Hep C Discussion Forum

Tig · Admin

RE: Viekirax and Exviera (OPrD) - Real World Data

Canuck · Guru

Weird, when it rains it pours! Yet another recent Journal article (2018), just being published, on the subject of our "OLD" friend "Viekirax" (OPr) - no "Exviera"/Dasabuvir in this, but, instead - with Sof, and with/without Riba, trial data from about 2015! Um, funny that, why is this older trial data hitting a journal publication now?

Efficacy and Safety Results of Patients With HCV Genotype 2 or 3 Infection Treated With Ombitasvir/Paritaprevir/Ritonavir and Sofosbuvir With Or Without Ribavirin (QUARTZ II-III)

S. D. Shafran; D. Shaw; M. Charafeddine; K. Agarwal; G. R. Foster; M. Abunimeh; T. Pilot-Matias; R. K. Pothacamury; B. Fu; E. Cohen; D. E. Cohen; E.Gane

J Viral Hepat. 2018;25(2):118-125.

(Excerpts Only)

... Results

... Patients ...

In total, 70 patients were enrolled from study sites in Australia, New Zealand, Canada and the United Kingdom. Fifty-one patients with HCV genotype 3 infection were enrolled between 16 January 2015 and 30 April 2015. All genotype 3-infected patients were subtype 3a; 21 patients had cirrhosis, and 30 did not have cirrhosis. Of the 30 genotype 3-infected patients without cirrhosis, 11 were randomized to receive OBV/PTV/r + SOF with RBV and 9 to receive OBV/PTV/r +SOF without RBV; the remaining 10 were allocated to receive OBV/PTV/r + SOF without RBV. Nineteen patients with genotype 2 infection were enrolled in the study between 8 June 2015 and 17 June 2015. Patient demographics are summarized in Table 1. The majority of patients were white (87%), male (61%), treatment-naïve (57%) and had F0-F1 fibrosis (51%) ...

... Discussion

The QUARTZ II-III study investigated the strategy of combining three DAAs that are approved in over 60 countries: OBV/PTV/r plus SOF with or without RBV; the safety and efficacy of this investigational regimen was evaluated in patients with HCV genotype 2 or genotype 3 infection without cirrhosis or with compensated cirrhosis. In patients with genotype 3 infection, high SVR12 rates with no virologic failures were observed with 12 weeks of treatment. This included 21 patients with cirrhosis, 12 of whom were IFN-experienced. There were no virologic failures among the genotype 3 patients without cirrhosis, regardless of whether or not they received RBV, suggesting that RBV is not necessary in this population. Genotype 3 infection appears to be one of the last remaining challenges in the era of the latest generation of DAAs, and these results suggest that novel combinations of DAAs may provide a treatment option for this population, particularly in settings where newer regimens with pangenotypic activity are not available.

In patients with genotype 2 infection, this study aimed to determine whether combining multiple DAAs with activity against genotype 2 could allow the treatment duration to be shortened. Among the patients treated with OBV/PTV/r + SOF + RBV for 8 weeks, 9 of 10 (90%) achieved SVR12, with one relapse in the only patient previously exposed to SOF. However, the same regimen administered for 6 weeks yielded an SVR12 rate of only 44% (4/9), with 5 relapses. The absence of treatment-emergent substitutions and adequate drug exposures suggests that the short treatment duration was responsible for the low SVR12 rates in this treatment arm. Thus, although this particular combination for 8 weeks may have efficacy comparable to a 12-week course of SOF + RBV for treatment of genotype 2 infection,^[23,24] it does not appear that the duration of this combination regimen can be reduced any further without incurring an unacceptably high relapse rate.

Previous studies have examined the efficacy of the IFN-free regimen of SOF + RBV given for 12 weeks and yielded SVR rates of up to 97% for patients with genotype 2 infection; however, SVR rates in "real-world" cohorts appear to be lower.^[8] Furthermore, SVR rates with SOF + RBV given for 12 weeks were much lower (56%) in patients with genotype 3 infection,^[23] but improved to 80-85% with 24 weeks of treatment.^[24,25] SOF + DCV given for 12 weeks yielded high SVR rates in noncirrhotic patients with genotype 3 infection (96%; 105/109), but SVR rates were only 63% (20/32) in cirrhotic patients with genotype 3,^[²⁶^] leading to recommendations to treat cirrhotic patients for 24 weeks.^[15]

More recent data on the RBV-free treatment option of sofosbuvir/velpatasvir for 12 weeks showed that 99% of patients with HCV genotype 2 infection and 95% of patients with genotype 3 infection achieved SVR12.^[25] In the phase 2 C-SWIFT study, 12-week treatment with elbasvir/grazoprevir + SOF yielded SVR12 rates of 91% (10/11) in HCV genotype 3 patients with cirrhosis; the follow-up phase 3 C-ISLE study yielded SVR12 rates of 96% (23/24) and 100% (17/17) in treatment-naïve and non-DAA treatment-experienced cirrhotic patients with HCV genotype 3 infection, respectively.^[27] Shorter treatment durations for patients with HCV genotype 2 or genotype 3 infection have yielded high SVR12 rates following treatment with glecaprevir/pibrentasvir; however, this regimen is not currently available.^[28] Here, we have shown that an IFN- and RBV-free 12-week regimen of OBV/PTV/r + SOF achieved a high SVR12 rate of 100% in patients with genotype 3 infection, and a comparable SVR12 rate (90%) in patients with genotype 2 infection treated with OBV/PTV/r + SOF + RBV for 8 weeks.

The safety profile of this DAA combination regimen was favourable; AEs occurred in 91%-100% of patients who received a RBV-containing regimen, and the majority of these events were mild in severity. The safety profile is consistent with previous results from an open-label, exploratory, phase 2 trial investigating OBV/PTV/r ± RBV wherein 87% experienced mild-to-moderate treatment-emergent AEs, and one patient discontinued due to an AE.^[20]Furthermore, the addition of SOF to the OBV/PTV/r regimen improved overall efficacy without significantly impacting safety; the 12-week regimen of OBV/PTV/r alone investigated in a previous phase 2 trial resulted in SVR12 rates of 60% and 9% for genotype 2 and genotype 3,^[20] respectively, while the SVR12 rates presented here following 8-12 weeks of treatment with OBV/PTV/r + SOF ± RBV have improved to 90%-100%.

Limitations of this study include the low number of patients enrolled per treatment arm, particularly treatment-experienced patients with cirrhosis. However, other pilot studies investigating short treatment durations, including those with genotype 2 infection, had similarly limited numbers of patients enrolled, and yielded comparably low SVR12 rates.^[29-32] Another limitation of the current study is that OBV/PTV/r + SOF was not evaluated without RBV in genotype 3-infected patients with cirrhosis. The results of the C-ISLE study as well as the POLARIS-3 study^[33] suggest that RBV may not be needed when a regimen comprising these three mechanisms of action is used in genotype 3-infected patients with cirrhosis. Finally, this regimen has not been studied in patients with prior DAA experience.

Unlike HCV genotype 2, HCV genotype 3 has in recent years been the most difficult genotype to cure, calling for longer treatment durations and IFN-containing regimens yet consistently producing lower SVR rates than other genotypes^[34] The investigational, IFN-free combination of the DAAs OBV/PTV/r + SOF with RBV for 8 weeks achieved an SVR12 rate of 90% in patients with genotype 2 infection, and 12-week OBV/PTV/r + SOF with or without RBV achieved an SVR12 rate of 98% in patients with genotype 3 infection ...

Canuck · Guru

Funny (not) how "real world" data takes so long to "come out"! Here is a recent publication (2018), all about "Viekirax" (ombitasvir/paritaprevir/ritonavir) and "Exviera" (dasabuvir) - also known as "OPrD" (similar to later and further formulations named Viekira Pak and then Viekira XR).

Below is not trial data but "real world" data, after Viekirax/Exviera was approved for use in Israel in Feb 2015. Between Feb 2015 and Dec 2015 the "real world" data compiled (on how well it did in that population, within that limited time period) is just being published recently!

J Viral Hepat. 2018 Feb;25(2):144-151. doi: 10.1111/jvh.12800. Epub 2017 Nov 7.

Sustained virological response to ombitasvir/paritaprevir/ritonavir and dasabuvir treatment for hepatitis C: Real-world data from a large healthcare provider.

Weil C¹, Mehta D^2,3, Koren G¹, Pinsky B², Samp JC², Chodick G^1,4, Shalev V^1,4.

Author information

Abstract

Treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin (OPrD ± RBV), was the first interferon-free direct-acting antiviral for hepatitis C virus (HCV) introduced to Israel's national basket of health services in February 2015. Patients with HCV genotype 1 (GT1) and advanced fibrosis (F3-F4) were eligible for treatment in 2015. This study aimed to characterize patients initiating OPrD ± RBV and assess sustained virological response (SVR). A retrospective cohort study was performed using the database of Maccabi Healthcare Services (MHS), a 2-million-member health plan in Israel. The study population included adults who initiated OPrD ± RBV through December 2015 per health basket criteria. A gap in medication fills (>14 days between a fill's run-out and the next fill) was used to estimate adherence. SVR was defined by the viral tests at least 12-week post-treatment. The study population consisted of 403 patients (56.3% male), with a mean age of 60.7 years (SD 11.0). Overall, 71.0% were naïve to prior HCV treatment, and 95.6% were treated with a 12-week regimen. A total of 348 patients (86.4%) completed the regimen in the usual time frame (highly adherent), whereas 8.2% completed with a gap, and 4.7% purchased less than the recommended dose. SVR rates overall and among highly adherent patients were 395/403 (98.0%; 95% CI 96.1-99.1) and 346/348 (99.4%; 95% CI 97.9-99.9), respectively. GT1b patients on 12-week regimens attained SVR rates of 194/196 (fibrosis F3) and 170/176 (cirrhosis). After a first year of provision of OPrD ± RBV with good adherence, high SVR rates were achieved in various patient subgroups and comorbidities.

PMID: 28984012 DOI: 10.1111/jvh.12800

(Continued) - "Discussion" via a Medscape article on the data presentation

Discussion

The study results indicate high rates of adherence and high SVR rates with OPrD + RBV in the first year of its provision in the Israeli health basket, among HCV patients in a large health plan. The SVR-12 rate in the present study population of 403 patients was 98.0% (95% CI: 96.1-99.1). These results are consistent with the SVR rates found in the clinical trials,^[10,11] as well as recently published real-world data. A meta-analysis of 5726 patients treated in several countries reported an SVR-12 rate of 97%,^[12] and early evidence of OPrD + RBV use in Poland indicated a rate of 207/209 (99.0%), ranging from 96.4% to 100.0% across subgroups.^[13]

In line with these findings, results from an early US Veterans Affairs study indicate SVR rates of 98.0% (248/253) and 95.5% (705/738) with 12 weeks of OPrD without or with RBV, respectively.^[14]

Cirrhotic patients in our study population had very high rates of SVR-12, similar rate to noncirrhotic patients, which supports currently available real-world data.^[12] As shown previously, SVR-12 can be attained in GT1b patients with compensated cirrhosis and early HCC that has been eradicated.^[23] In our study, all 5 patients with a definite history of HCC achieved SVR-12. In this population, OPrD is contraindicated for patients with moderate and severe hepatic impairment (for Child-Pugh B, treatment was not recommended and then contraindicated following the FDA safety warning in October 2015). Although data were not readily available to confirm Child-Pugh A in all the early OPrD users in this study, upon review of gastroenterologists' summaries in the medication approval records of 50 randomly sampled patients with an ICD-9 code for cirrhosis, we found confirmation of Child-Pugh A in 76% of cases, with no mention of Child-Pugh or decompensation in the remaining records.

Studies suggest that HCV infection may be associated with a more rapid decline in renal function^[24,25] and increased risk of CKD,^[26,27] and more studies are needed to show that clearance of HCV can improve outcomes in CKD patients. Clinical trial results have demonstrated high SVR-12 rates with OPrD + RBV among GT1 patients with advanced CKD (stages 4-5).^[28] This real-world study suggests that high SVR rates can be achieved among CKD patients. More information is needed on the subpopulation with advanced stages of CKD, and this should be confirmed in larger studies and with different stages. While concomitant medications that increase gastric pH can alter the bioavailability of antiviral drugs, data from Phase 3 trials indicate that HCV-GT1 patients who use acid-reducing agents or proton pump inhibitors attained high SVR-12 rates with OBV/PTV/r+DSV and RBV in clinical trial setting.^[29] Our data are consistent with this trend, where 108/110 of our patients receiving acid-reducing or proton pump inhibitors achieved SVR-12.

Given the challenges to adherence in real-world settings, the results of the present early study are encouraging, demonstrating high rates of adherence and SVR in different HCV patient subgroups, including patients with advanced fibrosis combined with chronic comorbidities. These results stand in contrast to our previous study of interferon-based therapy for HCV in the same healthcare setting, which showed substantially lower adherence and SVR rates.^[30]

Studies of interferon-based therapy have demonstrated that failure to achieve SVR is strongly associated with nonadherence,^[30] often due to lack of treatment effect or occurrence of adverse events.^[6] Failure to reach SVR-12 with OPrD in our study could potentially also be related to a lower actual consumption of dispensed medication (ie missed doses), or to potential resistance to DAAs.^[31]

The health plan members have similar demographics to the general population of Israel, and the results can therefore be generalizable to the national level.^[32] By establishing an open cohort in the second largest Israeli health plan, real-world evidence will continue to be updated in future studies to monitor a growing cohort and assess the long-term effectiveness and safety of OPrD + RBV. In the present analyses, 1% of patients had a record of on-treatment decompensation and nonetheless achieved SVR-12. Early real-world data suggest that 2%-5.4% of patients experience a serious adverse event, while less than 3% discontinue due to an adverse event.^[12] Future studies can utilize MHS' comprehensive databases to investigate adverse events and assess broader outcomes such as healthcare resource utilization. Treated patients will continue to be monitored for long-term outcomes, such as liver progression or regression.

In summary, this large early real-world cohort of HCV GT1 patients with advanced fibrosis treated with the new regimen of OPrD + RBV showed high efficacy on par with that in the clinical trials. After the first year of its provision in the Israeli health basket, high rates of adherence and SVR were achieved. The high effectiveness of this new regimen was independent of patient characteristics and underscores the potential for improving outcomes of HCV patients in a new era of HCV treatment.