Shortened 8 Weeks Course of Dual Sofosbuvir/Daclatasvir Therapy in Adolescent Patients, With Chronic Hepatitis C Infection.

Recently, sofosbuvir and the fixed-dose combination of sofosbuvir/ledipasvir were approved for the treatment of chronic hepatitis C virus infection in adolescents, criteria being 12 years old and above or weighing at least 35 kg. Here we present the results of a pilot single cohort of 10 consecutive adolescent patients with chronic hepatitis C virus and treated with dual sofosbuvir/daclatasvir therapy for a response-tailored duration of 8 weeks for those who achieved very rapid virologic response (vRVR) and 12 weeks for those who did not. All patients achieved vRVR at week 2 and completed the shortened 8 weeks course. All patients (10/10) (100% [confidence interval 72.25-100%]) achieved sustained vRVR at week 12 post-treatment with good tolerability and no serious adverse events. These data could provide support to our suggested response-tailored protocol of dual therapy with sofosbuvir/daclatasvir in adolescents particularly for shortened duration in those who achieved vRVR. Further larger randomized controlled studies are recommended.

Dual Sofosbuvir/Daclatasvir Therapy in Adolescent Patients With Chronic Hepatitis C Infection.

OBJECTIVES: Dual sofosbuvir/daclatasvir (SOF/DCV) therapy is currently recommended by the European Association for Study of Liver (EASL) as an option for the treatment of chronic hepatitis C virus (HCV) infection in adults for all genotypes; however, it is still not considered for patients younger than 18 years old. We aimed to test safety and efficacy of SOF/DCV in adolescent patients 12 to 17 years old with chronic HCV, genotype 4 infection. METHODS: We conducted a prospective, uncontrolled, open-label multicenter study. A total of 30 chronic HCV-infected adolescents, aged from 12 to 17 years old were included and treated with dual SOF/DCV for 12 weeks. Patients were monitored throughout the treatment and follow-up period for safety and efficacy outcome measures including the sustained virologic response 12 (SVR12) rate. RESULTS: The intention-to-treat (ITT) SVR12 rate was 29 of 30 (96.7%; 95% confidence interval [CI] 83.3%-99.4%). The only patient who did not achieve SVR12 was lost to follow-up after showing viral negativity at the end of treatment (EOT) visit. Whereas all the remaining 29 patients (100%, 95% CI 88.3%-100%) who completed the follow-up visits achieved SVR12. All patients showed normalized liver enzymes with normal hematological, liver and renal function tests at the end of the study. No fatalities or treatment-emergent serious or severe adverse events were reported throughout the study. CONCLUSIONS: SOF/DCV combined therapy could be a safe and effective treatment in adolescent patients 12 to 17 years old with chronic HCV genotype 4 infection. (See Video, Supplemental Digital Content, http://links.lww.com/MPG/B348).

Effects of Dual Sofosbuvir/Daclatasvir Therapy on Weight and Linear Growth in Adolescent Patients with Chronic Hepatitis C Virus Infection.

Negative effects on growth indices had been reported in children treated with interferon for chronic viral hepatitis. Forty chronic hepatitis C virus-infected adolescents, 12-17 years of age, were treated with sofosbuvir/daclatasvir therapy for 12 weeks. The intent-to-treat sustained virologic response rate at 12 weeks after end of treatment was 39/40 (97.5%). Unlike interferon-based therapy, we did not detect significant negative effects on linear growth or weight. Contrarily, a trend to increased appetite and insignificant weight gain was observed, but further larger studies are needed to confirm. See Video-Abstract, http://links.lww.com/ASAIO/A381.

Response Tailored Protocol Versus the Fixed 12Weeks Course of Dual Sofosbuvir/Daclatasvir Treatment in Egyptian Patients With Chronic Hepatitis C Genotype-4 Infection: A Randomized, Open-label, Non-inferiority Trial.

BACKGROUND: The most recent European Association for the Study of the Liver (EASL) 2016 Guidelines on treatment of hepatitis C (HCV), allowed for shortening the course of treatment for some subsets of patients with sofosbuvir/ledipasvir and with grazoprevir/elbasvir based on cutoff baseline HCV RNA values. We hypothesized that it would be prudent to also consider an objectively assuring very rapid, on-treatment, virologic response to therapy at week 2 (vRVR) before taking the decision of shortening the treatment duration. So we planned this study to test whether a dual sofosbuvir/daclatasvir (SOF/DCV) treatment duration tailored according to achieving vRVR to 8 or 12weeks is non-inferior to the recommended fixed 12weeks course in non-cirrhotic Egyptian chronic HCV genotype-4 patients. METHODS: The study was conducted in an outpatient setting according to a prospective, randomized, open-label, comparative, non-inferiority study design. A hundred twenty eligible, non-cirrhotic, chronic HCV patients were randomly assigned (1:1) to receive daily doses in the form of one Gratisovir 400mg table (generic sofosbuvir produced by Pharco Pharmaceuticals, Alexandria, Egypt) plus one Daktavira 60mg tablet (generic daclatasvir produced by Dawood Pharm, Egypt) for either a fixed 12weeks duration (reference group) or a response tailored duration (test group). In the test group the treatment duration was tailored according to the virus load tested by real time PCR into 8weeks for patients who had undetectable HCV RNA level in their serum by the end of the second week of treatment (vRVR)), or 12weeks for those who did not show vRVR. The primary outcome of the trial was the proportions of patients achieving SVR12 (HCV RNA below lower level of quantification at week 12 after end of treatment). The comparison between groups was based on testing the null hypothesis of inferiority of the response-tailored group with a pre-specified margin of non-inferiority (NI-m) of 0.1 (10%). The protocol was registered with a WHO Clinical Trial Registration ID: ACTRN12617000263392. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372041 FINDINGS: Starting from Jun, 5 2016, a hundred twenty eligible patients from 4 outpatient clinics in Alexandria, Egypt were randomized to either a fixed duration group (reference group: n=60 patients) or a response tailored duration group (test group: n=60 patients). During the whole period of the study, only 1 patient dropped-out from each group. Both were lost to follow-up after the 4th week's visit. Baseline characteristics in both groups were almost matching. Fifty eight out of the total 60 intention-to-treat (ITT) patients in the reference group achieved SVR12 (96.67% (95% confidence interval (CI): 88.64-99%). Whereas, 59 out of the total 60 (ITT) patients in the test group achieved SVR12 (98.33% (CI: 91.14-99.71%). The per-protocol (PP) analysis, excluding patients who dropped-out before collecting their final result, showed that 58/59 (98.31% (CI: 91-99.7%)) of patients in the reference group and 59/59 (100% (CI: 93.89-100%) of the test group achieved SVR12. Non-inferiority was declared since the upper bound of the two-sided 95% CI for the difference in proportions of SVR12 between groups (P(reference)-P(test)) did not exceed the specified non-inferiority margin of +0.1 (10%), both in ITT population (-1.67%, CI: -9.8%-+5.9%), and in the PP population (-1.69%, CI: -9%-+4.58%). No fatalities or serious adverse events were reported during the period of the study. Similar rates of non-serious adverse events were reported in both groups with a trend of higher incidence rate in the fixed 12weeks group; all were mild in severity. INTERPRETATION: Shortening the duration of therapy based on observed vRVR could provide a prudent basis to avoid unnecessary long treatment courses. This could not only reduce the drug exposure and the risk of adverse drug reactions, but also cut the cost of full treatment course with such expensive medications by one third. This could economize the treatment budget at the individual out-of-pocket level as well as the public health services and insurance levels and allow for better utilization of public health resources.

Very rapid virologic response and early HCV response kinetics, as quick measures to compare efficacy and guide a personalized response-guided therapy.

BACKGROUND: This is the second and final report for our study designed to compare two generic sofosbuvir products for the degree and speed of virologic response to a dual anti-hepatitis C virus (HCV) treatment protocol. We aimed to test the applicability of the early virus response kinetics and the very rapid virologic response (vRVR) rate as quick outcome measures for accelerated comparative efficacy studies and as a foundation for a personalized response-guided therapy. METHODS: Fifty eligible chronic HCV patients were randomized to either one of two generic sofosbuvir products (Gratisovir or Grateziano) at a daily dose of one 400 mg tablet plus a weight-based ribavirin dose. Data were compared between the groups for early virus response kinetics and vRVR rates in relation to the rates of final sustained virologic response at week 12 posttreatment (SVR12). RESULTS: The Log10 transformed virus load (Log polymerase chain reaction) curves showed fairly similar rapid decline during the first 2 weeks, with no significant difference between the groups at four analysis points throughout the study by repeated-measures factorial analysis of variance test (P=0.48). The SVR12 rates were 96% (95% confidence interval, 79.6%-99.9%) in Gratisovir group (24/25) and 95.7% (95% confidence interval, 78%-99.9%) in Grateziano group (22/23). There was no statistically significant difference found by exact test (P>0.999). There was a significant association between the vRVR and the SVR12, with 100% positive predictive value (38/38 of those who had vRVR, achieved a final SVR12) and 82.6% sensitivity (among the total 46 with SVR12, 38 were having vRVR). CONCLUSION: We can conclude from our study that the early HCV response kinetics and the vRVR rates could be used as sensitive quick markers for efficacy (with a very high positive predictive value for SVR12), based on our accelerated comparative efficacy research model. This might open the way for new models of accelerated equivalence efficacy studies along with the bioequivalence kinetics studies to test a generic drug against a reference. Also, the early response kinetics and the vRVR might be used as qualifiers for a personalized course of treatment. This could shorten unnecessarily long treatment courses in rapid responders and might help to avoid relapses in slow responders.

The very-rapid and the ultra-rapid virologic response to two treatment options in patients with chronic hepatitis C: an interim report of a prospective randomized comparative effectiveness study.

BACKGROUND: We aimed in this interim report to compare two registered generic sofosbuvir products for the degree and speed of virologic response to a dual antiviral treatment protocol within the first 2 weeks of treatment. METHODS: Data collected during the period of this interim report from the first 25 patients randomized to either one of two generic sofosbuvir products (Grateziano or Gratisovir) at a daily dose of one 400 mg tablet plus a weight-based ribavirin dose were analyzed for both the degree and speed of virus load reduction at the end of 1 and 2 weeks from starting treatment. RESULTS: The baseline Log10 transformed virus load (Log polymerase chain reaction) showed a fairly similar marked and significant reduction in both groups by more than 4 and 5 Logs at the end of week 1 and 2 of starting treatment, respectively. The differences between the two treatment groups at both analysis points were not statistically significant (P>0.05) by repeated measures factorial analysis of variance test. The differences in proportions of patients with ultra-rapid virologic response at the end of week 1 and very-rapid virologic response at the end of week 2 in both groups were also not statistically significant (P>0.05). CONCLUSION: We can conclude from this interim report that the two generic products Gratisovir and Grateziano are almost equally fast and efficacious in reducing the hepatitis C virus load in our study setting.