Alimentary Pharmacology and Therapeutics

Virological outcomes and treatment algorithms utilisation in observational study of patients with chronic hepatitis C treated with boceprevir or telaprevir R. K. Sterling*, A. Kuo†, V. K. Rustgi‡, M. S. Sulkowski§, T. G. Stewart¶, J. M. Fenkel**, H. El-Genaidi††, M. A. Mah’moud‡‡, G. M. Abraham§§, P. W. Stewart¶, L. Akushevich¶, D. R. Nelson¶¶, M. W. Fried¶ & A. M. Di Bisceglie***

*Virginia Commonwealth University Health System, Richmond, VA, USA. † University of California San Diego, San Diego, CA, USA. ‡ Metropolitan Liver Diseases/ Gastroenterology Center, Fairfax, VA, USA. § John Hopkins University, Baltimore, MD, USA. ¶ University of North Carolina, Chapel Hill, NC, USA. **Thomas Jefferson University Hospital, Philadelphia, PA, USA. †† Our Lady of Lourdes Medical Center, Camden, NJ, USA. ‡‡ Duke University School of Medicine/Boice-Willis Clinic, Rocky Mount, NC, USA. §§ Saint Vincent Hospital, Worcester, MA, USA. ¶¶ Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, FL, USA. ***Saint Louis University, Saint Louis, MO, USA.

Correspondence to: Dr R. K. Sterling, Virginia Commonwealth University Health System, 1200 E Marshall Street, Richmond, VA 23298, USA. E-mail: [email protected]

Publication data Submitted 22 October 2014 First decision 25 November 2014 Resubmitted 7 January 2015 Accepted 10 January 2015 This article was accepted for publication after full peer-review.

ª 2015 John Wiley & Sons Ltd doi:10.1111/apt.13095

SUMMARY Background HCV-TARGET is a longitudinal observational study of chronic hepatitis C virus (HCV) patients treated with direct-acting anti-viral agents (DAAs) in a US consortium of 90 academic and community medical centres. Aim To assess utilisation of response-guided therapy (RGT) and sustained virological response (SVR) of a large cohort of patients. Methods Patients received peginterferon (PEG-IFN), ribavirin and either telaprevir or boceprevir. Demographical, clinical and virological data were collected during treatment and follow-up. RGT and treatment futility stopping rules was assessed at key time points. Results Of 2084 patients, 38% had cirrhosis and 56% had received prior treatment for HCV. SVR rates were 31% (95% CI: 24–40) and 50% (95% CI: 44–56) in boceprevir patients with and without cirrhosis, respectively. SVR rates were 46% (95% CI: 42–50) and 60% (95% CI: 57–64) in telaprevir patients with and without cirrhosis, respectively. Early clearance of virus, IL28B genotype, platelet counts and diabetes were identified as predictors of SVR among boceprevir patients, while early clearance of virus, IL28B, cirrhosis, HCV subtype, age, haemoglobin, bilirubin and albumin levels were identified as predictors of SVR for telaprevir patients. Conclusions In academic and community centres, triple therapy including boceprevir or telaprevir led to SVR rates somewhat lower than those noted in large phase 3 clinical trials. Response rates were consistently higher among patients without cirrhosis compared to those with cirrhosis regardless of DAA used and prior treatment response. Trial registration clinicaltrials.gov NCT01474811. Aliment Pharmacol Ther

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R. K. Sterling et al. INTRODUCTION It is estimated that between 2% and 3% of the global population is infected with hepatitis C virus (HCV), corresponding to approximately 130–170 million individuals.1–3 Chronic hepatitis C is one of the most common causes of liver disease in the USA and is responsible for approximately 12 000 deaths annually. Furthermore, it is expected that the morbidity and mortality associated with HCV infection will continue to increase over the next few decades.2, 4, 5 Until recently, the treatment of HCV included 48 weeks of peginterferon (PEG-IFN) combined with ribavirin (RBV) yielding sustained virological response (SVR) rates of 40–50% for those with genotype 1. In May 2011, the FDA approved two HCV NS3/4A serine protease inhibitors (PI), boceprevir and telaprevir for use in the USA, representing one of the most important advances in the management of chronic HCV genotype 1 in nearly a decade. The addition of a PI to PEG-IFN and RBV reportedly improved SVR rates to 60–75%.6–11 Importantly, these studies also allowed for development of response-guided therapy (RGT) algorithms and of new treatment futility stopping rules.12, 13 RGT, whereby treatment duration is shortened to 24 or 28 weeks in patients with rapid virological response, defined as undetectable HCV RNA by week 4 with telaprevir or week 8 with boceprevir-based regimen, respectively, is the standard of care for noncirrhotic patients. This allows one-half to two-thirds of treatment-na€ıve patients treated with these medications to require only 24–28 weeks of total treatment with the same success rate as a 48-week course.7, 8 HCV-TARGET, an observational study of patients with chronic HCV treated within the United States, provides the opportunity to better understand the impact of these drugs on a large cross-section of patients with hepatitis C in the USA. The evaluation of these regimens in a real world setting may provide data that could then be used as a comparator for next-generation therapies, including all oral therapies that are rapidly advancing clinical care. The aims of this study were to characterise the rates of the virological responses to the treatment regimens in terms of patient characteristics, and to observe practical application of RGT in order to assess adherence to treatment futility stopping rules in a large cohort of patients in both academic and community practices.

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METHODS Study population and design HCV-TARGET (HCVT, ClinicalTrials.gov number NCT01474811) is a longitudinal, observational study performed by a consortium of academic (n = 38) and community (n = 52) medical centres in the USA. From May 2011 to September 2012, patients treated with peginterferon and ribavirin in combination with boceprevir or telaprevir were enrolled. This study was designed to capture data for populations that were underrepresented by clinical trials; therefore inclusion criteria were very broad. All adult patients (18 years or older) being treated with anti-viral regimens that contained telaprevir or boceprevir at participating study sites were eligible to be included. Treatment was administered per local standards at the study site. The study protocol did not define specific treatment populations, regimens, dosing or safety management guidelines. Data was captured from enrolled patients using a central database and novel standardised source data abstraction methods. A centralised team of trained coders reviewed all de-identified medical records obtained from participating sites for data entry. Throughout treatment and during post-treatment follow-up, demographical, clinical, adverse event and virological data were collected. Independent data monitors systematically reviewed the data entries for completeness and accuracy. All database records were screened for extreme or unlikely values and verified/resolved with additional queries. Data from 301 patients from PEGBASE-USA, an observational study of Peginterferon [e.g. Pegasys]-Based Direct Acting Antiviral Triple Therapy in Patients With Chronic Hepatitis C Genotype 1 (NCT01508130), funded by Genentech (South San Francisco, CA, USA) were mapped to harmonise with the HCV-TARGET database and were included in the analyses reported here. Patients received peginterferon alfa-2a or peginterferon alfa-2b and ribavirin plus either telaprevir or boceprevir in accordance with local standard of care and US labelling and were followed up for the duration of their treatment and for up to 24 weeks post-treatment. Treating physicians were encouraged to follow RGT based on US labelling information. The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. A central IRB approved the protocol if a local IRB and independent ethics committee at each participating study centre was not in place. All

Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Virological outcomes with boceprevir or telaprevir patients provided written informed consent for their participation or an informed consent waiver was granted by the IRB overseeing the site.

Definitions ‘Treatment-na€ıve’ participants were those who had never received interferon-based treatment for HCV, whereas ‘treatment experienced’ patients had received treatment with an interferon-based regimen at any point prior to the current treatment with protease inhibitor-based treatment. Subcategories of treatment-experienced patients were defined by the investigators based upon their clinical evaluation and data available to them in routine practice. Thus, ‘null responders’ had received at least 12 weeks of PEG-IFN and RBV with HCV RNA decrease 2 log10 by week 12 of treatment but remained detectable; ‘prior relapsers’ were defined as patients who completed a prescribed course of PEG-IFN and RBV, becoming HCV RNA undetectable during therapy, but relapsed with detectable HCV RNA once treatment was discontinued; ‘unknown response’ was defined as patients who have previously completed a prescribed course of PEG-IFN and RBV but whose treatment response based on HCV RNA determinations was not available; and ‘prior intolerant’ as those patients who were treated with PEG-IFN and RBV but discontinued due to adverse event or patient choice prior to completion of therapy. Finally, ‘other treatment’ included those patients who were treated with a nonpeginterferon based regimen (such as interferon-alfa only, ribavirin plus interferon alfa-2b, interferon alfacon-1). If a patient had other treatment and a subsequent course of therapy with peginterferon and ribavirin, the patient was defined according to their PEG-IFN/RBV treatment experience. The criteria for the diagnosis of cirrhosis were either confirmation by liver biopsy or a combination of clinical, laboratory, histological and imaging features. Patients with the equivalent of stage 3 fibrosis (bridging fibrosis) by liver biopsy were defined as cirrhotic if they had any of the following: platelets count 100 IU/mL at week 12 who completed 48 weeks of treatment according to RGT. Most of the boceprevir patients with HCV RNA >100 IU/mL (n = 60) at week 12 discontinued treatment (median 109 days; range 91–284) in keeping with RGT recommendation. Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Virological outcomes with boceprevir or telaprevir (a) OR (95% Cl

Predictor Age

0.98 (0.96, 1.00)

Albumin: > 35 vs. < 35 g/L

2.14 (0.99, 4.60)

Cirrhosis status: yes vs. no

0.50 (0.32, 0.77)

Creatinine clearance (mL/min)

0.99 (0.98, 1.00)

Diabetes: yes vs. no

0.46 (0.27, 0.79)

Gender: female vs. male

1.05 (0.71, 1.55)

HCV genotype: 1a vs. 1b

0.82 (0.52, 1.30)

HCV RNA (In IU)

0.97 (0.89 1.06)

Hemoglobin

1.03 (0.89, 1.20)

IL28B genotype: CC vs. CT/TT

5.91 (3.05, 11.47)

Platelet: > 100 000 vs. < 100 000 n/µL

2.88 (1.55, 5.37)

Total bilirubin (In mg/dL)

0.78 (0.54, 1.13)

Trt experience: experienced vs. naïve

0.61 (0.41, 0.91) 0

1

2

4

6

(b) Predictor

OR (95% Cl

Age

0.98 (0.97, 1.00)

Albumin: > 35 vs. < 35 g/L

2.74 (1.92, 3.92)

Cirrhosis status: yes vs. no

0.57 (0.47, 0.71)

Creatinine clearance (mL/min)

1.00 (0.99, 1.00)

Diabetes: yes vs. no

0.77 (0.58, 1.03)

Gender: female vs. male

1.07 (0.88, 1.32)

HCV genotype: 1a vs. 1b

0.54 (0.42, 0.69)

HCV RNA (In IU)

0.96 (0.91, 1.02)

Hemoglobin

1.10 (1.01, 1.19)

IL28B genotype: CC vs. CT/TT

3.03 (1.99, 4.62)

Platelet: > 100 000 vs. < 100 000 n/µL

2.08 (1.60, 2.72)

Total bilirubin (In mg/dL)

0.66 (0.54, 0.80)

Trt experience: experienced vs. naïve

0.99 (0.80, 1.21) 0

1

2

4

Figure 4 | Age- and gender-adjusted odd ratio estimates and 95% CI for the association of various predictors and SVR to anti-viral therapy with boceprevir (a) or telaprevir (b) in chronic hepatitis C patients. Black dots indicate point estimate for OR.

Of the patients who started telaprevir (n = 1629), 1390 (85%) had HCV viral load assessed at week 4 (defined as treatment day 21–34) (Table S2). Those with HCV RNA ≤1000 IU/mL (n = 1323) continued RGT and 745/1323 achieved SVR (57%, 95% CI: 54–59). Of those with HCV RNA >1000 IU/mL (n = 67) at week 4, most discontinued treatment at a later visit (median Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

63 days; range 37–287) while only 10 completed a full course. Of those with HCV RNA >1000 IU/mL at week 4, SVR was achieved in 9/67 patients (14%, 95% CI: 6–24). Adherence to RGT in telaprevir patients was 97% (1333/1390). No difference in adherence to RGT was observed between academic and community sites (data not shown). 9

R. K. Sterling et al. Table 2b | Sustained virological response in telaprevir patients Patients with cirrhosis (n = 648) n/N (%, 95% CI) Overall SVR All patients 298/648 SVR by prior treatment response Treatment-na€ıve 103/237 Treatment-experienced 194/410 Prior relapse 98/148 Prior null response 22/87 Prior partial response 31/61 Prior breakthrough 8/13 Prior response unknown 25/72 Prior interferon intolerant 9/24 SVR by race White 261/549 Black 28/79 SVR by IL28B status CC 41/62 CT, TT 61/152 SVR according to presence of diabetes Diabetes 54/122 No diabetes 244/526 SVR by HCV genotype 1a 145/353 1b 72/134 SVR by HCV RNA level 45 Years Gender Female Male Race Black White HCV genotype 1a 1b IL28B genotype CC CT or TT

Figure 5 | Sustained virological responses and 95% CI in various subpopulations of chronic hepatitis C patients with genotype 1, treated with telaprevir and stratified by treatment-experienced (925 patients) vs. treatment na€ıve (701 patients).

Baseline HCV RNA < 800 000 (IU/mL) ≥ 800 000 (IU/mL) Cirrhotic NO YES

(65–75%),6–8 as observed in other reports in routine clinical practice.20 In treatment-experienced patients, SVR was highest in those with prior relapse (58% and 72% in boceprevir and telaprevir patients, respectively) and lowest in those with prior null response (29% and 31% in boceprevir and telaprevir patients, respectively). Seventy-five per cent of prior relapsers and 52% of prior nonresponders treated with a fixed triple therapy boceprevir regimen achieved SVR. Relapsers and prior partial responders in the response-guided treatment arm had SVR rates of 69% and 40%, respectively.10 The lower SVR rates observed in HCV-TARGET compared with those reported in clinical trials could be explained by the higher proportion of patients with cirrhosis and of African-American patients in our study, factors that have all been associated with lower SVR.21, 22 Adherence to RGT was high: 84% for boceprevir and 97% for telaprevir. The higher rate for telaprevir may be due to its simpler treatment algorithm. In Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

0

25

50

75

100

prior relapsers treated with telaprevir, similar SVR were observed in noncirrhotics patients treated for 24 weeks (80%) or longer (83%) whereas more cirrhotic patients achieved SVR when treated for >24 weeks (76%) as compared to those who received 24 weeks of treatment (44%). These data support the FDA recommendation to use RGT in prior relapsers to PEG-IFN and ribavirin undergoing retreatment with telaprevir,23 and the longer treatment course duration of prior cirrhotic relapsers with telaprevir. In addition to RGT, stopping rules have also been revised for PI-based therapy.12 In this study, stopping rules for anti-viral therapy were correctly followed in 30–33% of patients, who stopped treatment within 12 days of meeting futility rules. In those who continued treatment despite meeting futility rules, only 5% of boceprevir patients and 11% of telaprevir patients achieved SVR, supporting the recommendations that treatment be stopped in these individuals. As expected, those 11

R. K. Sterling et al. Percent SVR (Cirrhotic: solid; non-cirrhotic: dotted)

Subgroup All Age ≤ 45 Years > 45 Years Gender Female Male Race Black White HCV genotype 1a 1b IL28B genotype CC CT or TT Baseline HCV RNA < 800 000 (IU/mL) ≥ 800 000 (IU/mL) 0

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with BLOQ/undetectable HCV RNA at key time points had higher SVR rates compared to those who had HCV RNA BLOQ but detectable, reflecting the presence of ongoing viral replication.24, 25 As previously reported,26 rates of anaemia and treatment discontinuations in HCV-TARGET were far higher than reported for the pivotal registration trials, and similar to those observed in a large studies in European patients with compensated cirrhosis,27 highlighting the reduced tolerability of these regimen in patients with advanced disease. Findings from both studies identified baseline level of platelets and anaemia as important baseline factors to take into consideration during treatment decision.26, 27 There were several pragmatic features and limitations in our study. First, because all patients were treated as standard of care based on local practice, differences among patient populations or among sites, including academic and community sites may have affected our 12

75

100

Figure 6 | Sustained virological responses and 95% CI in various subpopulations of chronic hepatitis C patients with genotype 1, treated with telaprevir and stratified by cirrhosis (648 patients) vs. no cirrhosis (947 patients).

results. In addition, week 4 and week 12 samples were rarely re-tested, which could have led to higher accuracy of SVR prediction as described in-patients treated with telaprevir.28 We also did not systematically assess adherence, which has been shown to impact SVR in triple therapy.29 Nor did we capture the proportion of uninsured patients in this study. Access to care and HCV medications is an important component of care. A recent study in the DAA era of uninsured patients showed that despite access to care and medications, the utility of evaluation and initiation of treatment remained low suggesting that eliminating barriers to health care may not lead to an increase in treatment rates.30 HCV-TARGET represents the largest prospective cohort of HCV treated patients in the USA and allows an in-depth analysis of ‘real life’ experience of HCV patients treated with first generation DAAs. As HCV treatment evolves from first generation protease inhibitors to sofosbuvir, simeprevir and other emerging Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Virological outcomes with boceprevir or telaprevir interferon-free regimens, it is important to consider that patients treated in real-life are likely to be more diverse, have more advanced fibrosis and have more comorbidities than patients included in registration trials. SVR rates, as demonstrated in our study, could be lower than predicted. This difference in real-life SVR rates may have a large economic impact and studies like HCV-TARGET, that include academic and community practices administering local standard of care treatment, can provide valuable reference data for prescribers, regulatory agencies and the public on the effectiveness of HCV therapy for years to come. Ongoing data from HCV-TARGET will assess the efficacy of newer all oral HCV regimens and will be able to how to better manage a diverse patient population and how to improve access to therapy.

AUTHORSHIP Guarantor of the article: Richard K. Sterling. Author contributions: David R Nelson and Michael W. Fried obtained funding, designed and supervised the study, contributed to data collection, analysis and interpretation of the data and manuscript preparation. Richard K. Sterling, Alexander Kuo, Vinod K Rustgi, Mark S. Sulkowski, Jonathan M. Fenkel, Hisham El-Genaidi, Mitchell A. Mah’moud, George M. Abraham, Adrian M. Di Bisceglie contributed to the data collection, analysis and interpretation of the data and preparation of the manuscript. Thomas G. Stewart, Paul W. Stewart and Lucy Akushevich performed statistical analysis, contributed to analysis and interpretation of the data and to manuscript preparation. All authors approved the final draft of the manuscript, including the authors list. ACKNOWLEDGEMENTS We thank the staff of Data Coordinating Center at UNC Chapel Hill: Kenneth Bergquist, John Baron, Dianne Mattingly, Wendy Robertson and Tiffany Marsh; the staff of Clinical Coordinating Center at UF Gainesville: Monika Vainorius, Lauren Morelli, Anthe Hoffman, Dona-Marie Mintz, Lasheaka McClellan, Angela Bauer, Patrick Horne, Rennie Mills, Amy Gunnett, Troy Chasteen, April Newsom, Jacob Harmer, Amanda Slater, Chante Taylor, Greg Riherd and Karentan Robinson; the nurses and patients who were involved in this study; and Valerie Philippon, PhD for her assistance in the preparation of the manuscript, with funding from University of Florida. Writing support: Medical writing and editing was provided by Valerie Philippon, PhD, with funding from the University of Florida, Gainesville, FL. Aliment Pharmacol Ther ª 2015 John Wiley & Sons Ltd

Declaration of personal interests: Richard K. Sterling has received research grants from AbbVie, Gilead, BMS, Merck, Vertex, Bayer, Boehringer Ingelheim and Roche/Genentech and has received honoraria for consulting from AbbVie, Gilead, Vertex, Roche/Genentech, Merck, Bayer, Salix and Bristol-Myers Squibb. Alexander Kuo has received research grants from AbbVie, BMS, Gilead, Roche/Genentech, Merck and Vertex. Vinod K Rustgi has received grant/research support from Abbott Laboratories, Anadys Pharmaceuticals, Inc, Bristol-Myers Squibb, Gilead Sciences and Novartis Pharmaceuticals Corporation; is a consultant for and has received honoraria from Genentech, Inc, Gilead Sciences, Inc, and Merck; and is on the advisory boards of Merck, Novartis Pharmaceuticals Corporation and Tibotec. Mark S. Sulkowski has received funds for research support paid to Johns Hopkins University from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and Vertex and consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and Tobira. Thomas G. Stewart has nothing to disclose. Jonathan M. Fenkel has received honoraria for consulting from Bristol-Myers Squibb, Gilead, Idenix, Janssen and Vertex. Hisham El-Genaidi has nothing to disclose. Mitchell A. Mah’moud has received research grants from Roche/ Genentech, Merck and Janssen and also honoraria for speaking or consulting from AbbVie, Merck and Salix. George M. Abraham has received research grants from Gilead, Merck, Vertex and Roche/Genentech and has received honoraria for consulting from AbbVie, Gilead, Vertex, Roche/Genentech, Merck and Kadmon. Paul W. Stewart has nothing to disclose Lucy Akushevich has nothing to disclose. David R Nelson has received grant/research support from Abbott, Achillion, Boehringer-Ingelheim, Bristol-Myers Squibb, Janssen, Kadmon, Genentech, Gilead, Merck and Vertex. Michael W. Fried has received research grants from AbbVie, Bristol-Myers Squibb, Genentech, Gilead, Janssen, Merck and Vertex and has received honoraria for speaking or consulting from AbbVie, Bristol-Myers Squibb, Genentech, Gilead, GlaxoSmithKline, Janssen, Merck, Vertex. Adrian M. Di Bisceglie serves on the advisory boards of Bristol-Myers Squibb, Merck, Pharmasset, Roche/Genentech, Salix, Tibotec and Vertex, serves on the Data Safety Monitoring Board for Bayer, and has received grant and research support from Abbott, Anadys, Bristol-Myers Squibb, Gilead, GlobeImmune, Idenix, Pharmasset, Roche/Genentech, Transgene, Tibotec and Vertex. 13

R. K. Sterling et al. Declaration of funding interests: HCV-TARGET is an investigator-initiated study jointly sponsored by The University of Florida, Gainesville, FL (PI: Nelson) and The University of North Carolina at Chapel Hill, Chapel Hill, NC (PI: Fried). It was funded in part by Vertex Pharmaceuticals, Inc., Merck & Co., Kadmon Corporation and Genentech and in part by CTSA UF UL1TR000064 and UNC 1UL1TR001111. Dr Fried is funded in part by NIH Mid-Career Mentoring Award K24 DK066144.

SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Figure S1. SVR in prior relapsers treated with telaprevir by treatment duration and cirrhosis status. Table S1. Sustained virological response according to HCV RNA detection and prior response. Table S2. Response-guided therapy and sustained virological responses. Appendix S1. HCV-TARGET investigators.

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