Despite the availability of efficacious direct-acting antiviral (DAA) therapy, the number of people infected with hepatitis C virus (HCV) continues to rise, and HCV remains a leading cause of liver-related morbidity, liver transplantation, and mortality. We developed and validated machine learning (ML) algorithms to predict DAA treatment failure. Using the HCV-TARGET registry of adults who initiated all-oral DAA treatment, we developed elastic net (EN), random forest (RF), gradient boosting machine (GBM), and feedforward neural network (FNN) ML algorithms. Model performances were compared with multivariable logistic regression (MLR) by assessing C statistics and other prediction evaluation metrics. Among 6525 HCV-infected adults, 308 patients (4.7%) experienced DAA treatment failure. ML models performed similarly in predicting DAA treatment failure (C statistic [95% CI]: EN, 0.74 [0.69-0.79]; RF, 0.74 [0.69-0.80]; GBM, 0.72 [0.67-0.78]; FNN, 0.75 [0.70-0.80]), and all 4 outperformed MLR (C statistic [95% CI]: 0.51 [0.46-0.57]), and EN used the fewest predictors (n = 27). With Youden index, the EN had 58.4% sensitivity and 77.8% specificity, and nine patients were needed to evaluate to identify 1 DAA treatment failure. Over 60% treatment failure were classified in top three risk decile subgroups. EN-identified predictors included male sex, treatment < 8 weeks, treatment discontinuation due to adverse events, albumin level < 3.5 g/dL, total bilirubin level > 1.2 g/dL, advanced liver disease, and use of tobacco, alcohol, or vitamins. Addressing modifiable factors of DAA treatment failure may reduce the burden of retreatment. Machine learning algorithms have the potential to inform public health policies regarding curative treatment of HCV.

Background. Despite high efficacy rates for direct acting antiviral regimens to cure hepatitis C virus infection, many patients experience treatment-related symptoms. Accurate reporting of adverse events is mandatory to determine drug safety. Previous research in other medical conditions has documented discordance between clinician-reported and patient-reported symptomatic adverse events. Aims. To explore concordance and associated factors, between clinician-recorded and patient-reported fatigue, headache, and nausea/vomiting during a clinical trial of three treatment regimens. Methods. Data were collected between treatment start and 31 days posttreatment. Patients completed Patient-Reported Outcomes Measurement Information System measures of fatigue and nausea/vomiting and the Headache Impact Test. Clinician-recorded data were abstracted from medical records. Concordance was evaluated by weighted kappa. Demographic and clinical factors associated with concordance were identified using logistic regression models. Results. Participants included 1,058 patients treated for chronic hepatitis C (average 54.9 years; 43% Black; 59% male). Weighted kappa estimates and 95% confidence intervals between patients (no/mild vs. moderate/severe symptoms) and clinicians (not present vs. present) were fatigue ( k = 0.09 , 0.02-0.16), headache ( k = 0.08 , 0.02-0.14), and nausea/vomiting ( k = 0.20 , 0.11-0.28). Older age and having private insurance (compared to Medicaid) were associated with better headache concordance. Older age, male, absence of psychiatric condition, and ≤2 comorbidities were associated with better nausea/vomiting concordance. Conclusions. Poor concordance was observed between patient-reported and clinician-recorded symptomatic adverse events. Despite study limitations, previous literature in other conditions support these findings. Integrating patient-reported data to inform adverse event reporting would improve evaluations of treatment safety (http://CT.gov/ Registration: NCT02786537).

The PRIORITIZE trial (clinicaltrials.gov: NCT02786537) was the first comparative effectiveness study to directly compare ledipasvir/sofosbuvir (LDV/SOF) and elbasvir/grazoprevir (EBR/GZR) for the treatment of chronic hepatitis C virus (HCV). A secondary aim of this study was to compare LDV/SOF and EBR/GZR on sustainable changes in several HCV-associated symptoms and functional well-being in patients who achieved sustained virological response (SVR). PRIORITIZE, a randomized controlled trial conducted between 2016 and 2020, evaluated change in six PROMIS® symptom scores (fatigue, sleep disturbance, cognitive disturbance, nausea, diarrhoea, abdominal pain) and functional well-being using the disease-specific HCV-PRO instrument. Survey assessments were administered at baseline, early post-treatment (median = 6 months) and late post-treatment (median = 21 months). Constrained longitudinal linear mixed-effects models were used to evaluate within-treatment change and between-treatment differences. Data from 793 participants (average 55 years old, 57% male, 44% black, 17% with cirrhosis) were analysed. From baseline to early post-treatment, 5 out of 6 symptoms and functional well-being significantly improved (all p's < .05). In the LDV/SOF arm, mean changes ranged from -3.73 for nausea to -6.41 for fatigue and in the EBR/GZR, mean changes ranged from -2.19 for cognitive impairment to -4.67 for fatigue. Change of >3 points was consider clinically meaningful. Improvements in most symptoms slightly favoured LDV/SOF, although the magnitude of differences between the regimens were small. Both regimens demonstrated significant improvements in symptoms and functional well-being that were sustained during the late post-treatment phase. EBR/GZR and LDV/SOF regimens had clinically equivalent and durable improvements in HCV symptoms and functional well-being up to two years after SVR.

BACKGROUND AND AIMS:We aimed to develop and validate machine learning algorithms to predict direct-acting antiviral (DAA) treatment failure among patients with HCV infection.APPROACH AND RESULTS:We used HCV-TARGET registry data to identify HCV-infected adults receiving all-oral DAA treatment and having virologic outcome. Potential pretreatment predictors (n = 179) included sociodemographic, clinical characteristics, and virologic data. We applied multivariable logistic regression as well as elastic net, random forest, gradient boosting machine (GBM), and feedforward neural network machine learning algorithms to predict DAA treatment failure. Training (n = 4894) and validation (n = 1631) patient samples had similar sociodemographic and clinical characteristics (mean age, 57 years; 60% male; 66% White; 36% with cirrhosis). Of 6525 HCV-infected adults, 95.3% achieved sustained virologic response, whereas 4.7% experienced DAA treatment failure. In the validation sample, machine learning approaches performed similarly in predicting DAA treatment failure (C statistic [95% CI]: GBM, 0.69 [0.64-0.74]; random forest, 0.68 [0.63-0.73]; feedforward neural network, 0.66 [0.60-0.71]; elastic net, 0.64 [0.59-0.70]), and all four outperformed multivariable logistic regression (0.51 [0.46-0.57]). Using the Youden index to identify the balanced risk score threshold, GBM had 66.2% sensitivity and 65.1% specificity, and 12 individuals were needed to evaluate to identify 1 DAA treatment failure. Over 55% of patients with treatment failure were classified by the GBM in the top three risk decile subgroups (positive predictive value: 6%-14%). The top 10 GBM-identified predictors included albumin, liver enzymes (aspartate aminotransferase, alkaline phosphatase), total bilirubin levels, sex, HCV viral loads, sodium level, HCC, platelet levels, and tobacco use.CONCLUSIONS:Machine learning algorithms performed effectively for risk prediction and stratification of DAA treatment failure.

Background & Aims: Retreatment with glecaprevir/pibrentasvir (G/P) resulted in a rate of sustained virologic response 12 weeks after treatment completion (SVR12) of >90% in HCV genotype 1 (GT1) patients who previously failed a regimen of sofosbuvir plus an NS5A inhibitor (NS5Ai). This study investigated the prevalence and impact of baseline NS3 and NS5A resistance-associated substitutions (RASs) on the efficacy of G/P in prior GT1 sofosbuvir+NS5Ai failures and the persistence of treatment-emergent RASs. Methods: Longitudinal samples from 177 patients enrolled in a phase Mb, randomized pragmatic clinical trial were analyzed. Patients without cirrhosis were randomized to 12 or 16 weeks of G/P, and patients with compensated cirrhosis were randomized to G/P and ribavirin for 12 weeks or G/P for 16 weeks. Linkage of RAS was identified using Primer-ID next-generation sequencing at a 15% cut-off. Results: Of 177 patients, 169 (95.5%) were PI-naive. All 33 GT1b-infected patients achieved SVR12. In GT1a-infected patients, baseline NS5A RASs were prevalent (74.5%, 105/141) but NS3 RASs were uncommon. Baseline NS3 RASs had no impact on G/P efficacy and patients with baseline NS5A RASs showed a numerically but not statistically significantly lower SVR12 rate compared to those without NS5A RASs (89% vs. 97%). SVR12 was achieved in 34 of 35 (97%) patients without NS5A baseline substitution, and 53 of 57 (93%), 35 of 40 (88%), 5 of 8 (63%) with single, double-linked, and triple-linked NS5A substitutions, respectively. Among 13 patients with virologic failure, 4 acquired treatment-emergent NS3 RASs and 10 acquired NS5A RASs. Conclusion: Baseline NS5A RASs were highly prevalent. The presence of an increasing number of linked NS5A RASs in GT1a showed a trend in decreasing SVR12 rates, although no specific NS5A RASs or their linkage pattern were associated with lower SVR12 rates. Lay summary: Direct-acting antivirals have revolutionized the treatment of chronic hepatitis C infection, but treatment failure occurs in some patients. Retreatment of patients who previously failed a regimen consisting of sofosbuvir and an NS5A inhibitor with a regimen of glecaprevir and pibrentasvir (G/P) is >90% effective. Herein, we analyzed samples from these patients and showed that retreatment efficacy with G/P is lower in patients with double- or triple-linked NS5A resistance mutations than in patients with single or no NS5A resistance mutations. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

Background and Aims Multiple direct‐acting antiviral (DAA) regimens are available to treat HCV genotype 1 infection. However, comparative effectiveness from randomized controlled trials of DAA regimens is unavailable. Approach and Results We conducted a pragmatic randomized controlled trial (NCT02786537) to compare the effectiveness of DAAs for HCV genotype 1a or 1b on viral response, safety, tolerability, and medication nonadherence. Adults with compensated liver disease, HCV genotype 1, not pregnant or breastfeeding, and with health insurance likely to cover ledipasvir/sofosbuvir (LDV/SOF) were recruited from 34 US viral hepatitis clinics. Participants were randomized (± ribavirin) to LDV/SOF, elbasvir/grazoprevir (EBR/GZR), and paritaprevir/ritonavir/ombitasvir+dasabuvir (PrOD; treatment arm stopped early). Primary outcomes included sustained viral response at 12 weeks (SVR12), clinician‐recorded adverse events, patient‐reported symptoms, and medication nonadherence. Between June 2016 and March 2018, 1,609 participants were randomized. Among 1,128 participants who received ≥1 dose of EBR/GZR or LDV/SOF (± ribavirin), SVR12 was 95.2% (95% CI, 92.8%‐97.6%) and 97.4% (95% CI, 95.5%‐99.2%), respectively, with a difference estimate of 2.2% (−0.5% to 4.7%), falling within the “equivalence” interval (−5% to 5%). While most (56%) participants experienced adverse events, few were serious (4.2%) or severe (1.8%). In the absence of ribavirin, discontinuations due to adverse events were rare. Patient‐reported symptoms and medication nonadherence were similar. Study limitations were dropout due to insurance denial and loss to follow‐up after treatment, limiting the ability to measure SVR12. Conclusions This pragmatic trial demonstrated high SVR12 for participants treated with EBR/GZR and LDV/SOF with few adverse effects. Overall, the two regimens were equivalent in effectiveness. The results support current HCV guidelines that do not distinguish between ribavirin‐free EBR/GZR and LDV/SOF.

BACKGROUND & AIMS: Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS: We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. RESULTS: Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS: In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis.

Baseline resistance-associated substitutions (RASs) have variable impacts in clinical trials but their prevalence and impact in real-world patients remains unclear. We performed baseline resistance testing using a commercial assay (10% cutoff) for 486 patients treated with LDV/SOF or SMV/SOF, with or without ribavirin, in the multi-center, observational HCV-TARGET cohort. Linkage of RASs was evaluated in selected samples using a novel quantitative single variant sequencing assay. Our results showed that the prevalence of NS3, NS5A, NS5B RASs was 45%, 13%, and 8%, respectively, and 10% of patients harbored RASs in 2 or more drug classes. Baseline LDV RASs in GT1a, TE, and cirrhosis LDV/SOF subgroup was associated with 2–4% lower SVR12 rates. SMV RASs was associated with lower SVR12 rates in GT1a, treatment-experienced, cirrhotics SMV/SOF subgroup. Pooled analysis of all patients with baseline RASs revealed that SVR12 was 100% (19/19) in patients treated for longer than 98 days but was 87% (81/93) in patients treated for shorter than 98 days. These results demonstrate that RASs prevalence and their impact in real world practice are in general agreement with registration trials, and suggest that longer treatment duration may overcome the negative impact of baseline RASs on SVR12 rates in clinical practice.

The era of direct-acting antivirals (DAAs) has transformed the treatment landscape for chronic hepatitis C virus (HCV) infection. Primarily this is due to the approval of multiple DAAs that are highly efficacious with improved safety profiles that became available within a short time span.1Mishra P. Murray J. Birnkrant D. Direct-acting antiviral drug approvals for treatment of chronic hepatitis C virus infection: scientific and regulatory approaches to clinical trial designs.Hepatology. 2015; 62: 1298-1303Crossref PubMed Scopus (23) Google Scholar Regulatory agencies have a public health responsibility to ensure the safety and efficacy of approved drug products. Although the demonstrated safety and efficacy of the drugs in registrational trials is paramount, the continued safety and effectiveness of drugs and treatment outcomes in diverse clinical care settings after a drug’s approval are of great importance. This paper describes an innovative collaborative platform using real-world clinical practice settings to gather safety and effectiveness data for DAAs approved for the treatment of chronic HCV infection. The US Food and Drug Administration (FDA) strives to balance the timely access of novel therapies to patients in need with gathering additional data in subgroups in the postmarketing phase. A current approach is to request drug sponsors to conduct postmarketing phase IV studies or clinical trials to expand our knowledge and understanding of novel therapies. However, sometimes results from these postmarketing studies and trials may be outdated by the time final results become available owing to rapid advancements in the scientific field. This was particularly observed with first-generation HCV DAAs, boceprevir and telaprevir, which received regulatory approval in 2011. By the time some of the postmarketing trials for these drugs were completed, the results were outdated because the HCV treatment landscape rapidly moved into the interferon-free era.2Florian J. Mishra P. Arya V. et al.Direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection: interferon free is now.Clin Pharmacol Ther. 2015; 98: 394-402Crossref PubMed Scopus (15) Google Scholar In such a rapidly evolving treatment landscape, innovative solutions are required to obtain “real-world data” at the earliest time points feasible. An alternative approach can involve use of a systematic observational cohort evaluating new drugs or therapies that leverage real-world evidence. This approach could help the FDA to strike a balance between premarket evaluation and postmarket data collection to facilitate identification of emerging safety signals in the postmarketing setting. Using real-world evidence to enhance the safety and effectiveness of new drugs can be achieved through robust public–private partnerships. This approach has been used by the FDA's Center for Drug Evaluation and Research, Division of Antiviral Products in partnership with Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET).3HCV-TARGET. Hepatitis C Therapeutic Registry and Research Network. Available at: http://hcvtarget.org/index.php/2013/08/29/fda-news-release-aug-29-2013/. Accessed December 8, 2016.Google Scholar There are specific disease characteristics of chronic hepatitis C and its treatment that make it amenable to using real-world evidence for further informing safety and effectiveness. First, chronic hepatitis C is a disease that progresses over a long period of time and, if left untreated, chronic HCV infection is rarely associated with spontaneous cure.4Di Biscegelie A.M. Natural history of hepatitis C: its impact on clinical management.Hepatology. 2000; 31: 1014-1018Crossref PubMed Scopus (231) Google Scholar As such, there is a negligible placebo effect and clearance of the virus is attributed to the treatment intervention. Second, the clinical assessment of virologic cure, sustained virologic response (SVR), is an objective and reliable endpoint of treatment efficacy that correlates with improvement in clinical outcomes and is routinely assessed by practicing physicians.5US Food and Drug Administration (FDA). Guidance for industry chronic hepatitis C virus infection: developing direct-acting antiviral drugs for treatment (draft May 2016). Available at: www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm225333.pdf. Accessed March 8, 2017.Google Scholar Finally, chronic hepatitis C treatment durations are relatively short and highly effective interventions, limiting the extent of missing data from real-world observational studies. HCV-TARGET is a cooperative academic consortium that is partially supported through a National Institutes of Health Clinical and Translational Science Award, augmented with substantial support from pharmaceutical sponsors. The organization, headed by a Steering Committee of hepatology experts including a Clinical Coordinating Center based at the University of Florida and a Data Coordinating Center based at the University of North Carolina, has forged key partnerships between academic centers, community sites, and private industry (Figure 1). The Steering Committee provides oversight and guidance to HCV-TARGET. The HCV-TARGET Industry Advisory Council, composed of 1 representative from each industry sponsor, serves in a nonvoting advisory capacity to the Steering Committee and provides input on the use of network data and new initiatives consistent with the goals of HCV-TARGET. The FDA Advisory Council advises the HCV-TARGET Network as part of their ongoing charge to protect and improve public health by ensuring the safety, and efficacy of drugs, biological products, and medical devices related to HCV. The Community Advocate Representatives provide input on the needs and ideas of the HCV community in framing new initiatives and long-term goals for HCV-TARGET. A formal memorandum of understanding formed the basis for development of scientific collaborations, outreach, and educational initiatives, and intellectual partnerships between FDA and HCV-TARGET. Last, the Publications Committee oversees the activities of the scientific publications and presentations of HCV-TARGET. This committee assures the appropriate public dissemination of HCV-TARGET Network data, the completion of manuscripts, and adherence to principles of authorship and conflicts. HCV-TARGET established a common research database to be able to conduct a longitudinal observational study to evaluate use of approved DAAs for the treatment of hepatitis C in clinical practice to (1) rapidly inform strategies for better management of populations represented and underrepresented in clinical trials, (2) identify and remediate gaps relative to treatment guidelines, (3) describe adverse event management to optimize treatment, and (4) serve as the core resource for collaborative translational studies using biospecimens and clinical data from diverse patient populations. Through this collaboration, the FDA has access to the HCV-TARGET resources to further inform use of newly approved HCV drugs in an actual clinical practice setting. The collaboration provides a robust platform for FDA scientists to learn from study data to inform areas for improvement in clinical trial design. The HCV-TARGET model allows rapid data acquisition across multiple regimens being used in a disease population receiving care in routine clinical practice. Thus, the study design is disease focused, and not drug specific. This allows for continuous acquisition of data as new drugs enter the market. HCV-TARGET uses innovative approaches related to bioinformatics, epidemiology, biostatistics, and health care data systems integration. Patients at participating sites are consented prospectively for participation. HCV-TARGET uses a centralized data abstraction process that minimizes burden on research sites and reduces data variability owing to difference in interpretation of medical records. The site redacts protected health information from the entire electronic medical record and transmits it electronically to the Clinical Coordinating Center where the data are entered in a standardized format into the HCV-TARGET research electronic data capture database. The database was established to be compliant with Title 21of the Code of Federal Regulations Part 11 governing electronic records and adherent to Clinical Data Interchange Standards Consortium standards that facilitate data exchange to both sponsors and the FDA. HCV-TARGET’s comprehensive, observational cohort uses meticulous data collection methods that have <2% missing data elements and <5% loss to follow-up. Since inception in 2011, HCV-TARGET has enrolled >10,000 patients treated with HCV DAA-based regimens approved by the FDA (Table 1). The HCV-TARGET protocol allows for enrollment of populations that may have been underrepresented in premarket clinical trials; this data may be useful in understanding the safety and/or effectiveness in these subpopulations. Thus, patients from underrepresented minorities, those with cirrhosis, decompensated cirrhosis, and those undergoing liver transplant, for example, have been oversampled compared with the general population of patients treated for hepatitis C and those enrolled in clinical trials (Table 1).Table 1Selected Demographics and Baseline Characteristics of Enrolled Patient PopulationTARGET 1.0TARGET 2.0TARGET 3.0TimeframeDecember 2011–November 2013November 2013–December 2014December 2014–presentEnrollment (n)277424535226RegimensBoceprevir/pegylated interferon/ribavirinTelaprevir/pegylated interferon/ribavirinSofosbuvir/ribavirinSofosbuvir/pegylated interferon/ribavirinSimeprevir/pegylated interferon/ribavirinSimeprevir/sofosbuvir with or without ribavirinLedipasvir/sofosbuvir ± ribavirinDaclatasvir/sofosbuvir ± ribavirinParitaprevir/ritonavir/ombitasvir/dasabuvir ± ribavirinGrazoprevir/elbasvirSofosbuvir/velpatasvirDemographics (%) Age > 65 y7.319.322.8 Race (black)16.211.323.9 HCV genotype 197.070.089.6 Treatment naïve40.948.457.5 Treatment experienced59.151.642.4 Presence of cirrhosis39.150.335.3 Hepatic decompensation7.824.115.7 Liver transplantation1.811.48.9HCV, hepatitis C virus; TARGET, Hepatitis C Therapeutic Registry and Research Network. Open table in a new tab HCV, hepatitis C virus; TARGET, Hepatitis C Therapeutic Registry and Research Network. HCV-TARGET analyzed the experiences of >2000 patients who were among the first patients in the United States to receive triple therapy with telaprevir or boceprevir in combination with pegylated interferon (PEG-IFN) and ribavirin.6Sterling R.K. Kuo A. Rustgi V.K. et al.Virological outcomes and treatment algorithms utilisation in observational study of patients with chronic hepatitis C treated with boceprevir or telaprevir.Aliment Pharmacol Ther. 2015; 41: 671-685Crossref PubMed Scopus (23) Google Scholar, 7Gordon S.C. Muir A.J. Lim J.K. et al.Safety profile of boceprevir and telaprevir in chronic hepatitis C: real world experience from HCV-TARGET.J Hepatol. 2015; 62: 286-293Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar The results demonstrated that patients treated in clinical practice with these agents had high rates of advanced disease (38% cirrhosis), had lower SVR rates, and were more likely to sustain significant adverse events than participants in the registrational trials. Rates of anemia and treatment discontinuations in the HCV-TARGET analysis were higher than reported for the pivotal registrational trials, although the HCV-TARGET population had more advanced liver disease.8Poordad F. McCone Jr., J. Bacon B.R. et al.Boceprevir for untreated chronic HCV genotype 1 infection.N Engl J Med. 2011; 364: 1195-1206Crossref PubMed Scopus (2254) Google Scholar, 9Jacobson I.M. McHutchison J.G. Dusheiko G. et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416Crossref PubMed Scopus (2174) Google Scholar, 10Bacon B.R. Gordon S.C. Lawitz E. et al.Boceprevir for previously treated chronic HCV genotype 1 infection.N Engl J Med. 2011; 364: 1207-1217Crossref PubMed Scopus (1513) Google Scholar, 11Zeuzem S. Andreone P. Pol S. et al.Telaprevir for retreatment of HCV infection.N Engl J Med. 2011; 364: 2417-2428Crossref PubMed Scopus (1439) Google Scholar The lower SVR rates in HCV-TARGET could be explained by the higher proportion of patients with cirrhosis and of African American patients, factors that have all been associated with lower SVR.12Ghany M.G. Nelson D.R. Strader D.B. et al.An Update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice Guideline by the American Association for the Study of Liver Diseases.Hepatology. 2011; 54: 1433-1444Crossref PubMed Scopus (979) Google Scholar The usefulness of the HCV-TARGET model was apparent in 2013 when 2 new “triple therapy” regimens became available: simeprevir in combination with PEG-IFN and ribavirin, and sofosbuvir in combination with PEG-IFN and ribavirin. Given that PEG-IFN, the backbone of HCV treatment for more than a decade, had numerous side effects and contraindications for use in many patients, physicians were seeking all-oral, well-tolerated, and highly effective alternatives. A small phase II study that combined simeprevir plus sofosbuvir, without PEG-IFN, demonstrated remarkably high SVR rates with only 12 to 24 weeks of therapy in difficult-to-cure populations.13Lawitz E. Sulkowski M.S. Ghalib R. et al.Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study.Lancet. 2014; 384: 1756-1765Abstract Full Text Full Text PDF PubMed Scopus (678) Google Scholar Shortly thereafter, the “off-label” all-oral regimen of simeprevir plus sofosbuvir became one of the most frequently prescribed regimens for patients in the United States. The HCV-TARGET network accrued data on safety and effectiveness of this unapproved regimen in nearly 1000 patients in routine clinical practice.14Sulkowski M.S. Vargas H.E. Di Bisceglie A.M. et al.Effectiveness of simeprevir plus sofosbuvir, with or without ribavirin, in real-world patients with HCV genotype 1 infection.Gastroenterology. 2016; 150: 419-429Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar The FDA also became aware of the extent of “off-label” use of the simeprevir and sofosbuvir combination regimen and reviewed the FDA’s Adverse Event Reporting System database to identify any safety signals for this off-label combination use. However, a major limitation of the Adverse Event Reporting System is a reliance on passive reporting of adverse events by health care professionals or consumers, which unfortunately may include incomplete information on relevant patient characteristics, baseline disease information, comorbid conditions, or concomitant medications.15US Food and Drug Administration (FDA). Adverse Event Reporting System (FAERS). 2016. Available at: www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm. Accessed December 8, 2016.Google Scholar Selective reporting also makes it difficult to assess the incidence of unexpected adverse events when medications are used in a broader population outside of clinical trials. Coinciding with this “off-label” use of the simeprevir and sofosbuvir combination regimen, an efficacy supplement was submitted to the FDA in 2014 to support the use of these 2 drugs together based on the previously mentioned phase II results.16US Food and Drug Administration (FDA). Supplemental New Drug Application Approval letter. Available at: www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/205123Orig1s002ltr.pdf. Accessed March 23, 2017.Google Scholar The sponsor approached the HCV-TARGET group to obtain the overall safety and effectiveness data evaluated in the HCV-TARGET database and submitted the summary data to the FDA to provide supportive evidence and reassurance in terms of safety of the combination regimen. Based on a comprehensive review of the available data, the simeprevir indication was expanded to include its use in combination with sofosbuvir providing an all-oral treatment option for patients. Final results from 2 phase III confirmatory trials, specifically submitted to fulfill the postmarketing commitments, are comparable with the results generated from HCV-TARGET in a real-world setting.17Kwo P. Gitlin N. Nahass R. et al.Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study.Hepatology. 2016; 64: 370-380Crossref PubMed Scopus (153) Google Scholar, 18Lawitz E. Matusow G. DeJesus E. et al.Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: a phase 3 study (OPTIMIST-2).Hepatology. 2016; 64: 360-369Crossref PubMed Scopus (152) Google Scholar The HCV-TARGET consortium continued to accrue data as other approved therapeutic regimens entered clinical practice. A phase III study of sofosbuvir plus ledipasvir suggested that patients with favorable treatment characteristics at baseline when treated for an 8-week duration had similar SVR rates compared with those treated for 12 weeks.19Kowdley K.V. Gordon S.C. Reddy K.R. et al.Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.N Engl J Med. 2014; 370: 1879-1888Crossref PubMed Scopus (988) Google Scholar FDA labeling of the sofosbuvir plus ledipasvir regimen states that treatment for 8 weeks could be considered for patients who were genotype 1 without cirrhosis, treatment naïve, with pretreatment HCV RNA viral load of <6 million IU/mL. As a cost savings measure, payers frequently mandated the shortened duration regimen, which raised concerns for practitioners, particularly when patients had advanced fibrosis or levels of viremia at the upper boundary of 6 million IU/mL. HCV-TARGET performed a detailed analysis of patients who met the labeled criteria for shortened duration therapy and who subsequently received only 8 weeks treatment compared with similar patients who received 12 weeks of therapy.20Terrault N.A. Zeuzem S. Di Bisceglie A.M. et al.Effectiveness of ledipasvir-sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response.Gastroenterology. 2016; 151: 1131-1140Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar The SVR12 rate was 96% (95% CI, 94-99) in the group that received 8 weeks (244/255) and 98% (95% CI, 95-99) in the group that received 12 weeks (289/296). These results suggest that the shortened duration of treatment in usual clinical practice paralleled the results obtained in phase III clinical trials. Often, the safety and efficacy data to inform treatment decisions in specific subpopulations such as transplant recipients or those with advanced liver disease such as decompensated liver disease becomes available at some point after approval. The HCV-TARGET network was instrumental in systematically collecting these data as clinicians were using these regimens after approval in subpopulations with unmet needs (Table 1).21Brown Jr., R.S. O’Leary J.G. Reddy K.R. et al.Interferon-free therapy for genotype 1 hepatitis C in liver transplant recipients: real-world experience from the hepatitis C therapeutic registry and research network.Liver Transpl. 2016; : 2224-2233Google Scholar, 22Feld J.J. Maan R. Zeuzem S. et al.Effectiveness and safety of sofosbuvir-based regimens for chronic HCV genotype 3 infection: results of the HCV-TARGET Study.Clin Infect Dis. 2016; 63: 776-783Crossref PubMed Scopus (35) Google Scholar, 23Reddy K.R. Lim J.K. Kuo A. et al.All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.Aliment Pharmacol Ther. 2017; 45: 115-126Crossref PubMed Scopus (48) Google Scholar, 24Saxena V. Khungar V. Verna E.C. et al.Safety and efficacy of current DAA regimens in kidney and liver transplant recipients with hepatitis C: results from the HCV-TARGET Study.Hepatology. 2017 May 15; ([Epub ahead of print])Crossref Scopus (125) Google Scholar From the data on early DAA regimens assessed in HCV-TARGET database, treatment for genotype 3 patients with decompensated cirrhosis was identified as an unmet need.22Feld J.J. Maan R. Zeuzem S. et al.Effectiveness and safety of sofosbuvir-based regimens for chronic HCV genotype 3 infection: results of the HCV-TARGET Study.Clin Infect Dis. 2016; 63: 776-783Crossref PubMed Scopus (35) Google Scholar The FDA is committed to ensuring safety throughout the life cycle of a drug from premarket testing and clinical development through postmarketing surveillance and risk management.25US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drug safety priorities 2016: initiatives and innovation. Available at: www.fda.gov/Drugs/DrugSafety/ucm522941.htm. Accessed June 5, 2017.Google Scholar The FDA may identify a new safety signal or identify more serious or more frequent reports of a known safety risk from various sources during the postmarketing period once a drug is used in a real-world setting. The HCV-TARGET platform characterizes and tabulates all adverse events abstracted from redacted medical records provided by clinicians throughout treatment and posttreatment follow-up. Serious adverse events are monitored and queried to generate a complete understanding of the event and the results are reported to sponsors and the FDA. Both regulatory authorities and sponsors have access to HCV-TARGET resources that have been used to evaluate reports of unexpected adverse events for a variety of situations, including (1) the interactions of sofosbuvir and amiodarone causing bradyarrhythmia, (2) the safety of specific regimens in patients with decompensated cirrhosis, (3) the prevalence of baseline resistant-associated variants in usual clinical practice, and (4) the incidence of hepatocellular carcinoma recurrence after SVR with a DAA regimen. Thus, HCV-TARGET uses an evidence-based approach to evaluate the postmarketing experience of these drugs. These data are reviewed as part of the comprehensive assessment of the identified safety risk. In general, the interpretation of postmarketing safety data involves a benefit–risk assessment based on the review of data from multiple sources such as spontaneous adverse event reports, observational studies, clinical trials, published literature, and estimates of drug usage and background rates of the adverse event. The relevant data are interpreted in the context of the known safety and efficacy profiles, as demonstrated in clinical trials supporting approval. The totality of the existing information is taken into consideration when assessing the public health risks of an approved drug. Based on appropriate scientific data, the FDA may require certain postmarketing studies and clinical trials to further assess a known serious risk, and/or to assess signals of serious risk, and/or to identify an unexpected serious risk when available data indicate the potential for a serious risk.26US Food and Drug Administration (FDA). Guidance for industry postmarketing studies and clinical trials — implementation of section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act. April 2011). Available at: www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM172001.pdf. Accessed June 2, 2017.Google Scholar Nontraditional sources of information, such as that generated by HCV-TARGET, have demonstrated usefulness as an important component in informing the postmarketing safety of new HCV treatments. There are several limitations to HCV-TARGET database. First, there is no control group of untreated hepatitis C patients. Without an unexposed control group, the causality assessment of adverse outcomes cannot always be ascertained; uncertainty may remain as to whether the observed adverse reactions are due to the treatment regimen, progression of underlying disease, other comorbid conditions and/or effects secondary to concomitant medications. Second is the issue of selection bias; it cannot be determined how the proportion of patients who enrolled (received treatment) is different from nonenrollees who did not receive treatment. In addition, the demographics of the enrolled population may change over time based on criteria used by third-party payers for coverage of available treatment options. Comparative effectiveness trials are important and informative to compare the safety profile and the efficacy of various approved regimens. Although the approved DAA regimens have demonstrated robust efficacy and reasonable safety across a range of genotypes, most of the regimens have been approved using placebo-controlled, historic-controlled, or dose- and duration-controlled trials with limited direct comparison against other approved regimens. This information gap is important for practitioners who may be interested in a direct comparison between these approved regimens to best inform the ideal regimen based on a patient demographics and viral genotype and subtype. When comparative trials are not feasible to conduct before approval, effectiveness data can be collected postmarketing as demonstrated in HCV-TARGET database. This use of systematically collected observational cohort data to demonstrate clinical effectiveness holds promise. Real-world effectiveness data could provide supportive evidence if included as a component of an overall benefit–risk assessment with other studies and can contribute to the totality of data available for regulatory decision making. Longitudinal follow-up cohort studies provide a means to assess long-term outcomes in the setting of SVR and obtain much needed safety data once a drug is used more widely and under more diverse conditions in a real-world setting. The data generated will help to provide important safety and effectiveness information on how the drugs performed in the more diverse populations in which they are intended for use. In addition, the results may further guide providers and patients to assure safe and effective use of drugs. This public–private partnership provides a neutral platform for academia, pharmaceutical companies, and regulatory agencies to collaborate and work effectively to reach mutual goals of responding to public health needs in a timely manner. The authors acknowledge Dr Jeffrey Murray for helpful comments and suggestions.

The therapeutic landscape for the treatment of chronic hepatitis C virus infection has been rapidly evolving, and by 2016 there will be six approved, all-oral regimens for use in patients in the USA and most of Western Europe. However, as many as patient populations will have limited access to new direct acting antiviral regimens, patients and physicians are often faced with the challenge of selecting the best regimen available, as opposed to the optimal treatment. In this paper, the challenges and opportunities in developing a high cure regimen for different patient populations will be discussed and highlighted through case-based scenarios.

The therapeutic landscape for the treatment of chronic hepatitis C virus infection has been rapidly evolving, and by 2016 there will be six approved, all-oral regimens for use in patients in the USA and most of Western Europe. However, as many as patient populations will have limited access to new direct acting antiviral regimens, patients and physicians are often faced with the challenge of selecting the best regimen available, as opposed to the optimal treatment. In this paper, the challenges and opportunities in developing a high cure regimen for different patient populations will be discussed and highlighted through case-based scenarios.

Over the past year, interferon ( IFN ) free dosing regimens have become available to treat chronic hepatitis C. Offering high rates of sustained virological response ( SVR ), short treatment and improved tolerability, IFN ‐free treatment now represents the paradigm for both treatment‐naïve and ‐experienced patients. Patients with prior treatment failure, in particular those with cirrhosis, still represent some of the most difficult to treat, but the availability of multiple agents that can interrupt several steps of the HCV lifecycle affords providers and patients with options that can be combined and individually tailored to each patient's unique needs to obtain high rates of SVR .

Background & Aims : Sofosbuvir is a potent hepatitis C NS5B polymerase inhibitor that has led to high-sustained viral response rates when combined with other direct-acting antivirals. To date, no data exists on the combination of sofosbuvir with the NS3 protease inhibitor, telaprevir. The safety, tolerability, and efficacy of an all-oral 12-week regimen of telaprevir in combination with sofosbuvir were evaluated in this open-label, phase 2 study. Methods: Twenty adults with genotype 1 hepatitis C infection who were non-cirrhotic and naive to therapy received telaprevir 1125 mg orally twice-daily plus sofosbuvir 400 mg once daily for 12 weeks. Results : Telaprevir plus sofosbuvir was generally well tolerated, with all 20 subjects completing treatment. The five most common adverse events were nausea, rash, headache, ano-rectal symptoms, and pruritus. Two subjects required discontinuation of telaprevir after week 4 but were maintained on sofosbuvir till the end of treatment. Sustained virologic response 12 weeks after the end of treatment was 95%. Conclusion : The results provide valuable information regarding the safety, tolerability and efficacy of telaprevir combined with sofosbuvir as dual therapy in naive non-cirrhotic genotype 1 patients.