Sofosbuvir and Ribavirin for Hepatitis C Genotype 1 in Patients with Unfavorable Treatment Characteristics
STUDY PURPOSE: Was the purpose stated clearly? ✓ Yes ___ No Outline the purpose of the study (i.e., study objective or aim): – This study’s purpose was to assess the safety and effectiveness of sofosbuvir and ribavirin (either weight based or low dose) in patients who are of black race, have advanced liver fibrosis, elevated baseline HCV viral loads, IL28B CT or TT genotypes or previous treatment experience.
LITERATURE: Was relevant background literature reviewed? ✓ Yes ___ No Describe the justification of the need for this study (3-4 key points) o The concomitant use of ribavirin along with direct-acting antivirals have not been extensively studied. o The dosing of ribavirin has not been studied. o Certain factors such as: black race, advanced liver fibrosis, elevated HCV viral loads, IL28B CT or TT genotypes and those with previous treatment experience have been marginalized in previous studies. DESIGN: ✓ randomized ___ cohort (population -based) ___ before and after ___ case-control ___ cross-sectional (1+ group at 1 point in time) ___ single case design ___ case study Describe the study design:
– This study consisted of two parts. The first part was a proof of concept: which included 10 patients who were selected based on their mild-moderate liver fibrosis. The patients in the first part of the study were not randomized. They received weight-base dosing of ribavirin. Patients who weighed >75 kg received 1200 mg/day of ribavirin with 400mg of sofosbuvir. Patients who weighed ≤75 kg received 1000 mg/day with 400mg of sofosbuvir. – The second part of the study consisted of randomization of 50 patients from all stages of liver fibrosis. These patients received 400 mg of sofosbuvir with either weight-based or low dose ribavirin. – For patients in which the treatment failed, they receive the standard of care. Can the author answer the study question with the study design?
– Yes, the participant characteristics reflected patients who are underrepresented in previous studies. The proof of concept part of the study is relevant because it establishes the safety of the drug in the target population.
Were the design and/or method used introducing biases. If so describe:
– A potential bias with the study design is the small sample size. This may have an impact of how the results of the study are interpreted, it’s more difficult to find significance. SAMPLE SIZE: N = 60 Was sample size justified? ✓ Yes ___ No ___ N/A
Was Power Discussed? ✓ Yes ___ No ___ N/A Sample Description (e.g., age, gender, diagnosis, other characteristics) o Age: 48-54 years of age o Gender: ♣ Part I: 4 men ♣ Part II: 33 men o Diagnosis: ♣ Knodell Liver Score: • 0-1 • 3-4 o Characteristics: ♣ Ethnicity: Black, White, Hispanic How was sample identified? Was it a representative sample? – The sample was identified in a clinical research center of the National Institutes of Health located in Maryland, Bethesda. – The sample was representative, it included the population of unfavorable characteristics, however it was only from one location (Maryland), therefore it didn’t consider recruiting patients from all areas of the country. Consequently, the results may not be generalizable to the entire population.
If there were more than one group, was there similarity and differences between the groups? Describe: – Since the study consisted of two different parts, there were two groups. The first group included 10 patients which of whom were non-randomized and had mild to moderate liver fibrosis. The second part of the study (the actual randomized clinical trial) included 50 patients with all stages of liver fibrosis. The differences between the groups are the staging of liver fibrosis, this is reasonable however because the first part of the study was to establish safety (proof of concept) whereas the second part was intended to establish efficacy. Another difference was that the first part only considered weight based ribavirin, whereas the second part included both weight-based and low dose ribavirin.
Was informed consent and assent obtained? – Informed consent was acquired from all patients with the exception of two patients which had low literacy. However, the study addressed this by reading and explaining the consent to these two patients and they gave oral consent. OUTCOMES: Specify the frequency of outcome measurement (i.e., pre, post, follow-up): In the 24-week treatment, the outcomes were measured every 4 weeks. After the 24 weeks, outcomes were measured 2, 4, 4 and 12 weeks posttreatment. Outcome areas (e.g., self care, productivity)
– Safety of RBV+SOF o Minimize adverse events – Patient adherence – Relapse rates List measures used (e.g., Sensory Profile, VMI)
⇒ Sustained Virologic Response ⇒ Plasma HCV RNA levels ⇒ Improvement of LFTs ⇒ Improvement in inflammation Reliable and Valid? ⇒ ⇒ Yes, the outcome measures (undetectable hepatitis C virus (SVR24) are reliable and valid with regards to HCV.
INTERVENTION: Intervention was described in detail? ✓ Yes ___ No ___ Not addressed
Contamination was avoided? ___ Yes ___ No ✓Not addressed Provide a short description of the intervention including type of intervention, who delivered it, how often and in what setting. Part I: Proof of Concept – 10 participants with mild-moderate liver fibrosis – Intervention: SOF 400 mg/day + RBV 1000 mg/day (for patients ≤75) or RBV 1200 mg/day (for patients >75 kg) x 24 weeks Part II: 50 Randomized patients with all stages of liver fibrosis – Intervention 1: SOF 400 mg/day + RBV 1000 mg/day (for patients ≤75) or RBV 1200 mg/day (for patients >75 kg) x 24 weeks – Intervention 2: SOF 400 mg/day + RBV 600 mg x 24 weeks
The intervention was delivered daily by the patients themselves. Medication adherence was assessed during patient interviews and pill counts.
The setting of how the intervention was administered was not directly mentioned. RESULTS: Results were reported in terms of statistical significance? ___ Yes ✓ No ___ NA ___ Not addressed What were the results? Outcomes Results Statistical Significance ⇒ Undetectable HCV viral load 24 weeks post treatment completion. ⇒ In the proof of concept part of the study 90% of patients that had mild-moderate liver fibrosis achieved sustained virologic response.
⇒ In the latter part of the study, 68% patients with all stages of fibrosis who received the weight-based RBV achieved SVR, whereas 48% of patients on low-dose RBV achieved SVR. ⇒ Also, in the latter part of the study, 28% of the RBV weight-based group and 40% of the RBV low-dose group relapsed 24 weeks post treatment completion. ⇒ Was the analysis, that is the type of statistically tests used, appropriate for the type of outcome measures and the methodology? ✓ Yes ___ No ___ Not addressed
Explain: To make the results more generalizable, the study used the intention to treat analysis rather than the per-protocol analysis. They used 2-tailed p-values and the p-values were only considered significant if it was < 0.05 or 0.01), was study big enough to show an important difference if it should occur (power and sample size)? Yes, the study was big enough to show an important difference.
Clinical importance was reported? ✓Yes ___ No ___ Not addressed What is the clinical importance of the results (that is even if the results were statistically significant were the differences large enough to be clinically meaningful?
– Patients with a baseline HCV RNA of greater than 800,000 had higher rates of sustained virologic response with the use of RBV weight-based dosing. Therefore, clinically this would indicate that there are potential benefits with the use of weight-based RBV and SOF. These results would be clinically meaningful for the US population. Drop-outs were reported? ✓ Yes ___ No If yes, why did they drop out? How were drop-out participants included in the statistical analysis? o 4 patients (1 from weight-based, 3 from low-dose) dropped out due to non-adherence o 1 patient dropped prior to week 12 of the study, although he dropped out early, the study still included him in the analysis because his viral load was undetectable 24 weeks’ posttreatment.
CONCLUSIONS AND CLINICAL IMPLECATIONS: The conclusions made by the authors were appropriate given study methods and results. ✓ Yes ___ No What did the author concluded? – The author concluded that SOF/weight-based RBV in hepatitis C virus, resulted in a high sustained virologic response rate in patients with unfavorable characteristics (black race, genotype 1a, advanced fibrosis, BMI >30). – Due to the higher rates of relapse in patients with advance fibrosis, further studies are warranted to examine the efficacy of SOF/RBV. – Larger studies are warranted to determine HCV treatment response and RBV dosing.
What were the main limitations of the study as stated by the author(s) and from your point of view? o Limitations of the study from the author(s) point of view ♣ Small sample size ♣ Higher number of discontinuations in the low-dose RBV group o Limitations of the study from my point of view ♣ Small sample size leads to a wider confidence interval, therefore less precision. ♣ Did not mention if the patients were taking other medications concomitantly when on the trial medications.
What are the implications of these results for your practice? – It is important to consider the patient’s characteristics when considering HCV therapy. – Patients who are of black race, advanced liver fibrosis, baseline HCV RNA >800,000, IL28B CT or TT genotypes and previous treatment experience; are more likely to achieve high SVR with SOF/weight-based dosing than with interferon-based therapy. – Male patients with advanced liver fibrosis and high baseline HCV RNA are more likely to relapse when taking direct-acting antivirals and ribavirin. – Weight-based RBV is more effective than low-dose RBV in patients with HCV RNA >800,000. – This was a small study; therefore, the results were not considered significant. Larger studies are warranted for further evaluation of RBV dosing.
