Friday, October 21, 2016
Future role of gastroenterologists in HCV therapy
LAS VEGAS — In this exclusive video from ACG 2016, Tram T. Tran, MD, FACG, medical director of liver transplantation, Liver Disease and Transplant Center, Cedars-Sinai, Los Angeles, discusses the role of gastroenterologists in future hepatitis C virus treatment, and how they will play a role in assisting primary care physicians in treatment
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ACG American College of Gastroenterology
October 14, 2016 - October 19, 2016
Meeting Coverage
Healio brings you the highlights from the American College of Gastroenterology Annual Scientific Meeting. Refer back to this page often for the latest news from ACG, perspectives and interviews with leading researchers and clinicians, and to review archives of past meetings.
Thursday, October 20, 2016
Gilead Announces SVR12 Rates SOF/VEL/VOX(GS-9857) Treatment-Naïve/Treatment-Experienced HCV Geno 1-6
Update Of Interest - Nov 4
Reported by Jules Levin
IDWeek Oct 26-30
New Orleans 2016 Nov 4
Sofosbuvir/Velpatasvir Plus Voxilaprevir for 6, 8, or 12 Weeks in Genotype 1-6 HCV-infected Patients: An Integrated Analysis of Safety and Efficacy from Two Phase 2 Studies
IDWeek Oct 26-30
New Orleans 2016 Nov 4
Sofosbuvir/Velpatasvir Plus Voxilaprevir for 6, 8, or 12 Weeks in Genotype 1-6 HCV-infected Patients: An Integrated Analysis of Safety and Efficacy from Two Phase 2 Studies
Press Release
Oct 20
Gilead Announces SVR12 Rates From Four Phase 3 Studies of a Once-Daily, Fixed-Dose Combination of Sofosbuvir, Velpatasvir and Voxilaprevir in Treatment-Naïve and Treatment-Experienced Genotype 1-6 Chronic HCV-Infected Patients
Date(s): 20-Oct-2016 10:07 AM
- If Approved, SOF/VEL/VOX Would Be the First Once-Daily Single Tablet Regimen Available for Salvage for Patients Who Have Failed Prior HCV Therapy with Oral Direct-Acting Antiviral Agent Regimens -
- U.S. NDA Planned for Q4 2016 -
FOSTER CITY, Calif.--(BUSINESS WIRE)--Oct. 20, 2016-- Gilead Sciences, Inc. (NASDAQ: GILD) today announced topline results from four international Phase 3 clinical studies (POLARIS-1, POLARIS-2, POLARIS-3 and POLARIS-4) evaluating an investigational, once-daily, fixed-dose combination of sofosbuvir (SOF), a nucleotide analog NS5B polymerase inhibitor; velpatasvir (VEL), a pangenotypic NS5A inhibitor; and voxilaprevir (VOX; GS-9857), an investigational pangenotypic NS3/4A protease inhibitor, for the treatment of genotype 1-6 chronic hepatitis C virus (HCV) infection.
In the POLARIS-1 and POLARIS-4 studies, 445 patients with genotype 1-6 HCV infection who were previously treated with direct-acting antiviral agents (DAAs) received 12 weeks of SOF/VEL/VOX. The POLARIS-1 study enrolled patients who failed prior treatment with an NS5A inhibitor. The POLARIS-4 study enrolled patients who failed prior treatment with a DAA that was not an NS5A inhibitor, most with either an NS5B inhibitor alone (73 percent) or an NS5B inhibitor and an NS3/4A protease inhibitor (25 percent).
In the POLARIS-2 and POLARIS-3 studies, 611 patients who were not previously treated with a DAA received 8 weeks of SOF/VEL/VOX. The POLARIS-2 study enrolled patients with genotype 1-6 HCV infection with or without compensated cirrhosis. The POLARIS-3 study enrolled patients with genotype 3 HCV infection, all of whom had compensated cirrhosis.
The primary endpoint for all studies was SVR12. The intent-to-treat SVR12 rates observed in the POLARIS studies are summarized in the following table. Complete results from all four studies will be presented at The Liver Meeting® 2016 in Boston.
| Study | Population | Genotype | Treatment | Duration | SVR12 Rates | |||||
| POLARIS-1 | NS5A inhibitor-experienced
41 percent (172/415) had cirrhosis
| 1, 2, 3, 4, 5, 6 | SOF/VEL/VOX | 12 Weeks | 96%
(253/263)
| |||||
| Placebo | 12 Weeks | 0%
(0/152)
| ||||||||
| POLARIS-4 |
DAA-experienced (No NS5A inhibitor)
46 percent (153/333) had cirrhosis
| 1, 2, 3, 4 | SOF/VEL/VOX | 12 Weeks | 97%
(177/182)
| |||||
| SOF/VEL | 12 Weeks | 90%
(136/151)
| ||||||||
| POLARIS-2 | DAA-naïve
18 percent (174/941) had cirrhosis
| 1, 2, 3, 4, 5, 6 | SOF/VEL/VOX | 8 Weeks | 95%
(476/501)
| |||||
| SOF/VEL | 12 Weeks | 98%
(432/440)
| ||||||||
| POLARIS-3 | DAA-naïve
All had cirrhosis
| 3 | SOF/VEL/VOX | 8 Weeks | 96%
(106/110)
| |||||
| SOF/VEL | 12 Weeks | 96%
(105/109)
|
"Despite recent advances that have provided high cure rates and simplified treatment for most HCV patients, those who have failed previous treatment with direct acting antivirals continue to represent an unmet medical need. The POLARIS study results demonstrate that combining three potent antivirals with different mechanisms of action and high barriers to resistance can provide high cure rates for patients who have failed other highly effective oral DAA regimens," said Norbert Bischofberger, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer at Gilead. "Based on these Phase 3 results, we plan to submit regulatory applications for SOF/VEL/VOX for the treatment of chronic HCV in the United States in the fourth quarter of 2016 and shortly thereafter in Europe."
About the POLARIS Studies
The POLARIS-1 study was a double-blind, placebo-controlled study in 415 genotype 1-6 NS5A inhibitor-experienced patients. The most common prior NS5A inhibitors were ledipasvir (55 percent) and daclatasvir (23 percent).
The open-label POLARIS-4 study evaluated the use of SOF/VEL/VOX or SOF/VEL for 12 weeks in 333 genotype 1-4 HCV-infected patients with prior DAA experience that did not include an NS5A inhibitor. Most patients (85 percent) had prior DAA experience with sofosbuvir.
The open-label POLARIS-2 study evaluated the use of SOF/VEL/VOX for eight weeks or SOF/VEL for 12 weeks in 941 genotype 1-6 DAA-naïve HCV-infected patients, including 18 percent with cirrhosis and 23 percent who had previously failed treatment with an interferon-based regimen.
The open-label POLARIS-3 study randomized patients with genotype 3 HCV infection and cirrhosis to receive SOF/VEL/VOX daily for eight weeks or SOF/VEL for 12 weeks. Of the 219 patients treated, 31 percent had previously failed treatment with an interferon-based regimen.
The POLARIS-1, POLARIS-3 and POLARIS-4 studies met their respective pre-specified primary endpoints for the patients receiving SOF/VEL/VOX. The POLARIS-2 study did not meet its primary endpoint; with a pre-specified 5 percent margin, the SVR12 rate for patients receiving treatment with SOF/VEL/VOX for eight weeks was not statistically non-inferior to the SVR12 rate for patients receiving SOF/VEL for 12 weeks.
About SOF/VEL/VOX
The SOF/VEL/VOX fixed-dose combination is an investigational product and its safety and efficacy have not been established. It has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration for the treatment of chronic genotype 1 HCV patients who have previously failed an NS5A inhibitor-containing regimen.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases. Gilead has operations in more than 30 countries worldwide, with headquarters in Foster City, California.
Forward-Looking Statement
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that future trials involving the SOF/VEL/VOX fixed-dose combination may have unfavorable results. In addition, Gilead may be unable to file for U.S. regulatory approval of the SOF/VEL/VOX fixed-dose combination in the United States and Europe in the currently anticipated timelines. In addition, the FDA and other regulatory agencies may not approve the SOF/VEL/VOX fixed-dose combination, and any marketing approvals, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2016, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
For more information on Gilead Sciences, please visit the company's website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
Of Interest
Wednesday, October 19, 2016
Huge Spread in Patient Copays for HCV Drugs
Huge Spread in Patient Copays for HCV Drugs
From nothing to more than $25,000
by John Gever
Managing Editor, MedPageToday
Managing Editor, MedPageToday
October 17, 2016
LAS VEGAS -- One center's experience with arranging curative drug therapy for hepatitis C virus (HCV) infections showed an enormous variation in the out-of-pocket charges patients were asked to bear, researchers said here.
Among 300 patients treated in the Hofstra Northwell Physician Partners system in Manhasset, N.Y., with insurance from 31 private and public payors, copays ranged from zero to nearly $27,000, said Northwell's Susan Lee, PharmD at the American College of Gastroenterology annual meeting.
Continue reading @ MedPageToday
ACG
American College of Gastroenterology
Meeting Coverage
Among 300 patients treated in the Hofstra Northwell Physician Partners system in Manhasset, N.Y., with insurance from 31 private and public payors, copays ranged from zero to nearly $27,000, said Northwell's Susan Lee, PharmD at the American College of Gastroenterology annual meeting.
Continue reading @ MedPageToday
ACG
American College of Gastroenterology
Meeting Coverage
Tuesday, October 18, 2016
Care model demonstrates high SVR rates with different levels of fibrosis, genotypes, and HCV treatment history
Retrospective Study
World J Gastroenterol. Oct 14, 2016; 22(38): 8558-8567
Published online Oct 14, 2016. doi: 10.3748/WJG.v22.i38.8558
Published online Oct 14, 2016. doi: 10.3748/WJG.v22.i38.8558
Levin JM, Dabirshahsahebi S, Bauer M, Huckins E.
Retrospective analysis of hepatitis C infected patients treated through an integrated care model
Core tip: There are new effective options for treating hepatitis C virus. To maximize their effectiveness our health system developed an innovative integrated care model to manage these patients. Through our original therapy algorithm we were able to closely monitor patients from time of insurance approval to the time of obtaining a sustained virologic response (SVR). This real world retrospective study analyses our patient’s SVR rate, adherence, and interventions made by the patient care team. Additionally it will provide a model for other systems to improve their care coordination and response with direct acting antiviral treatment.
ABSTRACT
AIM
To determine if our health system’s integrated model reflects sustained virologic response (SVR) outcomes similar to those in clinical trial data, maximizes adherence, and averts drug interactions.
To determine if our health system’s integrated model reflects sustained virologic response (SVR) outcomes similar to those in clinical trial data, maximizes adherence, and averts drug interactions.
METHODS
Subjects with chronic hepatitis C had their medical records reviewed from November 1st, 2014 through March 1st, 2016. Patients eligible for treatment were entered into an integrated care model therapy algorithm. The primary outcome was SVR12 based on intention to treat (ITT) analysis. Inclusion criteria consisted of both treatment naïve and experienced patients over the age of 18 who were at least twelve weeks post-therapy completion with any genotype (GT) or METAVIR score. Secondary outcomes included adherence, adverse events, and number of drug interaction interventions.
Subjects with chronic hepatitis C had their medical records reviewed from November 1st, 2014 through March 1st, 2016. Patients eligible for treatment were entered into an integrated care model therapy algorithm. The primary outcome was SVR12 based on intention to treat (ITT) analysis. Inclusion criteria consisted of both treatment naïve and experienced patients over the age of 18 who were at least twelve weeks post-therapy completion with any genotype (GT) or METAVIR score. Secondary outcomes included adherence, adverse events, and number of drug interaction interventions.
RESULTS
At the time of analysis, 133 patients had reached twelve weeks post therapy with ITT. In the ITT analysis 70 patients were GT 1a, 26 GT 1b, 23 could not be differentiated between GT 1a or 1b, 8 GT 2, 4 GT 3, and 2 patients with multiple genotypes. The ITT treatment regimens consisted of 97 sofosbuvir (SOF)/ledipasvir (LDV), 8 SOF/LDV and ribavirin (RBV), 7 SOF and Simeprevir (SMV), 6 3D and RBV, 1 3D, 11 SOF and RBV, and 1 SOF, peg interferon alpha, and RBV. The overall SVR12 rate was 93% in the ITT analysis with a total of 6 patients relapsing. In patients with cirrhosis, 89% obtained SVR12. All 33 patients who were previous treatment failures achieved SVR12. Drug-drug interactions were identified in 56.4% of our patient population, 69 of which required interventions made by the pharmacist. The most common side effects were fatigue (41.4%), headache (28.6%), nausea (18.1%), and diarrhea (8.3%). No serious adverse effects were reported.
CONCLUSION
Dean Health System’s integrated care model successfully managed patients being treated for hepatitis C virus (HCV). The integrated care model demonstrates high SVR rates amongst patients with different levels of fibrosis, genotypes, and HCV treatment history.
Dean Health System’s integrated care model successfully managed patients being treated for hepatitis C virus (HCV). The integrated care model demonstrates high SVR rates amongst patients with different levels of fibrosis, genotypes, and HCV treatment history.
Discussion Only
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HCV treatment guidelines emphasize the importance of addressing adherence, adverse effects, and drug interactions with HCV regimens as clinically indicated. However, no specific recommendations are made regarding follow-up methods. Thus, effective real-world care models need to be identified for the newer DAA therapies to ensure the best HCV treatment outcomes are achieved in real-world practice settings. Our study describes an integrated multidisciplinary care team model with SVR12 rates comparable to those seen in controlled clinical trial settings. Overall SVR12 among patients in the current study was 93% in the ITT cohort and 95% in the PP cohort. Among patients with cirrhosis our SVR12 rates remained high at 89% for both PP and ITT cohorts, despite this patient population generally being more difficult to treat. Another patient population that achieved notably high SVR12 rates in our study was the treatment-experienced cohort with a 100% SVR12 rate for PP and ITT analyses. This cohort achieved a higher SVR12 rate compared to our treatment-naïve patients of which 91% in the ITT cohort and 94% in the PP cohort achieved SVR12. This was an unexpected finding we cannot explain. This was additionally unexpected because more patients in the treatment-experienced cohort were cirrhotic compared to the treatment-naïve cohort (57.6% and 28.9% cirrhotic, respectively).
SVR12 achievement rates were similar to clinical trial results based on the specific treatment regimen as well. Patients who completed LDV/SOF regimens achieved 95% SVR12 PP (92% ITT) in our study. The ION-1 study included GT 1 treatment-naïve patients with or without cirrhosis treated with a fixed-dose combination of LDV/SOF with or without RBV[16]. SVR12 rates were 99% with LDV/SOF. ION-2 included GT 1 treatment-experienced patients with or without cirrhosis treated with a fixed-dose combination of LDV/SOF with or without RBV[18]. SVR12 rates were 96% with LDV/SOF. The addition of RBV did not significantly impact SVR12 rates in our study or in ION-1 or -2; SVR12 remained high.
The SMV/SOF regimen resulted in 100% SVR12 PP (100% ITT) in our study patients. OPTIMIST-1 and OPTIMIST-2 investigated SMV/SOF among GT 1 treatment-naïve and treatment-experienced patients[19,22]. Patients without cirrhosis were included in OPTIMIST-1 and the resulting SVR12 was 97%. OPTIMIST-2 included patients with cirrhosis and the SVR12 was 84%. Although only seven patients total received the SMV/SOF regimen among our study patients, five out of the seven were cirrhotic. Our SVR12 rates of 100% were unexpectedly higher than those seen in the OPTIMIST trials.
Patients who completed the 3D plus RBV regimen achieved 100% SVR12 PP (100% ITT) in our study. Two of the six patients were cirrhotic. The SAPPHIRE I and SAPPHIRE II clinical trials included patients that were treatment-naïve and treatment-experienced, respectively, without cirrhosis treated with 3D plus RBV for 12 wk. SVR12 was 96% for both studies[17,23]. In the TURQUOISE II trial, 92% of treatment-naïve or experienced patients with cirrhosis who received 3D plus RBV for 12 wk achieved SVR12[20].
Compared to other real-world analyses of newer DAA treatments, our response rates are either higher than or similar to other studies, demonstrating the effectiveness of our model. A real-world analysis of treatment-naïve or experienced patients with HCV GT 1 with or without cirrhosis was conducted on patients in the HCV-TARGET cohort treated with SMV/SOF with or without RBV[24]. The overall SVR12 rate for SMV/SOF without RBV was 85%, which was lower than the SVR12 of 100% (PP and ITT) seen in our study for patients who were treated with the SMV/SOF regimen.
A real-world study from Israel included treatment-naïve or experienced HCV GT 1 patients with stage 3 or 4 fibrosis treated with 3D with or without RBV. Amongst the patients who completed therapy and retested 12 wk after completion, SVR12 rates were 97.8%[25]. Seven patients in our study received treatment with 3D plus RBV and only two were cirrhotic. Our SVR12 rates with this regimen were 100% for both PP and ITT analyses.
Another real-world effectiveness study from a large integrated health care system in the United States enrolled patients with GT 1 infection and receiving LDV/SOF with or without RBV. Patients were treatment-naïve or experienced and both cirrhotic and noncirrhotic. SVR12 for LDV/SOF was 93% in the ITT analysis[26]. The overall SVR12 in our study for patients treated with LDV/SOF was similar at 92% in the ITT analysis. The addition of RBV did not significantly impact SVR12 rates in either study.
Six patients in our study relapsed. One patient with GT 1b and underlying cirrhosis may have relapsed due to a 5-d break in therapy, another with GT 1a and cirrhosis was due to reinfection from reusing diabetes supplies, and one patient with GT 1a and cirrhosis relapsed for unknown reasons. The other three cases warrant further discussion. The GT 1a infected patient with advanced cirrhosis and HCC treated with LDV/SOF for 12 wk in the current study would also have been treated with RBV if evidence from the SOLAR-1 and SOLAR-2 Phase 2 trials were available at the time of treatment course selection, which may have prevented the relapse. SOLAR-1 and SOLAR-2 enrolled patients with HCV GT 1 or 4 with cirrhosis and moderate to severe hepatic impairment (Child-Pugh class B and C) with and without a history of previous liver transplant[27,28]. Patients were treated with 12 or 24 wk of a fixed-dose combination of LDV/SOF once daily plus RBV. SVR12 was 87% in non-transplant patients treated for 12 wk in SOLAR-1. In SOLAR-2, SVR12 was approximately 86% after 12 wk of treatment in non-transplant patients with GT 1.
The African American patient with GT 1a, cirrhosis, and HIV coinfection relapsed after 12 wk of treatment with LDV/SOF for an undermined reason. A recent study, ION-4, enrolled patients with HCV GT 1 or 4 coinfected with HIV-1. All patients received a 12-wk, fixed-dose combination of LDV/SOF for their HCV treatment regimen[29]. Thirty-four percent of patients in this study were black. Black patients had a lower SVR12 rate than other races (90% vs 99%, P < 0.001). Of note, 10 of the 335 patients in ION-4 relapsed and all were black. Seven of the relapsed patients had the TT allele in the gene encoding IL28B and 8 were receiving efavirenz as part of their HIV treatment regimen. Black race and presence of the TT allele were both significantly associated with relapse in ION-4. Among black patients in ION-4, 13% relapsed if they were also taking efavirenz and only 4% relapsed if they were taking other antiretroviral regimens. However, the difference was not found to be significant. It is possible that the patient in our case possesses the TT allele; however, we did not test patients in our study for the presence of this allele. Concomitantly taking efavirenz could have provoked the relapse in our patient, even though the role efavirenz plays in reduced effectiveness of HCV treatment remains unclear.
The non-cirrhotic, treatment-naive patient with GT2 who relapsed after being treated with 12 wk of SOF and RBV was somewhat surprising to us. The VALENCE trial confirmed that this same regimen is 96.7% effective in naïve, non-cirrhotic patients with GT2[30]. We cannot provide an explanation for why this particular patient relapsed.
In our study, 130 patients completed the analysis PP and 133 were in the ITT analysis. The high percentage of PP patients represents a high engagement between patient and clinical staff monitoring in our model. Furthermore, in our model, a high percentage (79.1%) of patients were 100% adherent on their treatment regimen and only one patient missed more than three doses. Other real-world studies looking at adherence demonstrated about 14% of patients were non-adherent to their treatment regimen and 18% had gaps in therapy of greater than 14 d[31]. A second study reported that 89.3% of patients completed treatment and 9% were non-adherent to therapy in a real-world setting[25].
The specialty pharmacist in our model identified drug interactions in 56.4% of patients. Sixty-nine drug interaction interventions were made with the most prevalent intervention being PPI dosing changes. Overall, drugs to lower gastric pH accounted for about 44% of all drug interaction interventions made. A study from Europe of drug-drug interactions identified that between 12%-19% of patients being treated for HCV were taking a drug that was contraindicated with one or more drugs in their HCV treatment regimen[32]. This same study showed that 29%-39% of patients were on two or more drugs that were either contraindicated or required additional monitoring or dose reduction with their HCV regimen. Similarly to our study, a high percentage (27%-38%) of interacting drugs in the Marra et al[32] study were drugs that target the gastrointestinal tract. The frequency and severity of drug-drug interactions with HCV therapies supports the workflow in our model where a specialty pharmacist consistently screened all patients for drug interactions.
Adverse reactions reported by our patients were consistent with those reported in DAA clinical trials and real-world experience with fatigue, headache, and nausea being the most common[24]. No serious adverse events were recorded. Drop-out rates due to adverse effects tend to be low with the newer generation DAAs, but no patients discontinued treatment for this reason in our study. One possible reason for this may be due to close follow-up by the pharmacist on adverse effects and management strategies.
Our study had some notable limitations. A major limitation is the lack of a control group to allow a statistical comparison of the effectiveness of our integrated model compared to a non-integrated model. Only qualitative comparisons to clinical trial data and other real-world data could be made. A second limitation is that this is a single-center study and results may not be generalizable to patient populations with different demographics. The population at our site is primarily Caucasian and insured. A third limitation is that the methodology of fibrosis determination was not standardized in our protocol. A fourth limitation was that adherence was self-reported by patients via tablet counts. There are inherent limitations with using patient-reported information in a study. The high adherence rates reported in our study likely reflected reality as shown by the high rates of SVR12 in our patients.
The results of this study have demonstrated the need to continue to manage patients using the integrated care model in our current practice. However, the limitations of this study have showed that future research is needed to find causation for patients that relapsed on DAAs. In the scope of our practice, follow up studies will be pursued to assess the impact of adherence and how new technology may assist in increasing adherence to therapy. Additionally, future studies at our practice will analyze if there is correlation of NS5A resistance associated variants and treatment efficacy in our patient population. Furthermore, additional focus will be put on the financial savings that the integrated care model has on the system and the patient.
In conclusion, there is a scarcity of published trials that describe real-world integrated care models for successful treatment of patients with the newer DAA HCV therapies. Dean Health System’s integrated care model helped successfully manage the patients being treated for HCV. The results of our study demonstrated favorable outcomes despite not being able to statistically compare across other studies. The integrated care model demonstrates high SVR rates amongst patients with different levels of fibrosis, genotypes, and HCV treatment history. The integrated care model assisted in catching and evading potential drug interactions that may have impacted treatment efficacy and tolerability. Overall, the evidence from this retrospective analysis demonstrates the benefits and value of treating HCV patients in an integrated care delivery model.
Monday, October 17, 2016
Sofosbuvir/velpatasvir in CHC: Hint of added benefit in two of ten subindications
Sofosbuvir/velpatasvir in CHC: Hint of added benefit in two of ten subindications
Oct 17
Historical comparisons and considerations of individual study arms unsuitable for conclusions on the other research questions
Institute for Quality and Efficiency in Health Care
The drug combination sofosbuvir/velpatasvir (trade name: Epclusa) has been approved since July 2016 for the treatment of patients with chronic hepatitis C (CHC). In an early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) has now examined whether the combination has an added benefit for the patients. In the assessment, a distinction was made regarding type of virus (genotype 1 to 6) and liver status (without cirrhosis, with compensated cirrhosis, and with decompensated cirrhosis). According to the findings, an added benefit in comparison with the respective appropriate comparator therapy was not proven for eight of ten research questions because no suitable study data were available. There was a hint of considerable added benefit for one research question, and a hint of a non-quantifiable added benefit for another one.
Research question based on virus type and liver status
Hepatitis C is caused by infection with an RNA virus, of which there are several genotypes. One of the factors determining treatment is whether patients already have cirrhosis and whether this cirrhosis is compensated or decompensated -- i.e. whether the liver tissue not yet affected can still maintain the functioning of the organ or not.
The Federal Joint Committee (G-BA) therefore distinguished eight groups of patients, two of which it divided further into subgroups, resulting in a total of ten research questions to be investigated. The appropriate comparator therapies consisted of other antiviral therapies in nine subindications, and in best supportive care, i.e. best possible, individually optimized treatment to alleviate symptoms and improve the quality of life, for patients with genotype 2 to 6 and decompensated cirrhosis.
Hint of considerable added benefit in virus genotype 2
Data from the ASTRAL-2 study, in which the antiviral treatment in both arms lasted 12 weeks, were available for patients without cirrhosis or with compensated cirrhosis infected with genotype 2 viruses. According to the approval of sofosbuvir, treatment in the comparator arm could have been extended to 24 weeks, however. The informative value of the results was limited by the fact that this option was not used and by the lack of analyses on the outcome "sustained virologic response" 24 weeks after the end of treatment: Only data on virologic response 12 weeks after the end of treatment were submitted.
There were no statistically significant differences between the study arms in the outcome categories "mortality" and "health-related quality of life". Regarding morbidity, sustained virologic response is considered to be a sufficiently valid surrogate for the patient-relevant outcome "liver cell cancer". In this outcome, there was a hint of an added benefit of the new combination for men, but not for women. A hint of lesser harm of the new combination in the total study population was shown for two side effects - fatigue and psychiatric disorders. Hence overall, there is a hint of considerable added benefit of sofosbuvir/velpatasvir in comparison with the appropriate comparator therapy in this subindication.
Virus genotype 3: hint of non-quantifiable added benefit
The ASTRAL-3 study, which was conducted in participants infected with genotype 3 viruses, compared 12-week treatment with the new drug combination with a 24-week antiviral comparator therapy. The different treatment durations in the study arms were accompanied by different observation periods. As a result, the data on many outcomes could not be meaningfully interpreted. In addition, only data recorded 12 weeks after the end of treatment were submitted on the important outcome "sustained virologic response" also in this case, although analyses on a follow-up period of 24 weeks would have been possible. As a result, no more than hints could be derived.
The new drug combination had an advantage over the comparator therapy in sustained virologic response. There were hints of lesser harm in the outcome "discontinuation due to adverse events"; no conclusions were possible for other outcomes. Overall, this resulted in a hint of an added benefit of the new drug combination, which is non-quantifiable, however.
Historical comparisons and consideration of individual study arms unsuitable
The drug manufacturer only submitted unadjusted historical comparisons for patients infected with genotype 1 viruses and for patients without cirrhosis infected with genotype 4 viruses. Based on these comparisons, conclusions on the added benefit would only be possible if the observed effects were so large that they could not be caused by systematic bias alone. Such so-called dramatic effects were not present in this case.
For the remaining four subindications, the manufacturer submitted data on the new drug combination, but not on the corresponding appropriate comparator therapies. Based on this, no added benefit could be derived for the research questions of the benefit assessment.
Overall, an added benefit of sofosbuvir/velpatasvir in comparison with the appropriate comparator therapies is not proven for eight of ten subindications. There is a hint of an added benefit in two subindications.
G-BA decides on the extent of added benefit
The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.
More English-language information will be available soon (Sections 2.1 to 2.13 of the dossier assessment as well as easily understandable information on informedhealth.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.
Oct 17
Historical comparisons and considerations of individual study arms unsuitable for conclusions on the other research questions
Institute for Quality and Efficiency in Health Care
The drug combination sofosbuvir/velpatasvir (trade name: Epclusa) has been approved since July 2016 for the treatment of patients with chronic hepatitis C (CHC). In an early benefit assessment, the German Institute for Quality and Efficiency in Health Care (IQWiG) has now examined whether the combination has an added benefit for the patients. In the assessment, a distinction was made regarding type of virus (genotype 1 to 6) and liver status (without cirrhosis, with compensated cirrhosis, and with decompensated cirrhosis). According to the findings, an added benefit in comparison with the respective appropriate comparator therapy was not proven for eight of ten research questions because no suitable study data were available. There was a hint of considerable added benefit for one research question, and a hint of a non-quantifiable added benefit for another one.
Research question based on virus type and liver status
Hepatitis C is caused by infection with an RNA virus, of which there are several genotypes. One of the factors determining treatment is whether patients already have cirrhosis and whether this cirrhosis is compensated or decompensated -- i.e. whether the liver tissue not yet affected can still maintain the functioning of the organ or not.
The Federal Joint Committee (G-BA) therefore distinguished eight groups of patients, two of which it divided further into subgroups, resulting in a total of ten research questions to be investigated. The appropriate comparator therapies consisted of other antiviral therapies in nine subindications, and in best supportive care, i.e. best possible, individually optimized treatment to alleviate symptoms and improve the quality of life, for patients with genotype 2 to 6 and decompensated cirrhosis.
Hint of considerable added benefit in virus genotype 2
Data from the ASTRAL-2 study, in which the antiviral treatment in both arms lasted 12 weeks, were available for patients without cirrhosis or with compensated cirrhosis infected with genotype 2 viruses. According to the approval of sofosbuvir, treatment in the comparator arm could have been extended to 24 weeks, however. The informative value of the results was limited by the fact that this option was not used and by the lack of analyses on the outcome "sustained virologic response" 24 weeks after the end of treatment: Only data on virologic response 12 weeks after the end of treatment were submitted.
There were no statistically significant differences between the study arms in the outcome categories "mortality" and "health-related quality of life". Regarding morbidity, sustained virologic response is considered to be a sufficiently valid surrogate for the patient-relevant outcome "liver cell cancer". In this outcome, there was a hint of an added benefit of the new combination for men, but not for women. A hint of lesser harm of the new combination in the total study population was shown for two side effects - fatigue and psychiatric disorders. Hence overall, there is a hint of considerable added benefit of sofosbuvir/velpatasvir in comparison with the appropriate comparator therapy in this subindication.
Virus genotype 3: hint of non-quantifiable added benefit
The ASTRAL-3 study, which was conducted in participants infected with genotype 3 viruses, compared 12-week treatment with the new drug combination with a 24-week antiviral comparator therapy. The different treatment durations in the study arms were accompanied by different observation periods. As a result, the data on many outcomes could not be meaningfully interpreted. In addition, only data recorded 12 weeks after the end of treatment were submitted on the important outcome "sustained virologic response" also in this case, although analyses on a follow-up period of 24 weeks would have been possible. As a result, no more than hints could be derived.
The new drug combination had an advantage over the comparator therapy in sustained virologic response. There were hints of lesser harm in the outcome "discontinuation due to adverse events"; no conclusions were possible for other outcomes. Overall, this resulted in a hint of an added benefit of the new drug combination, which is non-quantifiable, however.
Historical comparisons and consideration of individual study arms unsuitable
The drug manufacturer only submitted unadjusted historical comparisons for patients infected with genotype 1 viruses and for patients without cirrhosis infected with genotype 4 viruses. Based on these comparisons, conclusions on the added benefit would only be possible if the observed effects were so large that they could not be caused by systematic bias alone. Such so-called dramatic effects were not present in this case.
For the remaining four subindications, the manufacturer submitted data on the new drug combination, but not on the corresponding appropriate comparator therapies. Based on this, no added benefit could be derived for the research questions of the benefit assessment.
Overall, an added benefit of sofosbuvir/velpatasvir in comparison with the appropriate comparator therapies is not proven for eight of ten subindications. There is a hint of an added benefit in two subindications.
G-BA decides on the extent of added benefit
The dossier assessment is part of the early benefit assessment according to the Act on the Reform of the Market for Medicinal Products (AMNOG) supervised by the G-BA. After publication of the dossier assessment, the G-BA conducts a commenting procedure and makes a final decision on the extent of the added benefit.
More English-language information will be available soon (Sections 2.1 to 2.13 of the dossier assessment as well as easily understandable information on informedhealth.org). If you would like to be informed when these documents are available, please send an e-mail to info@iqwig.de.
Source
Related
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Related
Oct 18
New Hep C Panviral Not Better than Earlier Drugs?
MD Magazine-2 hours ago
German researchers looking for proof of the effectiveness of the drug combo sofosbuvir/velpatasvir (Epclusa/Gilead Sciences) found the studies submitted by the ...
HCV NEXT - Studying Factors Associated With Clearance and Relapse
Bringing Hepatology to the People: How Community-Based Care Succeeds
HCV Next offers information on a range of liver topics, which include diagnosis, new combination therapies, side effects, drug/drug interaction, guidelines, practice management issues, to name a few.
The following articles appeared in the October print edition of HCV NEXT, provided online at Healio.
The following articles appeared in the October print edition of HCV NEXT, provided online at Healio.
In the Journals
One-Step HCV Diagnostic Shows 99% Specificity, 100% Sensitivity
Combination Regimens Show Similarly High Real-World SVR Rate in VA Cohort
One-Step HCV Diagnostic Shows 99% Specificity, 100% Sensitivity
Combination Regimens Show Similarly High Real-World SVR Rate in VA Cohort
In the Journals Plus
Trend Watch
Penn Medicine Trial Investigates Kidney Transplants From HCV-Positive Donors
AASLD/IDSA Recommend HBV Testing in HCV Guidance Update
Penn Medicine Trial Investigates Kidney Transplants From HCV-Positive Donors
AASLD/IDSA Recommend HBV Testing in HCV Guidance Update
Friday, October 14, 2016
People infected by hepatitis C in Canada have limited access to direct-acting antivirals
People infected by hepatitis C in Canada have limited access to direct-acting antivirals
Montreal, October 14, 2016. - A pill a day for 12 weeks. The new direct-acting antivirals (DAA) are effective in curing the hepatitis C virus infection, a potentially fatal disease that attacks the liver. But they are expensive--approximately $60,000 per patient. A study conducted by researchers at the University of Montreal Hospital Research Centre (CRCHUM), The Kirby Institute, UNSW Australia, and the Canadian Network on Hepatitis C (CanHepC) shows that nearly everywhere in Canada, provinces and territories impose obstacles to the reimbursement of these medications by the public system because of their cost.
"There are many new direct-acting antivirals, marketed by different pharmaceutical companies. We studied reimbursement practices for simeprevir, sofosbuvir, ledipasvir-sofosbuvir and paritaprevir-ritonavir-ombitasvir plus dasabuvir. We found that 85 to 92% of the provinces and territories in Canada restrict access to these medications to persons with moderate fibrosis," affirmed Alison Marshall from the Kirby Institute, UNSW Australia, lead author of a study to appear today in CMAJ Open.
More than 220,000 people in Canada are infected by the Hepatitis C virus. The disease is transmitted by blood. One person in four spontaneously clears the virus before it attacks the liver. The rest often don't feel any symptoms at the beginning, but gradually develop liver disease, graded from F0 to F4. F0 corresponds to the initial infection without fibrosis and F4, to cirrhosis.
From one ocean to the other, provinces and territories impose all types of conditions before reimbursing any of the direct-acting antivirals: a fibrosis level of F2, prescription from a specialist physician, the absence of HIV infection, etc. "The pill isn't easy to get," says Michel Deschenes, 38. "I've been infected with hepatitis C for a year and I am still waiting for a FibroScan® examination. My doctor told me to come back later because my liver isn't sick enough to prescribe the medication. I have a girlfriend and am actively seeking work. This is putting my life on hold and I'd like to get rid of it," he said.
"The treatment is effective, safe and economically viable. We should treat all people infected with hepatitis C," insisted Dr. Julie Bruneau, a physician and researcher at the CHUM. Canada is committed to the World Health Organization's objective of eradicating hepatitis by 2030. "Currently, in Canada, the majority of new and existing hepatitis C infections occur in people with recent or former injection drug use. These people are often vulnerable and stigmatized and have a difficult relationship with the health-care system. Telling them to wait often means losing sight of them. If we want to significantly reduce infection in the future, we need to offer appropriate services, screen and treat these people. If they get reinfected, they have to be treated again immediately. If not, we'll lose the battle and that will be more costly in terms of money and human lives," explained Dr. Bruneau.
If the trend continues, the costs associated with treating patients with cirrhosis of the liver will increase from $161M to $258M a year in 2035, according to the calculations of the authors of the CMAJ Open study. "In terms of public health costs, it's less expensive to pay $60,000 now for an antiviral treatment than $500,000 for a liver transplant later," indicates Dr. Bruneau, also a Professor at the Université de Montréal.
Scientists at the Canadian Network on Hepatitis C are calling for a national strategy to eliminate hepatitis C in the country. "Even though health care is the responsibility of the provinces and we have 13 public health insurance plans in Canada, we need a national plan and shared goals that can be adapted to local realities. We did it for HIV and we should also do it for hepatitis C," argues Naglaa Shoukry, a researcher at the CRCHUM and the director of the Canadian Network on Hepatitis C.
In Australia, this type of approach provided leverage to negotiate the price of antivirals with pharmaceutical companies, enabling access to HCV therapy for all patients living with hepatitis C with no restrictions based on severity of liver disease. In the first five months of therapy being available, 26,500 have received treatment (12% of the estimated total with chronic hepatitis C). "At the present time in Canada, it's the law of supply and demand; there are negotiations on a company-by-company, pill-by-pill basis. There is no transparency and we don't really know how much the new antivirals really cost. The only way to eliminate hepatitis C is by adopting a national strategy to screen and treat all infected individuals, particularly people who inject drugs," concluded Naglaa Shoukry.
About this study
The study entitled "A review of restrictions of reimbursement of direct-acting antiviral treatment for hepatitis C virus infection in Canada" was conducted by researchers at the Canadian Network on Hepatitis C (CanHepC), headed by Naglaa Shoukry (CRCHUM & Université de Montréal) and Julie Bruneau (CRCHUM & Université de Montréal). The study does not necessarily represent the viewpoint of the main funding bodies: The Canadian Institutes of Health Research (CIHR) (grant: NHC-142832), the Public Health Agency of Canada and the Australian Department of Health and Ageing. To learn more, we invite you to read the study: cmajopen.ca.
Additional resources
Eliminating hepatitis C: an interview with Naglaa Shoukry, researcher at the CRCHUM and director of the Canadian Network on Hepatitis C (CanHepC) http://crchum.chumontreal.qc.ca/nouvelles/eliminer-lhepatite-c
Canadian Network on Hepatitis C
canhepc.ca/en (in English)
University of Montreal Hospital Research Centre
crchum.com
Université de Montréal
umontreal.ca
Source: University of Montreal Hospital Research Centre (CRCHUM)
More than 85 percent of Canadian provinces and territories restrict access to new direct-acting antivirals (DAA) for the treatment of the hepatitis C
"There are many new direct-acting antivirals, marketed by different pharmaceutical companies. We studied reimbursement practices for simeprevir, sofosbuvir, ledipasvir-sofosbuvir and paritaprevir-ritonavir-ombitasvir plus dasabuvir. We found that 85 to 92% of the provinces and territories in Canada restrict access to these medications to persons with moderate fibrosis," affirmed Alison Marshall from the Kirby Institute, UNSW Australia, lead author of a study to appear today in CMAJ Open.
More than 220,000 people in Canada are infected by the Hepatitis C virus. The disease is transmitted by blood. One person in four spontaneously clears the virus before it attacks the liver. The rest often don't feel any symptoms at the beginning, but gradually develop liver disease, graded from F0 to F4. F0 corresponds to the initial infection without fibrosis and F4, to cirrhosis.
From one ocean to the other, provinces and territories impose all types of conditions before reimbursing any of the direct-acting antivirals: a fibrosis level of F2, prescription from a specialist physician, the absence of HIV infection, etc. "The pill isn't easy to get," says Michel Deschenes, 38. "I've been infected with hepatitis C for a year and I am still waiting for a FibroScan® examination. My doctor told me to come back later because my liver isn't sick enough to prescribe the medication. I have a girlfriend and am actively seeking work. This is putting my life on hold and I'd like to get rid of it," he said.
"The treatment is effective, safe and economically viable. We should treat all people infected with hepatitis C," insisted Dr. Julie Bruneau, a physician and researcher at the CHUM. Canada is committed to the World Health Organization's objective of eradicating hepatitis by 2030. "Currently, in Canada, the majority of new and existing hepatitis C infections occur in people with recent or former injection drug use. These people are often vulnerable and stigmatized and have a difficult relationship with the health-care system. Telling them to wait often means losing sight of them. If we want to significantly reduce infection in the future, we need to offer appropriate services, screen and treat these people. If they get reinfected, they have to be treated again immediately. If not, we'll lose the battle and that will be more costly in terms of money and human lives," explained Dr. Bruneau.
If the trend continues, the costs associated with treating patients with cirrhosis of the liver will increase from $161M to $258M a year in 2035, according to the calculations of the authors of the CMAJ Open study. "In terms of public health costs, it's less expensive to pay $60,000 now for an antiviral treatment than $500,000 for a liver transplant later," indicates Dr. Bruneau, also a Professor at the Université de Montréal.
Scientists at the Canadian Network on Hepatitis C are calling for a national strategy to eliminate hepatitis C in the country. "Even though health care is the responsibility of the provinces and we have 13 public health insurance plans in Canada, we need a national plan and shared goals that can be adapted to local realities. We did it for HIV and we should also do it for hepatitis C," argues Naglaa Shoukry, a researcher at the CRCHUM and the director of the Canadian Network on Hepatitis C.
In Australia, this type of approach provided leverage to negotiate the price of antivirals with pharmaceutical companies, enabling access to HCV therapy for all patients living with hepatitis C with no restrictions based on severity of liver disease. In the first five months of therapy being available, 26,500 have received treatment (12% of the estimated total with chronic hepatitis C). "At the present time in Canada, it's the law of supply and demand; there are negotiations on a company-by-company, pill-by-pill basis. There is no transparency and we don't really know how much the new antivirals really cost. The only way to eliminate hepatitis C is by adopting a national strategy to screen and treat all infected individuals, particularly people who inject drugs," concluded Naglaa Shoukry.
The study entitled "A review of restrictions of reimbursement of direct-acting antiviral treatment for hepatitis C virus infection in Canada" was conducted by researchers at the Canadian Network on Hepatitis C (CanHepC), headed by Naglaa Shoukry (CRCHUM & Université de Montréal) and Julie Bruneau (CRCHUM & Université de Montréal). The study does not necessarily represent the viewpoint of the main funding bodies: The Canadian Institutes of Health Research (CIHR) (grant: NHC-142832), the Public Health Agency of Canada and the Australian Department of Health and Ageing. To learn more, we invite you to read the study: cmajopen.ca.
Additional resources
Eliminating hepatitis C: an interview with Naglaa Shoukry, researcher at the CRCHUM and director of the Canadian Network on Hepatitis C (CanHepC) http://crchum.
Canadian Network on Hepatitis C
canhepc.ca/en (in English)
University of Montreal Hospital Research Centre
crchum.com
Université de Montréal
umontreal.ca
Source: University of Montreal Hospital Research Centre (CRCHUM)
Tuesday, October 11, 2016
Deciding on Interferon-Free Treatment for Chronic Hepatitis C: Updating Liver Stiffness Cut-Off Values to Maximize Benefit
Deciding on Interferon-Free Treatment for Chronic Hepatitis C: Updating Liver Stiffness Cut-Off Values to Maximize Benefit
Agostino Colli, Mirella Fraquelli , Daniele Prati, Alessia Riva, Alessandra Berzuini, Dario Conte, Alessio Aghemo, Massimo Colombo, Giovanni Casazza Published: October 10, 2016
http://dx.doi.org/10.1371/journal.pone.0164452
Abstract
Introduction
In a perspective of economic constraints the prioritizing of patients to IFN-free regimens is mainly based on the determination of liver stiffness by transient elastography (TE). Being a continuous variable the interpretation of TE results requires the identification of cut-off values, to date set to maximize diagnostic accuracy even if such values should be better based on more helpful outcome prediction endpoints.
Aim
To define the TE cut-off values in different clinical scenarios, including new IFN-free regimens, and to balance the clinical benefits versus harms in treated and untreated patients.
Results
The estimated mean expected harm/benefit ratio for IFN-free regimens was 1/8.3 in patients with F≥2 and 1/10 in those with F≥3. The resulting optimal cut-off values were respectively 4.5 kPa with sensitivity at 99% and specificity at 12%, and 6.8 kPa with sensitivity at 94% and specificity at 41%. These cut-off values are lower than those maximizing accuracy and allow to reduce the number of false negative results.
Conclusions
The optimal TE cut-off values to prioritize patients for IFN-free regimens, are sensibly lower than those used to maximize diagnostic accuracy.
The consideration that a good level of cost effectiveness is obtained treating patients at an early stage of disease [13] and that chronic HCV infection also causes significant extra-hepatic morbidly [14], leads to the requirement of redefining the TE cut-off, switching from merely diagnostic criteria to disease-outcome-predicting endpoints, this implying an extensive hepatologic clinical judgment.
TE cut-off values actually serve the purpose of maximizing diagnostic accuracy according to Youden’s index, which is based on the sum of true positive and true negative results [12]. In this scenario, the downstream clinical consequences of testing are not explicitly evaluated, and the effect of the false positive and false negative results is implicitly considered equivalent. However, when there is the aim of setting a cut-off value in order to support clinical decision-making, the consequences of false results (i.e. from treating subjects who do not have the target condition and or from not treating subjects who have it) should be weighed, and the cut-off value should vary depending on the treatment options to avail.
Using chronic hepatitis C as an example, we have showed that the diagnostic test cut-off values can be defined with the aim of maximizing the benefit of treatment rather than overall diagnostic accuracy. The decisions concerning the treatment of patients with chronic hepatitis C are driven by the stage of fibrosis and liver disease severity [3, 13, 15–19] which can be accurately and safely assessed by measuring LS as an alternative to percutaneous liver biopsy. Furthermore, the results can be expressed as continuous variables, thus enabling the categorization of multiple cut-off values, which can be optimized for different clinical scenarios [8]. We have obtained two LS ROC curves for diagnosing significant and severe fibrosis/liver disease in patients with chronic hepatitis C, using liver histology as the reference standard. We have then identified the cut-off values maximizing treatment benefit in 6 therapeutic scenarios (Fig 1) by taking into account the harm/benefit ratio of the treatment defined by a group of expert clinicians and the prevalence of the target condition [6].
In the scenarios of IFN-based treatment, which is less effective and more harmful than IFN-free regimens, we have identified cut-off values that are close to those currently in use as calculated by maximizing diagnostic accuracy (7.65 kPa for significant fibrosis and 9.6 kPa for severe fibrosis) [4]. However, when the scenarios changed to those of IFN-free regimens, the optimal cut-off value decreased to 6.8 kPa when the aim was to treat patients with severe fibrosis, this figure being close to the upper reference limit obtained on the basis of the distribution of LS values in healthy blood donors (7.6 kPa) (Table 2). This indicates that, when highly effective and safe treatment options are available, clinicians favor sensitivity over specificity and end up electing for treatment patients with any degree of fibrosis. Furthermore, when the threshold was lowered in order to include patients with significant fibrosis, the optimal cut-off value (4.5 kPa) was close to the 50th percentile of the healthy donors, thus indicating that all people are potentially treated regardless of their LS values because the possibility of treating carriers without any degree of fibrosis is clinically acceptable.
As expected, our data shows that, in the case of a very low H/B ratio such as that of IFN-free regimens, the penalty from being false positive is more acceptable than that from being false negative. Furthermore, if the H/B ratio is close to one (as in the case of the two obsolete treatments), the same weight is attributed to false positive or negative test results, and the same cut-off value can maximize both accuracy and treatment benefit.
The application of the new cut-off values in a virtual cohort of 1,000 patients with chronic hepatitis C and a 30% prevalence of severe fibrosis increases the number of true positive results to 35 (with the consequent benefit of IFN-free treatment) at the expense of 310 more false positive results: i.e. the penalty from being false negative clearly outweighs the penalty from being false positive (Table 4). Similarly, in the case of significant fibrosis, the new cut-off value would lead to IFN-free treatment for further 313 patients (67 true and 246 false positive).
The estimated cut-off values obtained using Metz’s equation [11] has not only depended on the H/B ratio, but also on the prevalence of the target condition (severe or significant fibrosis) as a different prevalence leads to a different number of false results: in the case of a higher prevalence, there are usually more false negative results, and in the case of a lower prevalence, there are likely to be more false positive results. However, the prevalence of severe and significant fibrosis among the patients with chronic hepatitis C of this study appears to be quite similar to the rates observed also by other centers [9–12], and therefore the LS cut-off estimates are mainly due to the H/B ratios of the treatment options.
One major advantage of the clinically oriented approach described in this study is that any center can set its own cut-off value to reflect the prevalence of the target condition and balance the expected rates of false positive and negative results against treatment efficacy; the values could be even adjusted to an individual patient’s characteristics or preferences [20]. For example, a patient’s age which has not been taken into account in the 6 scenarios presented here for the sake of simplicity, is an important factor related to life expectancy and benefit estimation, and can be included in the model. Furthermore, the average of the H/B ratios estimated by different centers can help define homogenous rules against resource constraints, as in the case of very expensive IFN-free regimens. This approach has been suggested over 15 years ago for tuberculosis testing, mammography and palpation for breast cancer, Shotz tonometry for glaucoma, etc., but it has been very rarely applied in practice [10, 11]. There is a widespread perception that there needs to be a link between diagnosis and treatment, and it is generally accepted that tests should not be used unless their results change patient management [21]. The measurement of LS in patients with chronic hepatitis C seems to satisfy these requirements, and the same method of defining cut-off values can also be applied to other validated non-invasive tests for staging hepatitis C as FibroTest®, platelet ratio index (APRI) and FIB-4 or other liver diseases such as chronic hepatitis B.
A possible limitation of our study is that as healthy controls we have used a population of blood donors in whom the presence of latent liver disease cannot be absolutely excluded even against their repeated normal blood tests.
Another limitation is that we have compared the TE LS values with the histologic findings of liver biopsies, which are currently considered an imperfect reference standard as they lead to a false negative rate of 20% in the case of a diagnosis of severe fibrosis [23–27]. It is possible that some of the LS results were classified as false positive whereas they may be in fact true positive and false negative at biopsy histology, meaning that the specificity of LS measurements has been possibly underestimated despite our efforts to reduce biopsy sampling errors by accepting adequately sized specimens only. However, in order to counteract the possible underestimation of this specificity, the recommended cut-off values would have been even lower. Of note, we have used inclusion criteria requiring ALT elevation >1.5 ULN, which is no more required.
A further possible shortcoming of this study is that the estimated H/B ratios (Table 3) were obtained on the basis of the holistic clinical judgement of the specialists working in the participating centers, and are therefore a potential source of heterogeneity. However, it is unlikely that the alternative approach of building a more formal cost/benefit analysis would have addressed such an issue because there is little data concerning the natural history of hepatitis C or the extent of benefit or harm arising from treatment [22]. Interestingly, in the literature there are several examples supporting clinical judgment as a valid approach to complex clinical decisions [28, 29].
In conclusion, we suggest that a “one cut-off value fits all” approach is not appropriate, especially when the results of a single test are the major driver of a clinical decision, and that cut-off values should vary depending on the H/B profile of the proposed/available treatments. Given that for the IFN-free regimens of chronic hepatitis C treatment the benefits largely exceed the harms, the LS values justifying treatment initiation are lower than those computed on the basis of diagnostic accuracy, independently of the liver fibrosis score.
Specifically, our study emphasizes that in the setting of IFN-free regimens the values of LS indicating the need to start antiviral treatment are sensibly lower than those used only to maximize diagnostic accuracy as usually incorporated in the clinical guidelines. Thus, in the context of economic constraints the decision to treat or not to treat should be based on clinical considerations and the assessment of LS should be re-interpreted. From a practical viewpoint, when limited resources preclude the treatment of all patients, independently from the severity of the disease, an appropriate prioritization strategy is needed. Compared to the current cut-off set at 10 kPa chosen in most European countries, a new cut-off value defined on the basis of the expected harm/benefit ratio would reduce the number of inappropriately untreated patients, i.e. the false negative results.
On the other hand, in those national health system enjoying a more favorable level of resources and where the access to IFN-free regimens is broader, including also patients with mild to moderate, or absent fibrosis, LS determination by TE is not helpful or justified.
Continue reading...
Introduction
Materials and Methods
Results
Discussion
Acknowledgments
Author Contributions
References
Agostino Colli, Mirella Fraquelli , Daniele Prati, Alessia Riva, Alessandra Berzuini, Dario Conte, Alessio Aghemo, Massimo Colombo, Giovanni Casazza Published: October 10, 2016
http://dx.doi.org/10.1371/journal.pone.0164452
Abstract
Introduction
In a perspective of economic constraints the prioritizing of patients to IFN-free regimens is mainly based on the determination of liver stiffness by transient elastography (TE). Being a continuous variable the interpretation of TE results requires the identification of cut-off values, to date set to maximize diagnostic accuracy even if such values should be better based on more helpful outcome prediction endpoints.
Aim
To define the TE cut-off values in different clinical scenarios, including new IFN-free regimens, and to balance the clinical benefits versus harms in treated and untreated patients.
Methods
We assessed the accuracy of TE in staging 728 consecutive HCV patients and the distribution of TE values in 1,001 blood donors. Ten experts quantified the expected harm/benefit ratio for 6 scenarios resulting from 2 stages of liver disease (F≥2 or F≥3) and 3 treatment regimens: PEGIFN+ribavirin, PEGIFN+RBV+first-generation protease inhibitor, and IFN-free regimens. The optimal TE cut-off values were identified using the Metz equation.
We assessed the accuracy of TE in staging 728 consecutive HCV patients and the distribution of TE values in 1,001 blood donors. Ten experts quantified the expected harm/benefit ratio for 6 scenarios resulting from 2 stages of liver disease (F≥2 or F≥3) and 3 treatment regimens: PEGIFN+ribavirin, PEGIFN+RBV+first-generation protease inhibitor, and IFN-free regimens. The optimal TE cut-off values were identified using the Metz equation.
The estimated mean expected harm/benefit ratio for IFN-free regimens was 1/8.3 in patients with F≥2 and 1/10 in those with F≥3. The resulting optimal cut-off values were respectively 4.5 kPa with sensitivity at 99% and specificity at 12%, and 6.8 kPa with sensitivity at 94% and specificity at 41%. These cut-off values are lower than those maximizing accuracy and allow to reduce the number of false negative results.
Conclusions
The optimal TE cut-off values to prioritize patients for IFN-free regimens, are sensibly lower than those used to maximize diagnostic accuracy.
Discussion Only
The access of patients to antiviral treatment, especially after the introduction of the highly effective but extremely expensive IFN-free regimens, is mainly based on the assessment of liver fibrosis stage.The consideration that a good level of cost effectiveness is obtained treating patients at an early stage of disease [13] and that chronic HCV infection also causes significant extra-hepatic morbidly [14], leads to the requirement of redefining the TE cut-off, switching from merely diagnostic criteria to disease-outcome-predicting endpoints, this implying an extensive hepatologic clinical judgment.
TE cut-off values actually serve the purpose of maximizing diagnostic accuracy according to Youden’s index, which is based on the sum of true positive and true negative results [12]. In this scenario, the downstream clinical consequences of testing are not explicitly evaluated, and the effect of the false positive and false negative results is implicitly considered equivalent. However, when there is the aim of setting a cut-off value in order to support clinical decision-making, the consequences of false results (i.e. from treating subjects who do not have the target condition and or from not treating subjects who have it) should be weighed, and the cut-off value should vary depending on the treatment options to avail.
Using chronic hepatitis C as an example, we have showed that the diagnostic test cut-off values can be defined with the aim of maximizing the benefit of treatment rather than overall diagnostic accuracy. The decisions concerning the treatment of patients with chronic hepatitis C are driven by the stage of fibrosis and liver disease severity [3, 13, 15–19] which can be accurately and safely assessed by measuring LS as an alternative to percutaneous liver biopsy. Furthermore, the results can be expressed as continuous variables, thus enabling the categorization of multiple cut-off values, which can be optimized for different clinical scenarios [8]. We have obtained two LS ROC curves for diagnosing significant and severe fibrosis/liver disease in patients with chronic hepatitis C, using liver histology as the reference standard. We have then identified the cut-off values maximizing treatment benefit in 6 therapeutic scenarios (Fig 1) by taking into account the harm/benefit ratio of the treatment defined by a group of expert clinicians and the prevalence of the target condition [6].
In the scenarios of IFN-based treatment, which is less effective and more harmful than IFN-free regimens, we have identified cut-off values that are close to those currently in use as calculated by maximizing diagnostic accuracy (7.65 kPa for significant fibrosis and 9.6 kPa for severe fibrosis) [4]. However, when the scenarios changed to those of IFN-free regimens, the optimal cut-off value decreased to 6.8 kPa when the aim was to treat patients with severe fibrosis, this figure being close to the upper reference limit obtained on the basis of the distribution of LS values in healthy blood donors (7.6 kPa) (Table 2). This indicates that, when highly effective and safe treatment options are available, clinicians favor sensitivity over specificity and end up electing for treatment patients with any degree of fibrosis. Furthermore, when the threshold was lowered in order to include patients with significant fibrosis, the optimal cut-off value (4.5 kPa) was close to the 50th percentile of the healthy donors, thus indicating that all people are potentially treated regardless of their LS values because the possibility of treating carriers without any degree of fibrosis is clinically acceptable.
As expected, our data shows that, in the case of a very low H/B ratio such as that of IFN-free regimens, the penalty from being false positive is more acceptable than that from being false negative. Furthermore, if the H/B ratio is close to one (as in the case of the two obsolete treatments), the same weight is attributed to false positive or negative test results, and the same cut-off value can maximize both accuracy and treatment benefit.
The application of the new cut-off values in a virtual cohort of 1,000 patients with chronic hepatitis C and a 30% prevalence of severe fibrosis increases the number of true positive results to 35 (with the consequent benefit of IFN-free treatment) at the expense of 310 more false positive results: i.e. the penalty from being false negative clearly outweighs the penalty from being false positive (Table 4). Similarly, in the case of significant fibrosis, the new cut-off value would lead to IFN-free treatment for further 313 patients (67 true and 246 false positive).
The estimated cut-off values obtained using Metz’s equation [11] has not only depended on the H/B ratio, but also on the prevalence of the target condition (severe or significant fibrosis) as a different prevalence leads to a different number of false results: in the case of a higher prevalence, there are usually more false negative results, and in the case of a lower prevalence, there are likely to be more false positive results. However, the prevalence of severe and significant fibrosis among the patients with chronic hepatitis C of this study appears to be quite similar to the rates observed also by other centers [9–12], and therefore the LS cut-off estimates are mainly due to the H/B ratios of the treatment options.
One major advantage of the clinically oriented approach described in this study is that any center can set its own cut-off value to reflect the prevalence of the target condition and balance the expected rates of false positive and negative results against treatment efficacy; the values could be even adjusted to an individual patient’s characteristics or preferences [20]. For example, a patient’s age which has not been taken into account in the 6 scenarios presented here for the sake of simplicity, is an important factor related to life expectancy and benefit estimation, and can be included in the model. Furthermore, the average of the H/B ratios estimated by different centers can help define homogenous rules against resource constraints, as in the case of very expensive IFN-free regimens. This approach has been suggested over 15 years ago for tuberculosis testing, mammography and palpation for breast cancer, Shotz tonometry for glaucoma, etc., but it has been very rarely applied in practice [10, 11]. There is a widespread perception that there needs to be a link between diagnosis and treatment, and it is generally accepted that tests should not be used unless their results change patient management [21]. The measurement of LS in patients with chronic hepatitis C seems to satisfy these requirements, and the same method of defining cut-off values can also be applied to other validated non-invasive tests for staging hepatitis C as FibroTest®, platelet ratio index (APRI) and FIB-4 or other liver diseases such as chronic hepatitis B.
A possible limitation of our study is that as healthy controls we have used a population of blood donors in whom the presence of latent liver disease cannot be absolutely excluded even against their repeated normal blood tests.
Another limitation is that we have compared the TE LS values with the histologic findings of liver biopsies, which are currently considered an imperfect reference standard as they lead to a false negative rate of 20% in the case of a diagnosis of severe fibrosis [23–27]. It is possible that some of the LS results were classified as false positive whereas they may be in fact true positive and false negative at biopsy histology, meaning that the specificity of LS measurements has been possibly underestimated despite our efforts to reduce biopsy sampling errors by accepting adequately sized specimens only. However, in order to counteract the possible underestimation of this specificity, the recommended cut-off values would have been even lower. Of note, we have used inclusion criteria requiring ALT elevation >1.5 ULN, which is no more required.
A further possible shortcoming of this study is that the estimated H/B ratios (Table 3) were obtained on the basis of the holistic clinical judgement of the specialists working in the participating centers, and are therefore a potential source of heterogeneity. However, it is unlikely that the alternative approach of building a more formal cost/benefit analysis would have addressed such an issue because there is little data concerning the natural history of hepatitis C or the extent of benefit or harm arising from treatment [22]. Interestingly, in the literature there are several examples supporting clinical judgment as a valid approach to complex clinical decisions [28, 29].
In conclusion, we suggest that a “one cut-off value fits all” approach is not appropriate, especially when the results of a single test are the major driver of a clinical decision, and that cut-off values should vary depending on the H/B profile of the proposed/available treatments. Given that for the IFN-free regimens of chronic hepatitis C treatment the benefits largely exceed the harms, the LS values justifying treatment initiation are lower than those computed on the basis of diagnostic accuracy, independently of the liver fibrosis score.
Specifically, our study emphasizes that in the setting of IFN-free regimens the values of LS indicating the need to start antiviral treatment are sensibly lower than those used only to maximize diagnostic accuracy as usually incorporated in the clinical guidelines. Thus, in the context of economic constraints the decision to treat or not to treat should be based on clinical considerations and the assessment of LS should be re-interpreted. From a practical viewpoint, when limited resources preclude the treatment of all patients, independently from the severity of the disease, an appropriate prioritization strategy is needed. Compared to the current cut-off set at 10 kPa chosen in most European countries, a new cut-off value defined on the basis of the expected harm/benefit ratio would reduce the number of inappropriately untreated patients, i.e. the false negative results.
On the other hand, in those national health system enjoying a more favorable level of resources and where the access to IFN-free regimens is broader, including also patients with mild to moderate, or absent fibrosis, LS determination by TE is not helpful or justified.
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Introduction
Materials and Methods
Results
Discussion
Acknowledgments
Author Contributions
References
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