determined by fibrosis testing or clinical judgment. All patients had at least baseline ultrasound of the liver and blood tests such as transaminases levels, platelet count and International normalized ration (INR). We calculated overall fibrosis stages on biopsy, VCTE and FIBROSPECT II and found no difference in SVR across fibrosis stages although very few patients had stage 0, 3 and 4. Our finding suggests that clinical judgment of non-cirrhotic state results in same outcome of SVR 96% compared to SVR of patients who had liver biopsy, VCTE or FIBROSPECT tests.

In our cohort, all patients had pre-treatment HCV-RNA < 6 million IU/mL. We divided to 2 subgroups containing RNA < 800,000 IU/mL and > 800,000 IU/mL. We found that patients with lower RNA <800,000 IU/mL achieved significantly higher SVR compared to patients with higher RNA in both univariate and multivariate analyses. This finding suggests that HCV viral load plays an important role in predicting SVR although the determination of the optimal cut-off value of HCV-RNA level to consider 8-week therapy to achieve SVR is currently not available (14). While female gender and Hispanic ethnicity achieved slightly higher SVRs, there is no statistical difference compared to male gender and other ethnicities. We found no difference in SVR rates between African-Americans and Caucasians in contrast to other studies which demonstrated the decreased likelihood of SVR in African-American population [12, 17].

The wholesale acquisition cost (WAC) for LDV/SOF combination drug in the United States is $1,125 per pill. Cost of 8-week course of therapy is $63,000 and cost of 12-week course is $94,500 - net cost saving of $31,500 per patient when 8-week treatment is administered. Healthcare expenses can substantially be reduced by selecting 8-week LDV/SOF therapy in treatment-naïve, non-cirrhotic genotype 1 HCV patients.

The strengths of our study are its real-world experience and an integrated healthcare model involving all clinical services. We were able to abstract data regarding all clinic/emergency department/urgent care visits, hospitalizations, telephone/electronic-mail encounters and all laboratory tests from the integrated EMR system. All providers used KPSC-Regional HCV treatment guidelines which is readily available on the EMR system for review. Treatment duration, reasons for discontinuation and medication compliance were clearly documented. All patients in the final analysis had good post-treatment follow ups with available SVR12 data. 59 % also had SVR24. The limitation of our study is its retrospective nature.

In conclusion, our outcomes from real-world cohort validate high SVR rates in non-cirrhotic, treatment naïve HCV genotype 1 patients with HCV RNA < 6 million IU/mL who received 8-week LDV/SOF therapy. There was no difference in SVR between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. LDV/SOF is safe and well-tolerated with high adherence rates. Therefore, 8-week LDV/SOF therapy can be used in selected subset of patients with chronic HCV genotype 1 infection who meet aforementioned clinical criteria. 

Table 1. Demographic and Clinical Characteristics of Patients prior to Hepatitis C Treatment

Characteristics

N=736

Age, mean ± SD (years)

Range

58±10

(23-85)

Male sex, no. (%)

403 (55%)

Ethnicity, no. (%)

Caucasian

African American

Hispanic

                 Asian/Pacific islanders

374 (51%)

178 (24%)

158 (21%)

26 (4%)

HCV genotype-subtype, no. (%)

1a

1b

1 without confirmed subtype

475 (64%)

242 (33%)

19 (3%)

Liver biopsy, no. (%)

Vibration-controlled Transient Elastography, no. (%)

FIBROSpect II, no. (%)

Overall fibrosis score :

Stage 0

Stage 1

Stage 2

Stage 3

Stage 3-4 or 4

317 (43%)

25 (3%)

3 (0.4%)

45 (13%)

164 (48%)

104 (30%)

29 (8%)

2 (1%)

Non-cirrhotic state determined by clinical judgement, no. (%)

391 (53%)

HCV RNA - log10 IU/mL, mean ± SD

HCV RNA ≥ 2.2 million IU/mL - no. (%)

6.2±0.2

219 (30%)

Pre-treatment laboratory values:

GFR, mean ± SD (Range)

Platelet count (103 /mm3), mean ± SD (Range)

INR, mean ± SD (Range)

Albumin, mean ± SD (Range)

Missing, no. (%)

79±11 (40-89)

218±55 (45-495)

0.99±0.7 (0.8-1.3)

3.9±0.4(2.1-5.1)

101 (14%)

Co-morbid conditions

Psychiatric diagnoses

Chronic kidney disease

Psoriasis

HIV co-infection

Cryoglobulinemia

HCV-related glomerulonephritis

HBV co-infection

Hepatocellular carcinoma

145 (20%)

35 (5%)

16 (2%)

5 (0.7%)

4 (0.5%)

2 (0.3%)

2 (0.3%)

1 (0.1%)

 

Table 2: SVR12 Rate by Various Patient Characteristics for Non-Cirrhotic Patients with Genotype 1 HCV Infection Treated with 8-week Ledipasvir/Sofosbuvir Therapy

Characteristics

SVR 12 (%) (n=736)

p-value

Overall

96 (708/736)

Non-cirrhotic state determined by clinical judgement, no. (%)

Non-cirrhotic state determined by biopsy, VCTE, FIBROSPECT II, no. (%)

96 (376/391)

96 (332/345)

0.962

HCV RNA ≥ 2.2 million IU/mL

HCV RNA < 2.2 million IU/mL

92 (201/219)

98 (507/270)

<0.001

HIV co-infection

100 (6/6)

HBV co-infection

100 (2/2)

Gender

Male

Female

95 (383/403)

98 (325/333)

0.071

HCV genotype-subtype

1a

1b

Undetermined

96 (454/475)

98 (236/324)

95 (18/19)

0.414

Ethnicity

Caucasian

African American

Hispanic

Asian/Pacific Islander

96 (357/374)

96 (171/178)

98 (155/158)

96 (25/26)

0.544

Age groups

< 55 year

55-65 year

> 65 year

97 (216/223)

97 (369/382)

94 (123/131)

0.311

Fibrosis Tests

Liver biopsy

Vibration-controlled transient elastography

FIBROSPECT II

97 (306/317)

92 (23/25)

100 (3/3)

0.489

Overall fibrosis stage (cumulative: biopsy/VCTE/FIBROSPECTII)

Stage 0

Stage 1

Stage 2

Stage 3

Stage 4

98 (44/45)

95 (155/164)

98 (102/104)

97 (28/29)

100 (2/2)

0.611

 

Table 3: Odds Ratios for Sustained Viral Response at 12 weeks in Multivariate Logistic Regression for Non-Cirrhotic, Hepatitis C Genotype 1 Patients Treated with 8-week Ledipasvir/Sofosbuvir Therapy

Characteristics

Odds Ratio (95% CI) for SVR12

(n=736)

Significance Level (P value)

Age 55-65 years (ref. < 55)

0.92 (CI: 0.36-2.34)

0.861

Age > 65 years (ref. < 55)

0.5 (CI: 0.18-1.41)

0.188

Male (ref. female)

0.47 (CI: 0.21-1.08)

0.077

African-American (ref. Caucasian)

0.84 (CI: 0.11-6.57)

0.868

Hispanic (ref. Caucasian)

2.07 (0.21-20.66)

0.537

Asian/Pacific Islander (ref. Caucasian)

0.98 (CI: 0.16-8.28)

0.983

Non-cirrhotic state determined by clinical judgement

(ref. Fibrosis Test: biopsy/VCTE/FIBROSPECT)

1.02 (CI: 0.48-2.17)

0.962

HCV RNA ≥ 2,200,000 IU/ml (ref. < 2,200,000 IU/ml)

0.22 (CI:0.1-0.49)

<0.001

HCV genotype - subtype 1b (ref. 1a)

2.19 (CI: 0.25-19.15)

0.480

 

Table 4: Adverse Events, Hospital Admissions and Discontinuation Rates of Patients with Genotype 1 HCV Infection who Received 8-week Ledipasvir/Sofosbuvir Therapy

Adverse Events

No. (%)

No. adverse event, mean ± SD (Range)

0.5±0.7 (0-6)

Serious adverse events

Hospital admissions

Non-cardiac chest pain

Drug-induced liver injury

Pneumonia

4 (0.5%)

2

1

1

Minor adverse events

Fatigue

Headache

Insomnia

Arthralgia/Myalgia

Nausea

Cough

Rash

Dizziness

Diarrhea

Pruritus

Irritability/Anxiety

Edema

104 (14%)

98 (13%)

35 (5%)

29 (4%)

29 (4%)

15 (2%)

19 (3%)

12 (2%)

14 (2%)

11 (1%)

10 (1%)

2 (<0.5%)

Discontinuation

Drug-induced liver injury

Severe rheumatoid arthritis exacerbation

Intractable nausea

Decreased renal function during treatment (GFR < 30)

4 (0.5%)

1

1

1

1

Death

0

[U2][NL3]

Figure 1: Flow Chart of Patient Selection Process. This flow chart summarizes patient identification for eligibility and inclusion/exclusion criteria

 

Figure 2: Sustained Virologic Response Rates among Patients with Various Clinical and Demographic Characteristics

 

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Study Highlights

  • Validation of clinical outcome with high overall SVR24 96% in selected subset of patients with HCV infection and good safety profile in a large real-world cohort
  • SVRs in patients whose non-cirrhotic state determined by clinical judgment using simple, cheap, non-invasive tests are comparable with those who had liver biopsy, vibration-controlled transient elastography or specialized FIBROSPECT II test

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