Abstract
The introduction of sofosbuvir, a direct acting antiviral, has revolutionized the treatment of chronic hepatitis C virus (HCV). Phase 3 clinical trials have demonstrated the efficacy, simplicity, and tolerability of sofosbuvir-based regimens and report high rates of sustained virological response (SVR) rates. The purpose of this study was to assess whether clinical trial findings translate into a real-world setting, particularly with treatment of chronic HCV in our diverse, multiethnic population of Hawai‘i. Retrospective analysis was performed for 113 patients with genotype 1–6 HCV infection being treated at the Queen's Liver Center between January 2014 and March 2015. SVR rates for our cohort were slightly lower than the rates published by the clinical trials. Data analysis also suggested that most baseline characteristics previously associated with inferior response might not be as significant for sofosbuvir-based regimens; in our cohort, male gender was the only factor significantly related to increased risk of virologic relapse. Pacific Islanders also had higher rate of relapse compared to other ethnic groups, but the small number of patients treated in this subgroup make it difficult to validate this finding. While newer all-oral treatment regimens have been introduced since this study, we highlight the importance of comparing real-world versus clinical trial results for new treatments, and provide data analyses for treatment of chronic HCV in Hawai‘i.
Keywords: HCV, sofosbuvir, Sovaldi, real-world, effectiveness
Introduction
Hepatitis C virus (HCV) is the most common bloodborne infection, with at least 5.2 million people living with HCV in the United States.1 If left untreated, chronic HCV leads to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. Consequently, it is the leading cause of end-stage liver disease and liver transplantation. The introduction of direct acting antiviral agents, in particular sofosbuvir (SOF), has revolutionized the treatment for chronic hepatitis C virus. With SOF-based regimens, we have achieved high cure rates and decreased the duration of treatment. Phase 3 clinical trials (Neutrino, Fission, Valence) have demonstrated the efficacy, simplicity, and tolerability of SOF-based regimens in a clinical trial setting. Patients in large clinical trials are often selected for high adherence and limited comorbidities. Therefore, similar treatment outcomes may be difficult to achieve with patients in a real-world setting. In order to determine whether the results from these Phase 3 trials will translate to a community setting, we report our experience at the Queen's Liver Center with these SOF-based regimens. Our patient population consists of the multiethnic population of Hawai‘i, with patients that have factors previously associated with inferior treatment response that would not have been included in the clinical trials. Through this retrospective review, we analyze the effectiveness, tolerability, adherence, and overall outcomes and compare them to those reported by the Phase 3 trials.
Methods
Study Population
We performed a retrospective review of patients ≥18 years of age with HCV genotype 1–6 infection being treated with SOF-based regimens at the Queen's Liver Center between January 2014 and March 2015. Both treatment-naïve and treatment-experienced patients were included in the review. Patients with any of the following were excluded from review: HIV co-infection, hepatitis B virus co-infection, liver transplant recipient.
Study Design
Eligible patient charts were reviewed for demographic and relevant clinical data including age, sex, ethnicity, body mass index (BMI), comorbidities, presence of cirrhosis, HCV genotype, and prior treatment history. Patients with prior HCV treatment history were categorized based on their virological response during prior treatment; virologic relapse was defined as undetectable HCV RNA during treatment, but subsequent detectable HCV RNA after end of treatment. Presence of comorbidities was defined as having at least one of the following: chronic obstructive pulmonary disease, diabetes mellitus, coronary artery disease, or anxiety/depression. All patients were treated for chronic HCV according to AASLD guidelines at the time (Table 1), which were based on the results from the sofosbuvir Phase 3 trials.2,3
Table 1.
Sofosbuvir-based regimen for initial treatment of chronic HCV, 2014 AASLD guidelines
| Population | Regimen | Duration |
| Genotype 1/4/5/6 | Daily sofosbuvir (400 mg) + RBV* + Peg-INF | 12 weeks |
| Genotype 2 | Daily sofosbuvir (400 mg) + RBV* | 12 weeks |
| Genotype 3 | Daily sofosbuvir (400 mg) + RBV* | 24 weeks |
RBV Dosage is weight-based: 1000 mg [<75 kg] to 1200 mg [>75kg]
Baseline laboratory values were collected for all patients. Baseline values were defined as the most recent values prior to starting HCV treatment. These values included alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), creatinine, international normalized ratio (INR), hemoglobin (Hb), and platelets. After initiating treatment, these laboratory values were monitored every 4 weeks until end of treatment as well as post-treatment weeks 4 and 12.
This study was approved by the Institutional Review Board at the Queen's Medical Center of University of Hawai‘i (RA-2014-048).
Efficacy Assessment
Sustained virological response (SVR) is defined as the absence of detectable HCV RNA in serum after end of treatment, traditionally 24 weeks post-treatment. With the introduction of SOF-based regimens, SVR at 12 weeks post-treatment (SVR12) is now the standard clinical end point of successful antiviral treatment and was used as the primary end point in this study.4 SVR was evaluated using plasma concentrations of HCV RNA collected throughout and after the course of treatment. Patients provided samples at baseline and treatment weeks 2, 4, 8, 12 (also weeks 16, 20, 24 for genotype 3) as well as post-treatment weeks 4 and 12. The COBRAS TaqMan HCV Test v2.0, which has a lower limit of quantification of 15 IU/mL, was used to quantify HCV RNA. Patients missing HCV RNA results at end of treatment, SVR4, or SVR12 were considered as lost to follow-up. Patients with detectable HCV RNA after receiving SOF-based treatment were categorized accordingly.
Status of IL28B genotype, which has been shown to be an indicator of response to HCV interferon-based therapy, was determined by amplification and sequencing of the rs12979860 single-nucleotide polymorphism. Due to the retrospective nature of this study, IL28B genotype information was not available for all patients.
Safety Assessment
Patient charts were reviewed for adverse events as well as any abnormal findings on physical examination and clinical laboratory tests. Concomitant medications were also recorded.
Statistical Analysis
Data analysis was performed using R v3.0.3 and done by intention-to-treat. Continuous variables were summarized by descriptive statistics (eg, mean, standard deviation, range). Categorical variables were summarized using counts of patients and percentages. Statistical tests were two-sided and levels were set at 0.05. Multivariate logistic regression analyses were performed to compare SVR rates for subgroups.
Results
Baseline Characteristics and Demographics
A total of 113 patients were identified. Baseline characteristics of the patient population are summarized and categorized by regimen in Table 2. Compared to other genotypes, there were fewer genotype 1 patients with cirrhosis included in the cohort as they were being treated with combination of sofosbuvir and simeprevir, which was more tolerable for these patients and the only interferon-free option at the time. There were no other significant differences in baseline characteristics between each genotype group.
Table 2.
Baseline clinical characteristics of patient cohort, by genotype and regimen
| GT 1, 4, 5, 6 SOF+PEG+RBV for 12 wks (N = 35) | GT2 SOF+RBV for 12 wks (N = 45) | GT3 SOF+RBV for 24 wks (N = 31) | |
| Mean age (range) | 56 (29–71) | 61 (40–83) | 58 (28–72) |
| Mean BMI (range) | 27 (18–44) | 28 (15–46) | 30 (20–61) |
| Male sex - n (%) | 18 (51) | 25 (56) | 15 (48) |
| Ethnicity - n (%) | |||
| Caucasian | 18 (51) | 18 (40) | 14 (45) |
| Asian | 11 (31) | 18 (40) | 9 (29) |
| Hispanic/Latin | 2 (6) | 1 (2) | 2 (7) |
| Pacific Islander | 4 (12) | 6 (13) | 6 (19) |
| Other | 0 | 2 (5) | 0 |
| HCV subtype - n (%) | |||
| 1a | 19 (54) | -- | -- |
| 1b | 13 (37) | -- | -- |
| 2 | -- | 45 (100) | -- |
| 3 | -- | -- | 31 (100) |
| 4 | 0 | -- | -- |
| 5 | 0 | -- | -- |
| 6 | 3 (9) | -- | -- |
| Factors Previously Associated with Inferior Response | |||
| Age ≥ 50 - no. (%) | 26 (74) | 40 (89) | 29 (94) |
| BMI ≥ 30 - no. (%) | 9 (26) | 20 (44) | 10 (32) |
| HCV RNA ≥ 800,000 IU/ml - no. (%) | 26 (74) | 29 (64) | 21 (68) |
| Cirrhosis - n (%) | 5 (14) | 19 (42) | 12 (39) |
| Prior treatment - n (%) | |||
| Null responder† | 2 (6) | 5 (11) | 1 (3) |
| Partial Responder‡ | 2 (6) | 0 | 1 (3) |
| Relapse | 7 (20) | 4 (9) | 2 (6) |
| IL28B genotype - n (%)* | |||
| CC | 3 (9) | -- | -- |
| CT | 11 (31) | -- | -- |
| TT | 1 (3) | -- | -- |
| Not collected | 20 (57) | -- | -- |
Non-CC is associated with inferior response
Null response was defined as HCV RNA that did not decline by at least 2 log IU/mL at treatment week 12.
Partial response was defined as HCV RNA levels that dropped by at least 2 log IU/mL at treatment week 12, but HCV RNA is still detectable at end of treatment.
Efficacy
Overall SVR12 rates for our patients were lower than the rates seen during clinical trials (Table 3). Similar to the Phase 3 studies, SVR rates for our cirrhotic patients were lower compared to their non-cirrhotic counterparts (genotype 1/4/5/6: 80% vs 83%; genotype 2: 83% vs 96%; genotype 3: 88% vs 95%). There were no other differences in SVR12 rates for subgroups including ethnicity, age, sex, BMI, and prior treatment history. No patients experienced virologic breakthrough while on SOF-based regimens. All 11 cases of virologic failure were due to relapse; there were 2 genotype 1a, 2 genotype 1b, 1 genotype 6, 3 genotype 2, and 3 genotype 3 patients. Male gender was a statistically significant predictor for relapse, while other baseline characteristics showed no statistical significance (Table 4). Pacific Islander patients also had higher rates of relapse with borderline significance.
Table 3.
Comparison of SVR12 rates, Phase 3 Trial vs QMC Liver Center
| Study | Population | SVR12 Rates | |
| Phase 3 Trial | QMC Liver Center | ||
| NEUTRINO | Genotype 1,4,5,6; treatment-naïve | 90% | 75% |
| FISSION | Genotype 2; treatment-naïve | 97% | 93% |
| VALENCE | Genotype 3; treatment-naïve or experienced | 85% | 81% |
Table 4.
Bivariable analysis for baseline characteristics of virologic relapsers
| Baseline Characteristic | Odds Ratio (OR) | 95% Confidence Intervals | P values |
| Age: ≥ 50 vs < 50 | 1.8947 | 0.2282 to 15.7303 | .554 |
| Gender: Male vs female | 9.4828 | 1.1747 to 20.6342 | .0348 |
| BMI: ≥ 30 vs < 30 | 2.2769 | 0.6533 to 7.9361 | .197 |
| Viral load: HCV RNA ≥ 800,000 IU/mL vs < 800,000 IU/mL | 0.8867 | 0.2443 to 3.2178 | .855 |
| Cirrhosis vs no cirrhosis | 1.7824 | 0.5101 to 6.2279 | .365 |
| Prior treatment: Treatment-experienced vs treatment-naïve | 2.1190 | 0.5726 to 7.8426 | .261 |
| Ethnicity: Pacific Islander vs non-Pacific Islander | 3.4643 | 0.9094 to 13.1972 | .0686 |
There was high concordance (>97%) between SVR4 and SVR12 for all genotypes (Figure 1); 2 out of 104 patients that reached SVR4 had virologic relapse at SVR12.
Figure 1.
SVR4 and SVR12 rates of QMC Liver Center patients, by genotype
Adherence and Safety
Adverse effects and resulting treatment interruptions are summarized in Table 5. Most common side effects include fatigue, headache, and anemia. The rate of severe adverse effects was low in all genotype groups, particularly those on interferon-free regimens. Anemia, ribavirin dose reductions, and missed doses were more frequent among genotype 3 patients. Incidence and severity of adverse effects were similar across all subtypes.
Table 5.
Treatment adherence and side effects of SOF-based regimens, by genotype
| GT 1, 4, 5, 6 SOF+PEG+RBV for 12 wks (N = 35) | GT2 SOF+RBV for 12 wks (N = 45) | GT3 SOF+RBV for 24 wks (N = 31) | |
| Discontinuing treatment - n (%) | |||
| Due to adverse effect | 2 (6) | 0 | 2 (6) |
| Lost to follow-up | 0 | 1 (2) | 1 (3) |
| Adverse effects - n (%) | |||
| Any adverse effect during treatment | 32 (91) | 35 (78) | 25 (81) |
| Serious adverse effect during treatment | 4 (11) | 1 (2) | 1 (3) |
| Common adverse effects - n (%) | |||
| Fatigue | 24 (69) | 22 (48) | 12 (39) |
| Headache | 7 (20) | 10 (22) | 4 (13) |
| Nausea | 8 (23) | 3 (7) | 6 (19) |
| Anemia | 8 (23) | 5 (11) | 5 (16) |
| Insomnia | 6 (17) | 3 (7) | 2 (6) |
| Flu-like symptoms | 12 (34) | 3 (7) | 3 (10) |
| Pruritus | 10 (29) | 6 (13) | 4 (13) |
| Myalgia | 7 (20) | 2 (4) | 1 (3) |
| Neutropenia | 4 (11) | 0 | 0 |
| Depression and/or anxiety | 4 (11) | 2 (4) | 0 |
| Anemia-related event - n (%) | |||
| Hemoglobin < 10 g/dL | 4 (11) | 3 (7) | 5 (16) |
| Ribavirin dose change | 4 (11) | 6 (13) | 4 (13) |
| Use of erythropoietin | 2 (6) | 0 | 0 |
| Missed dose - n (%) | 4 (11) | 6 (13) | 7 (23) |
Out of the 113 patients treated with SOF-based regimens, 6 were discontinued on treatment: two patients were genotype 1 patients that stopped treatment due to Peg-INF intolerance; one genotype 2 patient was lost to follow-up; two genotype 3 patients discontinued treatment due to side effects while one was lost to follow-up.
Discussion
In this retrospective review, we compared our real-world experience with SOF-based regimens to the results reported by Phase 3 trials. These comparisons are important since the outcomes from large-scale studies are not necessarily reflected in the real world, where there is less control over patient adherence, comorbidities, and other factors that may affect SVR rates. Additionally, our cohort consisted of a higher percentage of Asian, Pacific Islanders, older age, and cirrhotic patients.
The SVR rates among our patients at the Queen's Liver Center were lower than the rates reported in clinical trials. This can be attributed to the inclusion of patients who may be excluded from clinical trials, such as those with prior treatment history, non-adherence, and comorbidities that make them more likely to discontinue treatment or become lost to follow-up. Furthermore, our genotype 3 patients had a higher rate of missed doses compared to other genotypes, which was most likely due to longer duration of the regimen (24 weeks vs. 12 weeks). Most factors previously associated with inferior response such as advanced fibrosis, high viral load, or older age may not hold the same importance with SOF-based regimens as they did for interferon-based therapy; based on our analysis, only male gender still remains a statistically significant factor for increased rate of relapse. These findings suggest that most baseline characteristics may no longer be relevant predictive factors when treating patients with SOF-based regimens. While Pacific Islanders also had notably increased rate of relapse, a larger patient pool for this ethnic group is needed to further explore this observation.
Newer all-oral, ribavirin-free treatments for chronic HCV have been approved since this review, along with ongoing efforts to develop a pan-genotypic drug. With the rapid development of more effective and tolerable treatments, the SOF-based regimens discussed here have been replaced with newer options to treat chronic HCV in the United States, although these regimens may remain relevant in developing countries. Yet, this study highlights the importance of evaluating efficacy (ie, will this treatment work under ideal circumstances?) and effectiveness (ie, will this treatment work under real-world circumstances?). We also provide data for future analyses of HCV treatment among our multiethnic populations of Hawai‘i.
Acknowledgments
The authors would like to acknowledge the contribution of our patients and their families for entrusting us with their medical care and our staff for their valuable support. We would also like to thank the Queen's Medical Center for supporting this research project.
Conflict of Interest
None of the authors identify any conflict of interest.
References
- 1.Chak E, Talal AH, Sherman KE, et al. Hepatitis C virus infection in USA: An estimate of true prevalence. Liver Int. 2011;31(8):1090–1101. doi: 10.1111/j.1478-3231.2011.02494.x. [DOI] [PubMed] [Google Scholar]
- 2.Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878–1887. doi: 10.1056/NEJMoa1214853. [DOI] [PubMed] [Google Scholar]
- 3.Jacobson I, Gordon S, Kowdley K V, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368(20):1867–1877. doi: 10.1056/NEJMoa1214854. [DOI] [PubMed] [Google Scholar]
- 4.Yoshida EM, Sulkowski MS, Gane EJ, et al. Concordance of sustained virological response 4, 12, and 24 weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus. Hepatology. 2015;61(1):41–45. doi: 10.1002/hep.27366. [DOI] [PubMed] [Google Scholar]