Disease Cure Remedy: geno1

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Friday, 9 September 2016

EASL/AASLD2016 - Achillion Reports 100% SVR In Phase2a Trial:Odalasvir, AL-335, and Simeprevir for Geno 1 Treatment-Naive

Achillion Announces 100% SVR Reported in Janssen’s Phase 2a Trial Evaluating Triple Combination of Odalasvir, AL-335, and Simeprevir for Genotype 1 Treatment-Naive HCV

New data released today in abstract for upcoming EASL / AASLD Special Conference: New Perspectives in Hepatitis C Virus Infection – The Roadmap For Cure -

- Janssen advancing triple combination into Phase 2b clinical trial -

NEW HAVEN, Conn., Sept. 09, 2016 (GLOBE NEWSWIRE) -- Achillion Pharmaceuticals, Inc. (Nasdaq:ACHN) announced today that new interim results from a phase 2a study being conducted by Alios BioPharma, Inc., part of the Janssen Pharmaceutical Companies (Janssen), were published as part of the abstracts released for the upcoming European Association for the Study of the Liver (EASL) Special Conference, September 23 - 24, 2016, in Paris, France.

This ongoing phase 2a study was designed to confirm the required dose and treatment duration for an all-oral combination regimen containing odalasvir (ODV) and AL-335 with or without simeprevir (SMV) for durations of eight or six weeks of treatment in treatment-naïve patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection.

“We are delighted by the significant progress Janssen has made in advancing the all-oral, short-duration treatment regimen of odalasvir, AL-335 and simeprevir and are impressed with the Phase 2a study results being presented. Based on these interim results, Janssen plans to advance a phase 2b program for the triple combination to further understand the potential of this 3DAA drug combination to shorten the duration of treatment for patients suffering from HCV,” commented Dr. Milind Deshpande, President and Chief Executive Officer of Achillion. “Despite recent therapeutic advances, we believe there remains a significant unmet need in addressing the global burden of hepatitis C virus in those living with the disease.”

Data included in the abstract were as of the time of submission in July 2016. Updated results, including sustained viral response 12 weeks after completion of therapy (SVR12) for all cohorts, are scheduled to be presented on Friday, September 23, 2016, in an ePoster entitled "Short duration treatment with AL-335 and odalasvir (ODV), with or without simeprevir (SMV), in treatment naïve patients with hepatitis C virus (HCV) genotype (GT) 1 infection." Interim results from cohorts 1-4, summarized in the table below, showed that the triple combination regimen was highly effective and well tolerated in non-cirrhotic patients with GT1 HCV.

Table 1: Interim Phase 2a Results for Cohorts 1 – 4

Cohort #	Dose			Dosing Duration (weeks)	Number (%) withundetectable* HCV RNA (EOT or SVR)
Cohort #	AL-335 (mg QD)	ODV (mg)	SMV (mg QD)	Dosing Duration (weeks)	Number (%) withundetectable* HCV RNA (EOT or SVR)
1	400	50 QD	100	8	20/20 (100%), SVR24
2	800	50 QOD	--	8	18/20 (90%), SVR12
3	800	50 QOD	75	8	20/20 (100%), SVR4
4	800	50 QOD	75	6	20/20 (100%), EOT

*Or below the limit of quantitation (N=2; Cohort 4 only)
EOT: end of treatment; QD: every day; QOD: every other day; RNA: ribonucleic acid

Summary of Phase 2a Study Design and Interim Results

This phase 2a study was designed to determine the pharmacokinetics, efficacy and safety of ODV and AL-335 with or without SMV, in treatment naïve patients with GT1 or 3 HCV infection for treatment durations of eight weeks or less.

Of the 20 patients treated in cohort 1, who received the triple combination of odalasvir (50mg QD), AL-335 (400mg QD) and simeprevir (100mg QD) for eight weeks (triplet, 8 weeks), 100 percent remained HCV RNA undetectable 24 weeks after completing therapy (SVR24). Additional patients were subsequently enrolled into two further cohorts (3 & 4), where they received adjusted doses of the same triplet combination for either eight or six weeks. In cohort 3 all were HCV RNA negative and remained HCV RNA undetectable 4 weeks after completing therapy (SVR4) and in cohort 4 all were HCV RNA negative (N=18) or below the limit of quantitation (N=2) at end of treatment. Of the 20 patients treated in cohort 2, who received the dual combination of odalasvir (50mg QOD) and AL-335 (800mg QD) for eight weeks (doublet, 8 weeks), 90 percent remained HCV RNA undetectable twelve weeks after completing therapy (SVR12).

All-oral combination regimens, containing odalasvir, AL-335 with or without simeprevir were generally safe and well tolerated. The majority of adverse events (AEs) were mild, most commonly headache, fatigue, and upper respiratory tract infection. In cohort 1, there was a single serious adverse event (Mobitz Type 1 2^nd degree atrioventricular block), which was attributed to treatment. This ECG abnormality was not associated with clinical or echocardiographic abnormalities, and resolved following treatment discontinuation. No clinically significant laboratory abnormalities were observed.

Ongoing Phase 2 Development Program

Based upon the interim results from the phase 2a study, which confirmed the required dose for each component and the treatment duration, the triple combination is being advanced into a phase 2b program consisting of once daily odalasvir 25mg, AL-335 800mg, and simeprevir 75mg. The development program will include two multi-center, randomized, open-label studies that will enroll treatment-naive and treatment-experienced non-cirrhotic patients chronically infected with hepatitis C virus genotypes 1, 2, 4, 5, and 6. These studies will be complemented by an expansion of the ongoing phase 2a study focusing on patients with or without compensated cirrhosis and on patients with HCV genotype 2 and 3 infection. The results from the phase 2 program will guide further development.

Further information on this study can be found at www.clinicaltrials.gov. Study identifier: CT02765490.

Friday, 26 August 2016

Hepatitis C/Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir

September 2016
Volume 151, Issue 3, Pages 457–471.e5

Effectiveness of Sofosbuvir, Ledipasvir/Sofosbuvir, or Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir Regimens for Treatment of Patients With Hepatitis C in the Veterans Affairs National Health Care System

George N. Ioannou, Lauren A. Beste, Michael F. Chang, Pamela K. Green, Elliott Lowy, Judith I. Tsui, Feng Su, Kristin Berry

DOI: http://dx.doi.org/10.1053/j.gastro.2016.05.049

Background & Aims

We investigated the real-world effectiveness of sofosbuvir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) in treatment of different subgroups of patients infected with hepatitis C virus (HCV) genotypes 1, 2, 3, or 4.

Methods

We performed a retrospective analysis of data from 17,487 patients with HCV infection (13,974 with HCV genotype 1; 2131 with genotype 2; 1237 with genotype 3; and 135 with genotype 4) who began treatment with sofosbuvir (n = 2986), ledipasvir/sofosbuvir (n = 11,327), or PrOD (n = 3174), with or without ribavirin, from January 1, 2014 through June 20, 2015 in the Veterans Affairs health care system. Data through April 15, 2016 were analyzed to assess completion of treatments and sustained virologic response 12 weeks after treatment (SVR12). Mean age of patients was 61 ± 7 years, 97% were male, 52% were non-Hispanic white, 29% were non-Hispanic black, 32% had a diagnosis of cirrhosis (9.9% with decompensated cirrhosis), 36% had a Fibrosis-4 index score >3.25 (indicator of cirrhosis), and 29% had received prior antiviral treatment.

Results

An SVR12 was achieved by 92.8% (95% confidence interval [CI], 92.3%–93.2%) of subjects with HCV genotype 1 infection (no significant difference between ledipasvir/sofosbuvir and PrOD regimens), 86.2% (95% CI, 84.6%–87.7%) of those with genotype 2 infection (treated with sofosbuvir and ribavirin), 74.8% (95% CI, 72.2%–77.3%) of those with genotype 3 infection (77.9% in patients given ledipasvir/sofosbuvir plus ribavirin, 87.0% in patients given sofosbuvir and pegylated-interferon plus ribavirin, and 70.6% of patients given sofosbuvir plus ribavirin), and 89.6% (95% CI 82.8%–93.9%) of those with genotype 4 infection. Among patients with cirrhosis, 90.6% of patients with HCV genotype 1, 77.3% with HCV genotype 2, 65.7% with HCV genotype 3, and 83.9% with HCV genotype 4 achieved an SVR12. Among previously treated patients, 92.6% with genotype 1; 80.2% with genotype 2; 69.2% with genotype 3; and 93.5% with genotype 4 achieved SVR12. Among treatment-naive patients, 92.8% with genotype 1; 88.0% with genotype 2; 77.5% with genotype 3; and 88.3% with genotype 4 achieved SVR12. Eight-week regimens of ledipasvir/sofosbuvir produced an SVR12 in 94.3% of eligible patients with HCV genotype 1 infection; this regimen was underused.

Conclusions

High proportions of patients with HCV infections genotypes 1–4 (ranging from 75% to 93%) in the Veterans Affairs national health care system achieved SVR12, approaching the results reported in clinical trials, especially in patients with genotype 1 infection. An 8-week regimen of ledipasvir/sofosbuvir is effective for eligible patients with HCV genotype 1 infection and could reduce costs. There is substantial room for improvement in SVRs among persons with cirrhosis and genotype 2 or 3 infections.

Discussion Only
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LDV/SOF, PrOD, and SOF-based antiviral regimens resulted in remarkably high SVR rates in the VA national health care system, approaching the rates reported in clinical trials. This is in contrast to previous interferon-based regimens, which consistently resulted in much lower SVR rates in real-world clinical practice than in clinical trials.¹²^, ¹³^, ¹⁴^, ¹⁵^, ¹⁶^, ¹⁷ SVR rates were higher in genotype 1– (SVR 92.8%) and genotype 4–infected patients (SVR 89.6%) than genotype 2– (SVR 86.2%) or 3–infected patients (SVR 74.8%), and these differences were even greater among cirrhotic and treatment-experienced patients. Among genotype 1–infected patients, there was no significant difference in SVR rates between LDV/SOF and PrOD regimens in either unadjusted or multivariable, propensity-score-adjusted analyses, and SVR rates >90% were achieved even in subgroups such as treatment-experienced or cirrhotic patients. The short, 8-week LDV/SOF monotherapy regimen resulted in excellent SVR rate (94.3%), but was used in only 48.6% of genotype 1–infected patients eligible for 8-week therapy (ie, treatment-naïve patients with viral load <6 million IU/mL, without cirrhosis). Long, 24-week regimens did not result in higher SVR rates and were rarely used, despite being FDA-approved and American Association for the Study of Liver Diseases/Infectious Diseases Society of America–recommended³² for certain genotype 1 patients with cirrhosis.

Among a total of 17,487 patients, our study included 5250 patients with a diagnosis of cirrhosis and 5960 with a FIB-4 score >3.25 (which is highly suggestive of cirrhosis), who achieved surprisingly high overall SVR rates of 86.8% and 87.4%, respectively. These high SVR rates were driven by genotype 1–infected cirrhotic patients who had much higher SVR (90.6%; 95% CI, 89.7%–91.5%) than genotype 2 (77.3%; 95% CI 73.3%–80.9%) or genotype 3 (65.7%; 95% CI, 61.2%–69.8%). To our knowledge, this is the largest study of DAAs in cirrhotic patients and the SVR rates in genotype 1–infected patients are the highest reported in real-world clinical practice. LDV/SOF, PrOD, and SOF regimens have allowed patients with cirrhosis to be cured of HCV in substantial numbers and proportions for the first time ever. Longer follow-up of these patients is necessary to determine whether patients with cirrhosis who achieve SVR by DAAs are protected from developing progressive liver dysfunction, liver failure, or HCC and, whether they are capable of liver remodeling and regression of cirrhosis.

American Association for the Study of Liver Diseases/Infectious Diseases Society of America guidelines during the time period of our study,³² as well as the LDV/SOF package insert,³³ recommend that LDV/SOF regimens should extend for 12 or 24 weeks, with the single exception of a short, 8-week LDV/SOF monotherapy regimen that “can be considered,”³³ “with caution and at the discretion of the practitioner”³² in treatment-naïve, genotype 1–infected patients without cirrhosis with an HCV viral load <6 million IU/mL. This is based on a post-hoc analysis of the ION-3 clinical trial showing higher relapse rates in those treated for 8 weeks who had a viral load ≥6 million (9 of 92 [10%]) compared with those with a viral load <6 million IU/mL (2 of 123 [2%]).³ VA treatment guidelines explicitly recommended 8 weeks of treatment for this subgroup of patients.³⁴ Indeed, our study confirmed that 8 weeks of LDV/SOF monotherapy had similarly high SVR rates (94.8%) as 12 weeks (95.3%) in this favorable subgroup. However, our results also showed that treatment was unnecessarily extended beyond 8 weeks in 1833 of 4066 patients in this subgroup, dramatically increasing the cost of treatment without increasing SVR. Our results should offer reassurance to treatment providers that 8 weeks of LDV/SOF monotherapy is sufficient duration in this subgroup.

VA treatment guidelines during the study period designated PrOD as the preferred regimen in genotype 1–infected patients except for prior null responders, those previously treated with protease inhibitors, and patients with Child’s B or C cirrhosis (in whom the preferred regimen was LDV/SOF and ribavirin for 12 weeks) and except for treatment naïve, non-cirrhotics with a viral load <6 million (in whom 8-week LDV/SOF and 12-week PrOD regimens were equally preferred). This was due to the lower cost of 12 weeks of PrOD ($22,850) compared with 12 weeks of LDV/SOF ($37,157) in the VA system during the study period and the absence of evidence that one is more effective than the other in the subgroups for which PrOD was preferred. Our data support the VA treatment recommendations because we found no difference in SVR between PrOD and LDV/SOF regimens in either adjusted or unadjusted analyses, in the entire population or in clinically relevant subgroups (cirrhosis or not, treatment-experienced or naïve). Despite these recommendations and the higher cost, LDV/SOF regimens constituted 77% and PrOD only 23% of regimens in genotype-1–infected patients. This could be due to higher prevalence of drug–drug interactions, higher pill burden, and more frequent requirement for co-prescription of ribavirin in PrOD regimens compared with LDV/SOF regimens.

After the end of the study period, and after FDA approval of elbasvir/grazoprevir as an additional regimen for genotype 1 HCV on January 28, 2016, regimen costs in the VA were further reduced dramatically, to approximately $17,000 per 12-week course for LDV/SOF, PrOD, and elbasvir/grazoprevir and treatment recommendations changed to “equally recommend” all 3 agents as of March 2016.

Genotype 3–infected patients had the lowest SVR rates in our study, just as in clinical trials. We found that the non-FDA–approved regimen of LDV/SOF and ribavirin had a higher SVR rate (77.9%; 95% CI, 73.1%–82.0%) than the longer and more expensive FDA-approved regimen of SOF and ribavirin for 24 weeks (70.6%; 95% CI, 66.9%–74.1%). However, the highest SVR rate in genotype 3–infected patients was observed in the regimen that included PEG together with SOF and ribavirin (87.0%; 95% CI, 80.0%–91.8%), the only interferon-containing regimen that is still recommended.³²
Few large real-world studies of interferon-free regimens are currently available for comparison with ours. The HCV-TARGET, a prospective cohort study of patients undergoing HCV treatment in routine clinical care in academic centers, reported SVR rate to SOF and simeprevir in genotype 1–infected patients of 88% among 151 transplant recipients and 84% among 836 non-transplant recipients.³⁵^, ³⁶ This regimen has been superseded by LDV/SOF and PrOD-based regimens. Among 487 patients with decompensated cirrhosis treated in the United Kingdom under an Expanded Access Programme with SOF, LDV/SOF, or daclatasvir, SVR was achieved in 90.5% of genotype 1– and 68.8% of genotype 3–infected patients³⁷—very similar to our findings. A smaller VA study looked at only treatment-naïve, genotype 1–infected patients treated with LDV/SOF and reported SVR rates almost identical to ours among this subgroup.³⁸ The TRIO Network, which compiles data from participating “real-world” academic and community HCV treatment clinics in the United States, reported in an abstract an SVR rate of 94% among 1521 genotype 1–infected patients treated with LDV/SOF monotherapy.³⁹
The main limitation of our study was that SVR data were unavailable in 9% of patients, which can lead to overestimated SVR rates among those with available SVR data. We think this is unlikely for 2 reasons. First, patients with missing SVR data were similar to those with available SVR data (Supplementary Table 2). Although early discontinuation of treatment in <8 weeks was more common in patients with missing SVR data (25% vs 4.4%), the majority of patients with missing SVR completed 8 or more weeks of treatment, demonstrating that patients with missing SVR data were not patients who “dropped out” of treatment or were “lost to follow-up,” but rather patients (or physicians) who were simply delinquent in getting their SVR viral load measured after the end of their treatment—not an uncommon phenomenon outside of clinical trials. Second, we used comprehensive multiple imputation models that included duration of treatment in addition to baseline, pretreatment characteristics to impute the missing SVR data and found only a non-substantial reduction in SVR after imputation (Table 5), suggesting that it is unlikely that our results of observed SVR are biased toward overestimation due to the missing SVR data. Important strengths of the study include the complete ascertainment of filled pharmacy prescriptions and the utilization of complete electronic medical records since 1999 from a national health care system that treats the greatest number of HCV-infected patients in the United States.

Our results demonstrate that LDV/SOF, PrOD, and SOF regimens can achieve remarkably high SVR rates in real-world clinical practice, especially in genotype 1–infected patients. The main obstacle to curing HCV infection in the maximum possible number of patients is currently the cost of HCV antiviral regimens. It is expected that cost will decline dramatically as more antiviral regimens become FDA-approved, resulting in competition between manufacturers. In fact, costs decreased dramatically within the VA after the completion of our study and after the FDA approval of elbasvir/grazeprevir in January 2016. The VA health care system has budgeted $1.5 billion nationally for antiviral medications for fiscal year 2016, while every health care organization in the United States is faced with similar budgetary constraints due to the cost of antiviral medications. We hope that our results will be used to determine the most cost-effective ways to treat HCV-infected patients and to reassure patients, clinicians, and health care systems that current treatments for HCV, though costly, appear to be effective in the real-world setting.

Acknowledgments

Author contributions: George Ioannou: Study concept and design, acquisition of data, statistical analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, obtained funding. Pamela Green: Analysis of data. Elliott Lowy: Analysis of data. Kristin Berry: Study design and analysis of data. Feng Su: Study design and critical revision of the manuscript. Michael F. Chang: Study design and critical revision of the manuscript. Judith Tsui: Study design and critical revision of the manuscript. Lauren Beste: Study design and critical revision of the manuscript. George Ioannou is the guarantor of this paper. All authors approved the final version of the manuscript.

Article Outline

Sunday, 31 July 2016

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 Genotype 1, 2,3,4 or 6 / Phase 2 Trial

Articles In Press

Source: Gastroenterology

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with HCV Genotype 2, 3, 4, or 6 Infections in an Open-label, Phase 2 Trial
Edward Gane, Kris V. Kowdley, David Pound, Catherine A.M. Stedman, Mitchell Davis, Kyle Etzkorn, Stuart C. Gordon, David Bernstein, Gregory Everson, Maribel Rodriguez-Torres, Naoky Tsai, Omer Khalid, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Myron Tong, Raymond T. Chung, Kimberly Beavers, John E. Poulos, Paul Y. Kwo, Mindie H. Nguyen
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.038
Publication stage: In Press Accepted Manuscript

Published online: July 30, 2016

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Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus (HCV) genotype 2, 3, 4, or 6 infections who have failed by a prior course of antiviral therapy, and the feasibility of further shortening treatment duration. We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in these patients.

DISCUSSION ONLY
With the recent approval of DAAs, safe and effective combination regimens are now available for the majority of patients chronically infected with HCV. SVR rates exceeding 90% can be achieved in most patient populations regardless of genotype, treatment experience, or presence of cirrhosis. Although the proportion of patients who do not achieve SVR with currently approved DAA regimens is small, the absolute number of DAA failures will steadily increase in parallel with the rate of treatment uptake. DAA failures represent an unmet medical need without, at this time, any approved retreatment options. In this open-label, phase 2 study, the combination of sofosbuvir velpatasvir plus GS-9857 for 12 weeks was safe and highly effective for the treatment of patients with genotypes 2, 3, 4, or 6 HCV infection with or without compensated cirrhosis who were treatment-experienced, including those who had failed previous DAA regimens. The high SVR12 rate among treatment-experienced patients with genotype 3 HCV infection and cirrhosis is noteworthy, given the lower SVR12 rates generally experienced by patients this patient population.

Currently approved regimens for non-genotype 1 HCV have durations of 12 to 24 weeks, depending on choice of regimen and patient’s baseline characteristics, such as HCV genotype, treatment history and presence or absence of cirrhosis. The feasibility of further shortening the duration of treatment has been a goal of research, especially for non-ribavirin containing regimens. Several trials have evaluated various combinations of DAAs for four weeks, but with uniformly disappointing 0utcomes—SVR12 rates of 20% to 40%

In this trial, 6 weeks of sofosbuvir-velpatasvir plus GS-9857 achieved suboptimal results (<90% SVR12 rate) in a historically easy-to-treat population of treatment-naïve patients without cirrhosis. Eight weeks of sofosbuvir-velpatasvir plus GS-9857 was safe and effective for treatment-naïve patients with cirrhosis, including those with HCV genotype 3. Thus, the 8-week regimen may serve as a shorter-duration option for treatment-naïve patients with or without cirrhosis and is currently being evaluated in Phase 3 clinical trials.

Additionally, the high SVR12 rates across genotypes suggests the pangenotypic treatment potential of sofosbuvir-velpatasvir plus GS-9857. While genotype 1 patients were not treated in this study, a parallel open-label, phase 2 study of patients infected with HCV genotype 1 was also conducted,where patients received treatment for 6 to 12 weeks.

This study was limited by its small sample size and open-label design. Although the first Phase 2 clinical trial to evaluate retreatment of non-genotype 1 HCV infected patients previously treated with DAA-regimens that included NS5A inhibitors, only six patients in this subgroup were enrolled. Also, no patients with genotype 5 HCV and only 3 patients with genotype 6 HCV were enrolled, reflecting the low prevalence of these infections in North America and New Zealand.

In conclusion, sofosbuvir-velpatasvir plus GS-9857 is a safe and effective treatment in patients with HCV genotypes 2, 3, 4, and 6, with and without compensated cirrhosis. High SVR rates were achieved in treatment-experienced patients, including those with DAA-experience, after12 weeks of sofosbuvir-velpatasvir plus GS-9857 and in treatment-naïve patients with compensated cirrhosis after 8 weeks of this regimen. These three potent pangenotypic DAAs have been coformulated into afixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination in patients for eight weeks treatment-naïve patients of all genotypes and for twelve weeks in patients of all genotypes who had received previous treatment with a DAA.

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Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients with Genotype 1 Hepatitis C Virus Infection in an Open-label, Phase 2 Trial
Eric Lawitz, Nancy Reau, Federico Hinestrosa, Mordechai Rabinovitz, Eugene Schiff, Aasim Sheikh, Ziad Younes, Robert Herring Jr., K. Rajender Reddy, Tram Tran, Michael Bennett, Ronald Nahass, Jenny C. Yang, Sophia Lu, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, John G. McHutchison, Brian Pearlman, Mitchell Shiffman, Trevor Hawkins, Michael Curry, Ira Jacobson
DOI: http://dx.doi.org/10.1053/j.gastro.2016.07.039
Publication stage: In Press Accepted Manuscript

The best regimen to retreat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus (HCV) genotype 1 infection.

Published online: July 30, 2016

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DISCUSSION ONLY
The development of oral DAAs represents a major advance in the treatment of HCV in patients of all genotypes. Currently available DAA combination regimens offer SVR rates well over 90% overall and in most patient subpopulations. Nevertheless, some patients do not achieve SVR with existing regimens. Patients who have failed prior treatment with first generation NS3/4A protease inhibitors (e.g., telaprevir, boceprevir, or simeprevir) may be retreated with ledipasvir sofosbuvir, but patients who have been unsuccessfully treated with a regimen that includes an NS5A inhibitor have no approved retreatment options. In a previous trial, patients with genotype 1 HCV who did not achieve SVR after 8 or 12 weeks of ledipasvir-sofosbuvir-based regimens and were subsequently retreated with 24 weeks of ledipasvir-sofosbuvir had an SVR12 rate of only 71%. In this population, the presence of baseline NS5A RASs was associated with a higher rate of virologic failure (Lawitz et al: J Hepatol 62:S192 Abstract, 2015).

In another small trial, 14 of 16 patients (88%) who had previously failed a daclatasvir-containing regimen achieved SVR12 after retreatment with simeprevir-sofosbuvir for 12 weeks. Thirteen of the 16 patients had NS5A RASs at baseline, and of these 13, 11 (85%) achieved SVR12. The 2 patients who did not achieve SVR12 had Q30K and L31M substitutions as the dominant viral populations at retreatment baseline.16

In this open-label, phase 2 study, 12 weeks of treatment with sofosbuvir-velpatasvir plus GS9857 was safe and highly effective in patients with HCV genotype 1, with and without cirrhosis, who did not achieve SVR after prior treatment with DAA, including those who had previously received an NS5A inhibitor. In treatment-naive patients, the 8-week regimen was safe and effective, regardless of cirrhosis status. Among the treatment-naïve patients who relapsed, the presence of baseline RASs appeared to have no impact on treatment outcome. Treatment emergent RASs by deep sequencing with a 1% cutoff were rare (3/17, 18%) and no treatment emergent RASs among relapsers were detected with the 15% cutoff. This is consistent with the anticipated high barrier of resistance of the combination therapy based on in vitro data (Lawitz et al: Hepatology XXX Abstract 2015).

Treatment-naïve patients without cirrhosis treated for 8 weeks achieved a SVR12 rate of 100%,which is higher than results reported in other recent studies of combining 3 or 4 DAAs for treatment for the same population and treatment duration.20,21 Treatment-naïve patients with cirrhosis treated for 8 weeks had lower SVR12 rates of 81-94% than patients without cirrhosis. Larger studies will determine whether this short duration is adequate for this patient population. One unexpected result in our trial was the apparent lack of benefit of the addition of ribavirin to sofosbuvir-velpatasvir plus GS-9857 for treatment-naïve patients with cirrhosis. Although patients in this group receiving ribavirin had a numerically lower rate of SVR12 than treatment naïve patients with cirrhosis who received sofosbuvir-velpatasvir plus GS-9857 without ribavirin (81% vs 94%), the confidence intervals overlap and it is likely that this reflects the small sample sizes.

Factors limiting the interpretation of these results of this trial include its small size and uncontrolled, open-label design. Although the trial enrolled only patients with genotype 1 HCV, another trial of similar design has been conducted to assess this combination regimen in patients with non-genotype 1 HCV.

In conclusion, sofosbuvir-velpatasvir plus GS-9857 for 12 weeks provided a high rate of SVR12 (100%) and was well-tolerated in a group of patients currently without treatment options—those with and without compensated cirrhosis who have not achieved SVR after previous treatment with a NS5A inhibitor-containing regimen. The addition of GS-9857 to sofosbuvir-velpatasvir was also safe in the treatment-naïve population where it was effective in reducing the treatment duration to 8 weeks while preserving a high rate of SVR12. These three potent pangenotypic DAAs have been coformulated into a fixed-dose combination tablet. The Phase 3 program will evaluate this fixed-dose combination for eight weeks in treatment-naïve patients and for twelve weeks in DAA-experienced patients, including those who have previously received an NS5A inhibitor.

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Monday, 20 June 2016

Enanta Initiates Proof-of-Concept Study with Pan-genotypic Cyclophilin Inhibitor EDP-494/Geno 1 or Geno 3 Chronic Hepatitis C Virus

Enanta Pharmaceuticals Initiates Proof-of-Concept Study with Pan-genotypic Cyclophilin Inhibitor EDP-494 in Patients with Genotype 1 or Genotype 3 Chronic Hepatitis C Virus

New non-DAA mechanism retains potency against important DAA resistance-associated variants (RAVs), regardless of class

EDP-494 represents a new host-targeted approach that may play an important role in future treatment regimens for chronic hepatitis C virus (HCV) patients that have failed therapy due to resistance arising from direct-acting antiviral (DAA) therapies currently on the market

WATERTOWN, Mass.--(BUSINESS WIRE)--Jun. 20, 2016-- Enanta Pharmaceuticals, Inc., (NASDAQ:ENTA), a research and development-focused biotechnology company dedicated to creating small molecule drugs for viral infections and liver diseases, today announced that it has initiated a proof of concept study (POC) and has begun dosing with EDP-494, a potent, pan-genotypic cyclophilin inhibitor to treat patients with genotype 1 (GT1) or genotype 3 (GT3) chronic hepatitis C virus.

The double-blind, randomized POC portion of this ongoing phase 1 study will assess the safety, pharmacokinetics and anti-viral activity of two planned different doses of EDP-494 in treatment-naïve HCV patients dosed orally, once daily for 14 days. Safety and pharmacokinetics of single and multiple ascending doses of once daily, orally administered EDP-494 have been established in healthy volunteers and these data support the testing of EDP-494 in a proof-of-concept study in HCV patients.

EDP-494, a Cyclophilin Inhibitor for HCV Infection
Due to resistance arising with direct-acting antiviral HCV therapies currently on the market, Enanta has developed an alternative treatment approach to HCV that targets the human host protein cyclophilin, which is essential for replication of HCV. Since cyclophilin inhibitors act as host-targeted antivirals, the viral mutation resistance that arises from direct-acting antiviral (DAA) treatments would not be expected for this mechanism, and thus cyclophilin inhibitors may have the highest barrier to resistance of any class of HCV treatments.

“As the number of patients treated with the current HCV DAA regimens on the market rapidly increases, the treatment failure population will become an important unmet medical need in patients with hepatitis C and may require new mechanisms of therapy such as cyclophilin inhibition,” commented Professor Edward J. Gane, MD, Professor of Medicine at the University of Auckland, New Zealand and Chief Hepatologist, Transplant Physician and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital and chief investigator of the EDP-494 study. “This host-targeted approach may prove valuable not only in the toughest to treat patients with DAA resistance, but also in the general HCV patient population, given its pangenotypic mechanism of action and high barrier to resistance.”

Data presented at the International Liver Congress™ ¹in Barcelona in April, 2016 demonstrated that EDP-494 in replicon assays is a potent inhibitor of HCV replication and has shown no loss of potency against all major NS5A RAVs, NS5B RAVs (both Nucleotide and non-Nucleotide) as well as NS3 protease inhibitor RAVs.

Following the completion of the phase 1 study, Enanta plans to develop EDP-494 in combination with one or more DAAs for the treatment of any emerging HCV resistance to currently marketed therapies or any other therapies in development that use DAAs. Enanta anticipates that a DAA-cyclophilin inhibitor combination could provide one of the highest barrier to resistance combination treatments for HCV.

About EDP-494
EDP-494 is a cyclophilin inhibitor that targets the human host protein, cyclophilin, which is essential for replication of chronic hepatitis C virus (HCV). Host-targeted antivirals (HTAs) such as cyclophilin inhibitors are not affected by changes in the virus and, therefore, use of this class of inhibitor may provide a unique solution for a subset of hard-to-treat HCV patients. Enanta has demonstrated in replicon assays that EDP-494 is a potent inhibitor of HCV. A phase 1 clinical study in HCV patients is currently underway.

About Enanta
Enanta Pharmaceuticals is a research and development-focused biotechnology company that uses its robust chemistry-driven approach and drug discovery capabilities to create small molecule drugs for viral infections and liver diseases. Enanta’s research and development efforts are currently focused on four disease targets: Hepatitis C Virus (HCV), Hepatitis B Virus (HBV), Non-alcoholic Steatohepatitis (NASH) and Respiratory Syncytial Virus (RSV).
Enanta has discovered novel protease inhibitors and NS5A inhibitors that are members of the direct-acting-antiviral (DAA) inhibitor classes designed for use against the hepatitis C virus (HCV). Enanta’s protease inhibitors, developed through its collaboration with AbbVie, include paritaprevir, which is contained in AbbVie’s marketed DAA regimens for HCV, and ABT-493, Enanta’s second protease inhibitor, which AbbVie is developing in phase 3 studies in combination with ABT-530, AbbVie’s NS5A inhibitor. Enanta has also discovered a cyclophilin inhibitor, EDP-494, a novel host-targeting mechanism for HCV, which is now in phase 1 clinical development, and EDP-305, an FXR agonist, which Enanta plans to advance into clinical development for NASH later in 2016. Please visit www.enanta.com

Tuesday, 14 June 2016

Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin HCV genotype 1 patients

Original Article

Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in 6961 genotype 1 patients treated in routine medical practice

Authors •L. I. Backus,
author notes Corresponding author1.Department of Veterans Affairs, Population Health Services, Palo Alto Health Care System, Palo Alto, CA, USA
First published: 13 June 2016
Full publication history •DOI: 10.1111/apt.13696

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Summary
Background Real-world data are needed to inform hepatitis C virus (HCV) treatment decisions.

Aim

To assess the comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV) vs. ombitasvir/paritaprevir/ritonavir + dasabuvir (OPrD) ± RBV in genotype 1 HCV patients treated in routine medical practice.

Methods

Observational intent-to-treat cohort of genotype 1 patients initiating 8 or 12 weeks of LDV/SOF ± RBV or 12 weeks of OPrD ± RBV. Sustained virological response (SVR) required RNA below the limit of quantification at least 10 weeks after end of treatment.
Results 6961 patients initiated LDV/SOF (N = 4478), LDV/SOF + RBV (N = 1269), OPrD (N = 297), and OPrD + RBV (N = 917) at 126 facilities. Intention-to-treat SVR rates were 91.4% (3813/4170) for LDV/SOF, 90.0% (1098/1220) for LDV/SOF + RBV, 95.1% (269/283) for OPrD and 85.8% (746/869) for OPrD + RBV. SVR rates in those completing 8 weeks of LDV/SOF were 91.7% (1223/1333) and 12 weeks of LDV/SOF 94.6% (2475/2615), LDV/SOF + RBV 92.2% (1033/1120), OPrD 98.0% (248/253) and OPrD + RBV 95.5% (705/738). Significant predictors of SVR were African American race (OR 0.71, 95%CI 0.59–0.86, P < 0.001), body mass index (BMI) > 30 kg/m2 (OR 0.73, 95% CI 0.60–0.89, P = 0.002), FIB4 > 3.25 (OR 0.60, 95% CI 0.49–0.72, P < 0.001), OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48–0.76, P < 0.001) and subtype 1b (OR 1.38, 95% CI 1.11–1.71, P = 0.003). For those completing 12 weeks, FIB-4 > 3.25 and high BMI remained significant predictors.

Conclusions

In this robust real-world cohort, SVR rates were similar to clinical trials. FIB-4 > 3.25 and high BMI were significant negative predictors of SVR. Reduced odds of SVR in African Americans and with OPrD + RBV likely arose from excess early discontinuation as these factors were no longer
significant, when limited to patients completing a 12-week course.

Introduction

The landscape of antiviral therapy for chronic hepatitis C virus (HCV) infection continues to advance as all-oral options expand. Sustained virological response (SVR) rates reported in clinical trials with all-oral regimens are consistently above 90% for most HCV-infected patient populations and have become the expected norm. Because of the rapidity with which HCV therapies are progressing and the absence of comparative clinical trials, providers are left to extrapolate information to make clinical decisions about medication selection. Emerging real-world data of individual therapies have demonstrated results comparable to registration trials, however, comparative effectiveness evaluations are needed to determine whether clinical differences exist between regimens.[1-6] Comparative effectiveness analyses will become increasingly important as patients, providers, healthcare systems and managed care organisations consider additional nuances of convenience, drug interactions, treatment duration and ultimately cost effectiveness.

Ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) have been extensively evaluated individually in clinical trials of HCV-infected adults. The SVR rates in LDV/SOF trials of genotype 1 patients with and without cirrhosis ranged from 94% to 99% and in OPrD trials SVR rates ranged from 89% to 99%.[7-14] While these outcomes appear similar, differences in study design and patient populations prevent direct cross-study comparison of results.
Hepatitis C virus disproportionally affects the veteran population and the Department of Veterans Affairs (VA) is the largest US provider of healthcare to HCV-infected individuals caring for nearly 5% of all individuals in the US with HCV infection.[15, 16] Thus, ongoing evaluation of the effectiveness of HCV antiviral regimens remains a priority for VA.[17] With the rapid uptake of all-oral HCV regimens across the VA system and the diverse HCV-infected veteran population receiving these regimens, we examined SVR rates and comparative effectiveness of LDV/SOF ± ribavirin (RBV) vs. OPrD ± RBV in genotype 1 HCV-infected veterans treated in routine medical practice.

Materials and methods

This was an observational intent-to-treat cohort analysis of HCV-infected veterans receiving LDV/SOF ± RBV or OPrD ± RBV from VA. Data for this study were obtained from the VA's national Clinical Case Registry for HCV, an extract of the VA electronic medical record that contains demographics, laboratory results, pharmacy information and International Classification of Diseases diagnosis codes from inpatient hospitalisations, outpatient visits and problem lists of HCV-infected veterans seen at all VA medical facilities.[18]

Eligible subjects included all genotype 1 HCV-infected veterans from any VA facility nationwide who initiated 8 or 12 weeks of VA-prescribed LDV/SOF ± RBV or 12 weeks of OPrD ± RBV by 31 March 2015 with an end of treatment (EOT) by 14 July 2015 and a days supply less than or equal to 91 days. For patients who received multiple courses of therapy, only the first course was included. The choice of regimen and timing of follow-up visits and laboratory testing was at the discretion of the provider as patients were treated in routine practice. The present cohort includes 4356 treatment naïve patients treated with LDV/SOF ± RBV who were reported on previously.[19] Patients were excluded if they changed regimens without a treatment interruption (n = 64), had a baseline HCV RNA ≤1000 IU/mL (n = 218), had a liver transplant (n = 141), or had genotype subtype 1a and received OPrD without RBV (n = 16).

Treatment outcome

Patients were considered to have SVR if they had HCV RNA results below the limit of quantification on all HCV RNA tests after the EOT including at least one test 10 weeks or more after the EOT. The 10 week time point was chosen to account for variability of clinic visits and of laboratory testing draws in clinical practice. Patients were categorised as not achieving SVR if they had a HCV RNA above the limit of quantification after the EOT, had no HCV RNA testing after the EOT and a HCV RNA above the limit of quantification on their last HCV RNA test while on treatment or died while on treatment or within 10 weeks of the EOT. Patients with HCV RNA below the limit of quantification on their last HCV viral load test, either on treatment or after the EOT, but no test 10 weeks of more after the EOT were excluded from the SVR analysis. The EOT was calculated as the last day covered by prescriptions of LDV/SOF or OPrD using the dates the medication was dispensed and the days’ supply. HCV RNA was categorised as above or below the lower limit of quantification based on the locally reported HCV RNA result of which 98% utilised assays with a lower limit of quantification of 15 U/mL or less. Patients were followed from the initiation of LDV/SOF ± RBV or OPrD ± RBV through 29 February 2016, allowing for more than 32 weeks of follow-up after the EOT for all patients in the cohort.

Control variables

Demographic and other baseline variables were determined at the time of treatment initiation and included age, gender, race/ethnicity, diabetes, HIV coinfection, history of decompensated liver disease (defined by oesophageal variceal haemorrhage, hepatic coma, hepatorenal syndrome or spontaneous bacterial peritonitis), prescribed proton pump inhibitor use, prior HCV antiviral treatment experience and HCV genotype 1 subtype. Subtype 1a included patients with reported results of 1a, mixed 1a/1b or 1 with subtype unspecified. Prior virological response was based on the most recent VA course of HCV antiviral treatment and categorised as relapse, partial response, null response and not defined. Baseline values for height and weight used to calculate body mass index (BMI) and the laboratory tests for alanine aminotransferase, aspartate aminotransferase, platelets and baseline HCV RNA were defined as the value within 1 year before and closest to the treatment start date. A FIB-4 score >3.25 at the start of treatment using baseline laboratory values was used as a marker of advanced liver disease.[20, 21] Patients with FIB-4 ≤ 3.25 were considered to be ‘noncirrhotic’.

In VA, HCV antiviral prescriptions are frequently filled for quantities less than 28 days. Patients were considered to have completed 8 weeks of LDV/SOF if they had received between 49 and 63 days’ worth of medication and 12 weeks LDV/SOF ± RBV or OPrD ± RBV if they received between 77 and 91 days’ worth of medication.

Statistical analysis

Univariate comparisons used the Pearson chi-squared test with Yates’ continuity correction for categorical variables. Multivariate logistic regression models were constructed to model SVR. Models included age, gender, race/ethnicity, diabetes, history of decompensated liver disease, treatment experience, BMI, FIB-4, genotype 1 subtype, and regimen. In a sensitivity analysis proton pump inhibitor use was included in the model. A set of models with the above baseline variables was constructed with all patients and with only patients who completed 12 weeks of treatment.
For all comparisons, a P < 0.01 was considered statistically significant. All analyses were performed using R version 3.1 (R Foundation for Statistical Computing, Vienna, Austria).
The protocol was approved by the Stanford University Institutional Review Board and the VA Palo Alto Health Care System Research and Development Committee.

Results

In total, 6961 patients with HCV genotype 1 initiated LDV/SOF ± RBV (n = 5747) or OPrD ± RBV (n = 1214) at 126 VA facilities. The mean age for the cohort was 61.4 years, 96.3% were male, 36.0% were African-American, 31.5% had diabetes, 3.2% had a history of decompensated liver disease, 23.6% were treatment experienced, 35.4% had a BMI ≥30 kg/m², and 29.5% had a FIB-4 > 3.25.

Baseline characteristics for the cohort by regimen appear in Table 1. For the cohort, 64.3% (n = 4478) received LDV/SOF, 18.2% (n = 1269) received LDV/SOF + RBV, 4.3% (n = 297) received OPrD and 13.2% (n = 917) received OPrD + RBV. Patients who received LDV/SOF+RBV were most likely to be treatment-experienced and to have markers of advanced liver disease including a history of decompensated liver disease, lower mean platelet count, higher mean FIB-4 score, and FIB-4 > 3.25.

Table 1. Baseline characteristics and 4 week on-treatment response of genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens with durations of 12 weeks or less

	Genotype 1 cohort (N = 6961)	LDV/SOF (N = 4478)	LDV/SOF + RBV (N = 1269)	OPrD (N = 297)	OPrD + RBV (N = 917)
Continuous variables reported as mean ± s.d. (range). Categorical variables reported as % (n). ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DAA, direct-acting antiviral; LDV/SOF, ledipasvir/sofosbuvir; OPrD, ombitasvir/paritaprevir/ritonavir + dasabuvir; PEG, pegylated interferon; SOF, sofosbuvir; RBV, ribavirin. *Some patients received more than one prior DAA regimen and are included in the count for each regimen they received.
Age (years)	61.4 ± 6.2 (24.5–90.8)	61.2 ± 6.5 (25.3–90.8)	61.9 ± 5.2 (24.5–86.2)	62.3 ± 5.9 (28.5–77.2)	61.5 ± 6.0 (26.7–85.3)
Gender, male	96.3 (6703)	95.9 (4295)	97.2 (1233)	96.3 (286)	96.9 (889)
Race/ethnicity
African-American	36.0 (2506)	38.2 (1712)	29.0 (368)	46.8 (139)	31.3 (287)
Caucasian	51.6 (3591)	50.5 (2263)	54.5 (692)	43.4 (129)	55.3 (507)
Hispanic	5.4 (376)	4.5 (304)	8.0 (102)	4.0 (12)	6.4 (59)
Other/multiple	7.0 (488)	6.7 (300)	8.4 (107)	5.7 (17)	7.0 (64)
Diabetes	31.5 (2195)	30.3 (1357)	37.7 (479)	33.3 (99)	28.4 (260)
Proton pump inhibitor	27.7 (1927)	26.3 (1178)	35.4 (449)	25.3 (75)	24.5 (225)
HIV coinfected	4.5 (310)	5.3 (237)	3.7 (47)	2.4 (7)	2.1 (19)
Decompensated liver disease	3.2 (224)	1.9 (87)	8.6 (109)	0.7 (2)	2.8 (26)
Any treatment experience	23.6 (1645)	16.0 (718)	53.0 (673)	19.2 (57)	21.5 (197)
DAA experience (% of treatment experienced)	44.1 (726)	39.1 (281)	62.4 (420)	7.0 (4)	10.7 (21)
Prior SOF + simeprevir (n)*	71	12	57	0	2
Prior SOF + PEG + RBV or SOF + RBV (n)*	131	29	96	0	6
Prior boceprevir (n)*	494	222	253	4	15
Prior telaprevir (n)*	74	21	53	0	0
Prior treatment response	N = 1645	N = 718	N = 673	N = 57	N = 197
Relapse	29.9 (492)	24.0 (172)	39.2 (264)	14.0 (8)	24.4 (48)
Partial	10.2 (167)	9.1 (65)	10.1 (68)	21.1 (12)	11.2 (22)
Null	11.3 (186)	9.6 (69)	11.1 (75)	12.3 (7)	17.8 (35)
Unknown	48.6 (800)	57.4 (412)	39.5 (266)	52.6 (30)	46.7 (92)
BMI (kg/m²)	28.8 ± 5.3 (15.8–65.2)	28.5 ± 5.2 (15.8–65.2)	30.0 ± 5.5 (16.4–60.1)	28.2 ± 5.0 (16.0–53.7)	28.8 ± 5.3 (17.6–58.5)
BMI (kg/m²)
<25	23.1 (1605)	24.8 (1109)	17.9 (227)	24.2 (72)	21.5 (197)
25–29	41.6 (2893)	41.6 (1863)	37.6 (477)	49.8 (148)	44.2 (405)
≥30	35.4 (2463)	33.6 (1506)	44.5 (565)	25.9 (77)	34.4 (315)
ALT (U/L)	74.1 ± 56.5 (8–659)	71.4 ± 55.9 (8–659)	80.3 ± 52.3 (13–445)	62.6 ± 50.7 (13–552)	82.4 ± 64.3 (11–560)
AST (U/L)	64.4 ± 45.5 (6–614)	60.5 ± 43 (6–614)	76.6 ± 48.2 (11–503)	50.6 ± 34.8 (14–322)	70.4 ± 52.1 (13–499)
Platelets (Κ/μL)	185.6 ± 69.9 (6–759)	194.4 ± 68.2 (6–661)	150.3 ± 67.9 (22–759)	214.6 ± 59.6 (81–421)	181.8 ± 66.7 (32–470)
FIB-4	3.2 ± 3.7 (0.1–185.0)	2.8 ± 3.8 (0.1–185.0)	4.7 ± 4.1 (0.5–34.7)	2.0 ± 1.2 (0.3–10.0)	3.3 ± 2.9 (0.4–27.3)
FIB-4	N = 6936	N = 4460	N = 1267	N = 296	N = 913
≤3.25	70.5 (4889)	76.4 (3406)	47.8 (605)	89.5 (265)	67.1 (613)
>3.25	29.5 (2047)	23.6 (1054)	52.2 (662)	10.5 (31)	32.9 (300)
HCV RNA (log IU/mL)	6.2 ± 0.7 (3.0–7.9)	6.2 ± 0.7 (3.1–7.9)	6.2 ± 0.7 (3.0–7.8)	6.3 ± 0.6 (3.9–7.6)	6.3 ± 0.7 (3.0–7.8)
HCV RNA (IU/mL)
<6 000 000	82.0 (5705)	82.7 (3705)	84.6 (1073)	76.8 (228)	76.2 (699)
≥6 000 000	18.0 (1256)	17.3 (773)	15.4 (196)	23.2 (69)	23.8 (218)
HCV subtype 1b	27.3 (1897)	24.2 (1085)	23.4 (297)	100.0 (297)	23.8 (218)
IL28B polymorphism	N = 989	N = 598	N = 204	N = 33	N = 154
CC	20.3 (201)	22.6 (135)	15.2 (31)	9.1 (3)	20.8 (32)
CT	54.0 (534)	52.7 (315)	58.3 (119)	51.5 (17)	53.9 (83)
TT	25.7 (254)	24.7 (148)	26.5 (54)	39.4 (13)	25.3 (39)

Among patients who received LDV/SOF, 3.6% (n = 159) discontinued treatment before 8 weeks, 32.7% (n = 1464) received 8 weeks, 1.7% (n = 77) discontinued treatment between 8 and 12 weeks and 62.0% (n = 2778) received 12 weeks. In total, 94.7% completed either an 8 or 12 week course. Among people who received LDV/SOF + RBV, 8.1% (103/1269) discontinued treatment prior to completing 12 weeks. Among patients who received OPrD or OPrD+RBV, 11.4% (34/297) and 15.2% (140/917) of patients, respectively, discontinued treatment prior to completing a 12 week course. Significantly more patients receiving OPrD + RBV discontinued treatment prior to completing a 12-week course compared to those receiving LDV/SOF + RBV (P < 0.001).

Sustained virological response results were available for 94.0% (n = 6542) of patients in the cohort, including 24 patients who died while on treatment or shortly after who were categorised as no SVR. Four hundred nineteen patients whose last HCV RNA was undetectable, but occurred while still on treatment (n = 123) or less than 10 weeks after the EOT (n = 296), were excluded from the SVR analysis. Three hundred five patients had an undetectable HCV RNA obtained 10–11 weeks after the EOT and were included in the SVR analysis for reasons described previously.

Among 4170 LDV/SOF patients 91.4% achieved SVR; among 1220 LDV/SOF + RBV patients 90.0% achieved SVR; among 283 OPrD patients 95.1% achieved SVR and among 869 OPrD + RBV patients 85.8% achieved SVR (Table 2). For patients who received LDV/SOF, the SVR rates differed statistically based on categories of race/ethnicity, BMI, and FIB-4. For patients who received LDV/SOF + RBV, the SVR rates differed statistically based on proton pump inhibitor use and FIB-4. No statistically significant differences in SVR were observed according to baseline patient characteristics among patients receiving either OPrD or OPrD + RBV, and responses were generally similar to that observed in the overall population. SVR data for treatment naïve and experienced patients by subgroup can be found in Table S1A and B.

(Table 2). SVR rates by regimen for genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens with durations of 12 weeks or less

Click On Image To Enlarge

For patients who completed an 8 week course of LDV/SOF or a 12 week course of LDV/SOF ± RBV or OPrD ± RBV, SVR rates were consistently higher overall and among subgroups when compared to the intention-to-treat SVR rates (Table 3). With regard to the impact of treatment duration among patients who received LDV/SOF, the SVR rate in those who received 8 weeks was 91.7% (1223/1333) and 94.6% (2475/2615) in those who received 12 weeks. An SVR rate of 92.2% (1033/1120) was achieved in patients completing 12 weeks of LDV/SOF + RBV and 95.5% (705/738) in those completing 12 weeks of OPrD+RBV. In genotype 1b patients who received 12 weeks of OPrD, an SVR rate of 98.0% (248/253) was achieved. In 1098 patients who met the Food and Drug Administration (FDA) labelling considerations for a shortened LDV/SOF course consisting of treatment-naïve, without cirrhosis (defined as FIB-4 ≤ 3.25), and a baseline HCV RNA <6 000 000 IU/mL and who completed 8 weeks of LDV/SOF therapy, the SVR rate was 93.2% (1023/1098). In 905 patients who also met the FDA considerations for a shortened LDV/SOF course but nevertheless received 12 weeks of LDV/SOF therapy, the SVR rate was 96.6% (874/905)(P = 0.001 compared to 8 week course).

Table 3. SVR rates by regimen for genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens who received 8 or 12 weeks of LDV/SOF and 12 weeks of all other regimens

Click On Image To Enlarge

In multivariate analysis, significant independent predictors of decreased odds of SVR were African American race (OR 0.71, 95% CI 0.59–0.86, P < 0.001), BMI ≥30 kg/m² (OR 0.73, 95% CI 0.60–0.89, P = 0.002), FIB-4 > 3.25 (OR 0.60, 95% CI 0.49–0.72, P < 0.001) and use of OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48–0.76, P < 0.001) (Table 4). Genotype subtype 1b was an independent predictor of increased odds of SVR (OR 1.38, 95% CI 1.11–1.71, P = 0.003). Age, gender, diabetes, history of decompensated liver disease and treatment experience did not predict SVR. In the sensitivity analysis proton pump inhibitor use was not associated with a difference in the odds of achieving SVR (0.85, 95% CI 0.71–1.03, P = 0.09). In models limited to patients receiving 12 weeks of treatment, only BMI ≥30 kg/m² (OR 0.66, 95% CI 0.49–0.88, P = 0.004) and FIB4 > 3.25 remained significant (OR 0.46, 95% CI 0.35–0.60, P < 0.001).

Table 4. Odds ratios for sustained virological response in multivariate model for genotype 1 patients treated with ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens

	Intention-to-treat OR (95% CI), N = 6525	Received 12 weeks OR (95% CI), N = 4720
BMI, body mass index; CI, confidence interval; LDV/SOF, ledipasvir/sofosbuvir; OPrD, ombitasvir/paritaprevir/ritonavir+dasabuvir; OR, odds ratio; RBV, ribavirin; ref., reference; SVR, sustained virological response. †Subtype 1a includes 1a, mixed 1a/1b and 1 with subtype unspecified. P < 0.01, *P < 0.001.
Age <55 years (ref. 55–64)	1.37 (0.98–1.94)	1.36 (0.83–2.37)
Age ≥65 years (ref. 55–64)	1.17 (0.96–1.43)	1.26 (0.94–1.70)
Female (ref. Male)	2.23 (1.26–4.38)	2.51 (1.04–8.23)
African American (ref. Caucasian)	0.71 (0.59–0.86)***	0.86 (0.64–1.14)
Hispanic (ref. Caucasian)	0.77 (0.54–1.12)	1.00 (0.59–1.81)
Other/multiple (ref. Caucasian)	0.87 (0.62–1.23)	0.81 (0.51–1.34)
Diabetes (ref. no diabetes)	1.01 (0.83–1.22)	1.08 (0.82–1.42)
Decompensated liver disease (ref. no)	0.60 (0.41–0.90)	0.87 (0.51–1.54)
Treatment experienced (ref. naïve)	0.90 (0.73–1.11)	0.90 (0.67–1.21)
BMI <25 kg/m² (ref. 25–29 kg/m²)	0.77 (0.61–0.96)	0.99 (0.69–1.44)
BMI ≥30 kg/m² (ref. 25–29 kg/m²)	0.73 (0.60–0.89)**	0.66 (0.49–0.88)**
FIB-4 > 3.25 (ref. ≤3.25)	0.60 (0.49–0.72)***	0.46 (0.35–0.60)***
HCV subtype 1b (ref. 1a†)	1.38 (1.11–1.71)**	1.44 (1.04–2.02)
LDV/SOF + RBV (ref. LDV/SOF)	1.07 (0.84–1.37)	0.87 (0.64–1.19)
OPrD (ref. LDV/SOF)	1.27 (0.74–2.37)	1.68 (0.71–4.93)
OPrD+RBV (ref. LDV/SOF)	0.60 (0.48–0.76)***	1.22 (0.83–1.84)

Discussion

In this robust comparative effectiveness analysis of LDV/SOF ± RBV vs. OPrD ± RBV in genotype 1 HCV-infected veterans treated in routine medical practice, high SVR rates were achieved overall (86–95%) and within subgroups (83–100%). In multivariate models, OPrD + RBV was found to be less effective than LDV/SOF and patients receiving the former were 40% less likely to achieve SVR. However, in patients who completed a 12-week treatment course there was no difference in effectiveness. Similar to clinical trials, curative all-oral treatment has become a reality for over 90% of patients treated in the real-world, even in those with characteristics previously associated with poorer outcomes. This analysis demonstrates the real-world comparative effectiveness of all-oral DAA regimens in individuals with genotype 1 HCV infection that clinicians, patients and payers have anticipated.

The current HCV treatment landscape remains complex despite increasingly more effective HCV regimens, with variability in outcomes for patients with previous treatment experience, genotype subtype, race, degree of underlying liver disease and other comorbid conditions.[7, 8, 13, 14, 22-24] Because of the large sample size in this cohort, we were able to do robust subgroup analyses to examine differences among these characteristics and identify where challenges remain.
Despite SVR rates higher than any previously reported among veterans with advanced liver disease, the presence of advanced liver disease as indicated by a FIB-4 score greater than 3.25 remained a significant negative predictor of response with an apparent impact for treatment naïve and treatment experienced patients and across all regimens.[5, 23, 25] Over 2000 patients with advanced liver disease were included in this cohort. In multivariate models, the presence of advanced liver disease predicted reduced odds of achieving SVR by 40% independent of treatment experience and regimen. Absolute SVR rates in treatment naïve patients were generally four to five percent lower in those with advanced liver disease compared to those without advanced liver disease for patients who received LDV/SOF (87.6% vs. 92.6%), who received LDV/SOF + RBV (90.0% vs. 94.7%), and who received OPrD (91.7% vs. 96.1%). Current AASLD/IDSA treatment guidelines and FDA labelling recommend LDV/SOF for 12 weeks in treatment naïve patients with cirrhosis based largely on data from 34 patients in the ION-1 trial.[7, 26, 27] However, our observation of SVR rate of 87.6% with LDV/SOF in 889 treatment naïve patients with FIB4 scores >3.25 indicate SVR rates with this regimen may be below the 90% bar for which all-oral regimen expectations have been set and other treatment options might need to be considered in such patients.

In treatment experienced patients with and without advanced liver disease, reductions of 5–8% in SVR rates were seen in patients who received LDV/SOF (85.5% vs. 93.5%), who received LDV/SOF + RBV (85.4% vs. 90.9%), and who received OPrD + RBV (82.1% vs. 89.6%). The reduced SVR rates in the low to mid-80s in treatment experienced patients with advanced liver disease in this study mirror the 86% and 82% SVR rates observed in ION-2 in treatment-experienced cirrhotic patients receiving 12 weeks of LDV/SOF and LDV/SOF + RBV respectively.[8] In the TURQUOISE-II study SVR rates were 87% and 95% in treatment experienced cirrhotic null responders treated for 12 and 24 weeks respectively with OPrD+RBV.[14] The large number of patients included in our study coupled with the similar results obtained from ION-2 and TURQUOISE-II suggest that lower SVR rates may be expected in cirrhotic patients and particularly treatment-experienced cirrhotic patients treated in routine clinical practice. Extended treatment of 24 weeks in such patients may be warranted to achieve higher SVR rates.

In this cohort, SVR data were available for over 2300 African Americans. Multivariate modelling indicated African American race was associated with a 29% reduction in the odds of SVR. This effect was observed in multivariate models of the overall cohort but not in models limited to patients completing a 12 week treatment course suggesting that the reduced odds of SVR for African Americans arose in large part from excess early treatment discontinuations and from diminished effectiveness of 8-week LDV/SOF in African Americans, which has also been observed in retrospective analyses of the ION clinical trials.[22] Numerically lower SVR rates were observed in African Americans compared to Caucasians treated with LDV/SOF, OPrD and OPrD+RBV. In patients who received a full 12 weeks of treatment, SVR rates in African Americans were higher than in the intention-to-treat analysis and the numeric differences in SVR rates between African Americans and Caucasians were diminished.

This study included over 2300 patients with a BMI at or above 30 kg/m², and in the overall cohort those with high BMI were 27% less likely to achieve SVR. As one might expect, the effect of BMI on SVR was not dependent on whether the patient completed therapy and, as such, high BMI remained a negative predictor of response in those who completed a 12-week treatment course. For such patients, additional treatment options may need to be considered to optimise SVR rates.
Shorter 8 week regimens were widely used in treatment-naïve patients with baseline HCV RNA below 6 000 000 IU/mL without cirrhosis. We could only assess the use of 8 week LDV/SOF regimens in patients who completed therapy because we were unable to otherwise determine if the original provider intent was to treat for 8 or 12 weeks using the available electronic data. Although the difference in SVR rates between those who completed 8 weeks and those who completed 12 weeks was numerically small at 3.4% it was statistically significant suggesting that to optimise a patient's likelihood of SVR the 12-week duration may be preferred.

Real-world SVR rates achieved with these treatment regimens were remarkably high. The large differences between real-world effectiveness and clinical trial efficacy previously observed with HCV antiviral treatment have now been almost eliminated with the use of potent all-oral regimens. Most of the small decrement in observed effectiveness in this real-world cohort may be explained in large part by higher early discontinuation rates. Early discontinuations rates were highest in those receiving OPrD + RBV (15.2%), followed by OPrD (11.4%), LDV/SOF + RBV (8.1%) and LDV/SOF (5.3%). Clinical trials tend to have early discontinuation rates of less than 3%.[7-14] Higher early discontinuation rates had the greatest impact on SVR rates in those receiving OPrD + RBV with a nearly 10% difference in SVR rates comparing intention-to-treat (85.8%) to those who completed 12 weeks (95.5%). While we did not examine reasons for early discontinuation, adverse effects and adherence are often recognised as contributing factors. Setting appropriate expectations about potential medication side effects and continued emphasis on adherence and persistence will remain important elements in maximising treatment success. Any remaining decrement in clinical effectiveness compared to clinical trial efficacy may be explained by differences in patient populations. For example, higher BMI in our cohort was identified as a significant negative predictor of SVR.

Given the high SVR rates achieved in clinical practice even among subgroups, regimen selection will depend increasingly upon nuanced considerations. Genotype subtype, presence of cirrhosis, prior treatment regimen or presence of pre-existing resistance associated polymorphisms currently determines the need for RBV and subsequent length of treatment for certain regimens. Potential for drug interactions and comorbidities may limit use of a particular agent. Enough options presently exist to allow providers some flexibility in selecting regimens tailored to meet individual patient characteristics or needs without sacrificing effectiveness. Expectations for high SVRs have been set and now validated in real-world cohorts, thus regimen subtleties together with cost considerations and insurance coverage will be key determinants for utilisation.

While this study includes one of the largest cohorts of diverse HCV-infected patients treated in clinical practice published to date, there are limitations. Specific reasons for early discontinuation (i.e. adverse events, poor tolerability, social or behavioural issues) could not be determined from the electronic data. Duration of treatment and early treatment discontinuation rates were determined based on the cumulative dispensed days’ supply which may overestimate the treatment duration as patients may have discontinued treatment even with medication in their possession. In VA, many prescriptions are filled for small quantities (e.g. 2-week supplies) which would limit the extent of the overestimation. Baseline resistance testing was not performed thus we were unable to assess the impact of this factor.

Conclusions

In this large real-world cohort of genotype 1 HCV-infected veterans treated with LDV/SOF-based or OPrD-based therapy, high SVR rates comparable to clinical trials were observed and were consistently high across all subgroups evaluated. Odds of SVR were reduced in African Americans compared to Caucasians, those receiving OPrD + RBV compared to LDV/SOF, those with advanced liver disease and those with BMI ≥30 kg/m² compared to those with lower BMI. Reduced odds of SVR for African Americans and those receiving OPrD + RBV arose in large part from early discontinuation as these predictors no longer had a significant impact on odds of SVR in those who completed a 12-week course. Advanced liver disease and higher BMI, however, persisted as significant negative predictors of SVR even when considering only those patients who completed a 12-week course. For patients with advanced liver disease and high BMI longer durations of therapy or additional treatment options may still be needed to increase SVR rates. Real-world experience from large diverse cohorts such as this is necessary to better inform and refine HCV management strategies.

Authorship

Guarantor of the article: Lisa I. Backus.
Author contributions: Drs Backus, Belperio, Loomis and Mole: Study concept and design. Drs Backus, Belperio, Shahoumian, Loomis and Mole: Analysis and interpretation of data; Drs Backus, Belperio: drafting of the manuscript, Drs Backus, Belperio and Mole: Critical revision of the manuscript for important intellectual content; Dr Shahoumian: Statistical analysis. This statement acknowledges that all authors approved the final version of the article, including the authorship list.

Acknowledgement

Declaration of personal and financial interests: None.

Source http://onlinelibrary.wiley.com/enhanced/doi/10.1111/apt.13696