Clinical Trial Eligibility Gle/pib
For the glecaprevir/pibrentasvir Expedition-2 trial, 90% of patients met at least one exclusion criteria and 81% remained ineligible if the antiretroviral regimen was not included as an exclusion criterion. Top exclusion criteria met included: having a psychiatric disorder , a non-approved ART regimen , active alcohol or IDU , having a viral load > 20 copies/ml and hemoglobin < 12g/dl for men and< 11g/dl for women , a CD4 count < 200 cells/mm3 and a history of decompensated liver cirrhosis .
Model Structure And Assumptions
A decision tree was developed for various HCV treatment scenarios , and a Markov state transition model was used to simulate the natural history of HCV infection and progression of liver disease in people living with HCV . Similar to model structures used in the previous studies, the Markov model states included various stages of liver fibrosis based on METAVIR score, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, post-liver transplantation and death. METAVIR score defines four stages of liver fibrosis, including F0 , F1 , F2 , F3 and F4 . The model also included the liver disease states following HCV cure .
The estimates of treatment effectiveness, health utilities, transition probabilities, and costs, used as input parameters
Gilead Wins Hep C Patients Lose
The pricing of Sovaldi was first at $84,00 and Harvoni at $94,000 in effect valued the NS5A part at $10,000.
But BMS was charging about $50,000 for 84 Daclatasvir pills, which meant that relatively few people got access to the powerful drug combination of Sofosbuvir + Daclatasvir.
This strategy worked very well for Gileads profits but, for people who were infected with Genotype 2 or Genotype 3 this did not work not well at all
Eventually Gilead developed Velpatasvir which combined with Sofosbuvir created Epclusa, a genuine pan-genotype Hep C treatment. But Velpatasvir is expensive to make and, because of this Epclusa is actually still the most expensive of the Hep C treatments, even in generic form.
In the mean time another pharmaceutical giant, AbbVie, realized the potential profits to be made from a drug combination that treated all genotypes of Hep C and came up with the drug Mavyret.
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Study Design/ Setting/ Participants
This was a cross sectional study of HIVHCV co-infected patients at the Yale-New Haven Health system HIV clinic . The Yale-New Haven HIV clinic is the largest HIV clinic in the state of Connecticut, with over 20 physicians and mid-level providers, who provide specialty care and services to over 1500 patients primarily residing in the Greater New Haven area majority of whom are male and racial or ethnic minorities . Consultation and follow-up management for HCV therapy in the HIV clinic is typically performed by 23 physician providers once a week. Study data was collected between January 1, 2016 and December 31, 2016 and reflects the time point at which patient records were reviewed.
Critical Appraisal And Grade
The validity of randomized trials was assessed by the Risk of Bias instrument, endorsed by the Cochrane collaboration . Studies of other designs, including single-arm trials, cohort studies, and observational studies, were evaluated using the Tool to Assess the Risk of Bias in Cohort Studies, developed by the CLARITY group at McMaster University .
The Grading Recommendations of Assessment, Development and Evaluation approach was used to assign a rating of high, moderate, low, or very low, to reflect the certainty of evidence for each outcome , , , , , . The traditional approach was modified to suit the unique clinical and methodological characteristics of HCV research in the context of this review and to reflect the analysis approach, which combined both trial and non-trial evidence .
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Clinical Trial Eligibility Sof/vel
When eligibility criteria from the sofosbuvir/velpatasvir ASTRAL-1 trial was applied to our cohort, 89% of met at least one exclusion criteria with the most common reason for exclusion being on a non-approved antiretroviral regimen. When the antiretroviral regimen was removed as an exclusion criterion, 76% of patients remained ineligible. Other major exclusion criteria met by a significant number of our cohort included having a psychiatric disorder , active alcohol or injection drug use , having an HIV viral load > 50 copies/ml , a CrCl < 60ml/min and a history of decompensated cirrhosis .
Table 2 Selective exclusion criteria and number of patients excluded
Assessment Of Liver Disease Severity
The severity of liver disease was assessed noninvasively by shear wave elastography using Aixplorer equipment . Based on liver stiffness, fibrosis stage was defined from F0 to F4 according to the METAVIR score using the guidelines of the European Association for the Study of the Liver. The cutoff values of 9 and 13 kPa were used for the prediction of F3 and F4, respectively.7 Advanced liver fibrosis was diagnosed as stage F3. Patients with stage F4 were identified to be cirrhotic and subsequently classified according to the Child-Pugh score and the Model for End-Stage Liver Disease. Patients with liver cirrhosis were also evaluated for the presence of esophageal varices and data on past or present hepatic decompensation as well as the history of hepatocellular carcinoma and liver transplantation were collected.
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All Hcv Patients With Chronic Kidney Disease Should Be Treated
According to EASL guidelines, all patients, including those with CKD, should be treated to reduce the risk of hepatic and extra-hepatic complications . All patients with symptomatic cryoglobulinaemic vasculitis should be considered for treatment. This includes up to one-third of patients with renal involvement.
2.2.1 Which DAAs are recommended in patients with stage 4-5 CKD?
International guidelines for CKD patients with a glomerular filtration rate > 30 mL/min are the same as those for the general population with HCV.
Protease inhibitors or NS5A inhibitors do not require a dose-adjustment for estimated glomerular filtration rate . This explains the excellent results that have been obtained with the grazoprevir/elbasvir combination in the largest randomized controlled study in genotype 1-infected patients with severe renal impairment including those on dialysis : 99% SVR in a per protocol analysis.
The RUBY-1 trial also reported high SVR rates in HCV genotype 1-infected patients with stage 4-5 CKD. The SVR rate in the RUBY-2 trial without RBV was also high, even in genotype 1a patients. This seems to be a better option because it is RBV-free.
2.2.2 Pangenotypic combinations
Initial Treatment Of Adults With Hcv Infection
Initial treatment of HCV infection includes patients with chronic hepatitis C who have not been previously treated with interferon, peginterferon, ribavirin, or any HCV direct-acting antiviral agent, whether investigational, or US Food and Drug Administration approved.
Simplification of the treatment regimen may expand the number of healthcare professionals who prescribe antiviral therapy and increase the number of persons treated. This would align with the National Academies of Science, Engineering, and Medicine strategy to reduce cases of chronic HCV infection by 90% by 2030 .
Recommended and alternative regimens are listed in order of level of evidence. When several regimens are at the same recommendation level, they are listed in alphabetical order. Regimen choice should be determined based on patient-specific data, including drug-drug interactions. Patients receiving antiviral therapy require careful pretreatment assessment for comorbidities that may influence treatment response or regimen selection. All patients should have access to an HCV care provider during treatment, although preset clinic visits and/or blood tests depend on the treatment regimen and may not be required for all regimens/patients. Patients receiving ribavirin require additional monitoring for anemia during treatment .
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Hepatitis C Testing Treatment And Research News
British Columbia BC:HCV Stakeholder Survey Highlights
In March 2020, BCCDC conducted the Hepatitis C Stakeholders Survey to gather input from Hepatitis C stakeholders such as service and treatment providers on HCV education, prevention, support, testing and treatment services and programs in BC. The results of the survey will be used to inform coordination of HCV-related services and future HCV elimination efforts.
British Columbia – NON-URGENT HCV Testing Re-Started
British Columbia – Temporary Suspension of NON-URGENT HCV Testing
View/Download full details here: BC CDC | BC Ministry of Health
Routine/non-urgent HCV testing at the BCCDC Public Health Laboratory is temporarily suspended to redirect resources to support COVID-19 testing. This includes all routine HCV screening and testing related to HCV treatment. The BCCDC PHL performs more than 95% of all BCs HCV testing.
When HCV testing resumes, health care providers will be notified. People can sign up for HCV testing reminders through SmartSexResource.com, or sign up to the STI Updates blog to receive a notification when HCV testing resumes.
Blueprint to inform hepatitis C elimination efforts in Canada
May 2019The Canadian Network on Hepatitis C released their blueprint to inform Canada’s HCV elimination efforts.
Visit CanHepC to download the document.
CASL Updated HCV Treatment Guidelines
VOSEVI on BC, Ontario and Quebec drug plans
VOSEVI is for patients with chronic hepatitis C , who have
Definitions And Patient Characteristics
HIV infection was defined as patients who had a positive Ab test, Ag/Ab test, and or positive HIV RNA assay historically . HCV infection was defined as a positive HCV antibody test and/or at least one detectable HCV RNA assay . HIV and HCV viral load testing was performed using COBAS Ampliprep/COBAS Taqman, HIV and HCV version 2.0, Pleasanton California, USA respectively. HCV genotyping was performed using Versant HCV genotype, 2.0 assay , Siemens Healthineers, Erlagen, Germany. Active substance use was defined as any drug use in the past 12months. Cirrhosis status was defined as per liver biopsy, results of a single non-invasive test algorithm interpreted with recommended cut-offs for each test or by ICD-9/10 codes in chart. Decompensated cirrhosis was defined as the presence of ascites, history of portosystemic encephalopathy, and/or variceal bleeding. Prior treatment for HCV was captured regardless of agent used, treatment duration or outcome. For patients on cART, the regimen captured was the regimen that the patient was on at the time of data collection. Mental health disorders were captured by diagnostic codes based on chart documentation by providers. Other patient characteristics, comorbidities and laboratory values were captured and reflect the most recent values at the time of chart review for all patients.
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Study Population And Its Epidemic Features
As HCV genotype 1 is the most prevalent infection in China , the target population was identified as adult CHC patients with HCV genotype 1 infection who were naïve to drug treatment. The mean age was 45 years old as informed by the study investigating current CHC patients under drug treatment . Pan-genotypic DAAs are normally recommended to a wide range of patients.
Candidate Strategies And Primary Clinical Outcome
Similar to the previous studies , the SoC in China consisting of pegIFN + RBV for 48 weeks was set as the reference case. Although the decade-long pegIFN-based regimens are now less popular, they are still in use in many areas of China. Candidate strategies were SOP/LDV once daily for 12 weeks, as per the Chinese Clinical Guideline for Treatment and Prevention of Hepatitis C Infection . The SOF/VEL regimen prescribes SOF/VEL for 12 weeks as a once-daily oral administration. Another DAA, elbasvir/grazoprevir, which was also enrolled in NRDL in 2020 was not selected for comparison mainly because it is not pan-genotypic.
The primary clinical endpoint was the SVR rate at 24 weeks after a course of drug treatment. If SVR-24 was not reported, SVR-12 was taken as a substitute because of the high consistency between SVR-12 and SVR-24 . SVR refers to undetectable HCV RNA in blood indicating that patients have cleared the virus. Data of SVR were all extracted from clinical trial or real-world studies on Chinese populations . A serious adverse event refers to any unexpected clinical event occurring during drug treatment that was reported as a SAE in the original study. Failing to explicitly model SAEs would underestimate the value of the DAA regimens as they are associated with a lower SAE rate. SAE rates were inputted in the model and extracted from the same studies of SVR to maintain consistency between model parameters.
Table 1. Clinical profile of candidate strategies.
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Data Extraction And Outcomes
All titles and abstracts, as well as the full text publications of included abstracts, were screened independently and in duplicate by two reviewers . Data extraction of study characteristics and outcomes of included studies were performed independently and in duplicate by at least two reviewers . Outcomes extracted included the proportion of persons achieving SVR12 as well as the proportion of persons with serious adverse events , discontinuations due to adverse events , and all-cause mortality.
Ifn Monotherapy In Acute Hepatitis C
Although the short courses of standard IFN monotherapy introduced in the 1980s by Hoofnagle et al, Davis et al, and Di Bisceglie et al led to sustained improvement in liver disease and loss of virus in less than 10% of patients, these therapies were the first to cure chronic viral hepatitis.
Jaeckel et al reported that treatment with IFN alfa-2b prevented chronic infection in 98% of a group of 44 German patients with acute hepatitis C. In this study, patients received 5 million U/day of IFN alfa-2b subcutaneously for 4 weeks and then three times per week for another 20 weeks the IFN alfa-2b was well tolerated in all patients but one.
Because it has the poorest safety profile of all the HCV antiviral agents, with few exceptions PEG-IFN is no longer recommended in combination regimens. Spontaneous resolution of acute HCV infection may occur in 15% to 50% of patients. Monitoring for spontaneous clearance for a minimum of 6 months before initiating any treatment is therefore recommended.
References
World Health Organization. Hepatitis C: fact sheet. Available at . Updated: October 2017 Accessed: January 23, 2018.
Frank C, Mohamed MK, Strickland GT, et al. The role of parenteral antischistosomal therapy in the spread of hepatitis C virus in Egypt. Lancet. 2000 Mar 11. 355:887-91. .
Kim A. Hepatitis C virus. Ann Intern Med. 2016 Sep 6. 165 :ITC33-ITC48. .
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Interferons And Pegylated Interferons
The two most frequently used recombinant interferon preparations in clinical trials have been IFN alfa-2b and IFN alfa-2a , which differ from each other by only a single amino acid residue. IFN alfacon-1 , or consensus IFN, is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs. Roferon-A was discontinued from the market in 2007 and Infergen was discontinued from the market in 2013.
The addition of propylene glycol molecules to IFN has led to the development of long-lasting IFNs that have better sustained absorption, a slower rate of clearance, and a longer half-life than unmodified IFN, which permits more convenient once-weekly dosing. The FDA has approved PEG-IFNs for the treatment of chronic hepatitis C.
Two PEG-IFN preparations are available for the treatment of chronic hepatitis C. PEG-IFN alfa-2b consists of IFN alfa-2b attached to a single 12-kd PEG chain it is excreted by the kidneys. PEG-IFN alfa-2a consists of IFN alfa-2a attached to a 40-kd branched PEG molecule it is metabolized predominantly by the liver.
Data Collection And Synthesis
Data were retrieved mainly from literature. Meta-analytic techniques, such as inverse variance weighting, were used to generate model parameters for which multiple estimates were available. Data sources were judged in terms of relevance, internal validity and transferability to the Chinese healthcare setting. To improve the relevance of model outputs to the Chinese healthcare setting, efforts were made to retrieve data on Chinese populations.
Transitions Among Health States
Fibrosis progression was estimated from an up-to-date meta-analysis of the natural history of CHC . For patients who achieved SVR after pharmacologic treatment, fibrosis regression was incorporated into their pathway as studies have reported SVR-related regression from cirrhosis to fibrosis, and from F3 back to F2 . However, once patients developed DCC, HCC or received a LT, we assumed that SVR would not be relevant to the patient’s further prognosis. Data about disease progression after cirrhosis were synthesized from multiple studies . The probability of requiring a LT for patients with DCC or HCC was extracted from the data of the China Liver Transplant Registry .
Cost and Utility
Health utility was represented by the health-related quality of life scores in EQ-5D . Data were extracted from the literature and adjusted to reflect the utility of Chinese patients in different health states .
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Gilead Is A Greedy Beast
Because GILEAD is a greedy beast it did not want to share its potential profits with anyone else so GILEAD severed that relationship with BMS and Daclatasvir and went on to develop another drug to replace Daclatasvir, this was Ledipasvir.
It took a little longer to create Ledipasvir but GILEAD could not wait to start its profits rolling in so it began selling Sovaldi alone, which was not as effective as Sofosbuvir + Daclatasvir but it enabled GILEAD to recoup its 12 billion dollars in less than 12 months.
Sovaldi was not as effective as Sovaldi + Daclatasvir but GILEAD did not have to share its profits so GILEAD was happy, even though lots of people failed their treatment with Sovaldi alone.
So instead of the world getting a cheap pan-genotypic drug that cured all genotypes of Hep C the world got Sovaldi and then Harvoni.
Harvoni was only effective for the treatment of Hep C Genotype 1 but G1 represented about 70% of all Hep C infections in the USA and GILEAD knew that the USA was where it could make big bucks fastest. So GILEAD focused on Harvoni using Sofosbuvir and Ledipasvir which Gilead owned.
Because Gilead owned Sofosbuvir and because Daclatasvir by itself was not a viable treatment this was a commercial decision that helped no-one except Gilead and it allowed Gilead to take all the profits and delayed the release of a single dose pan-genotypic treatment for more than 3 years.
Hcv Clinical Trial Eligibility Assessment
Study protocol eligibility criteria of the following pangenotypic HCV-DAA trials which were either inclusive of or exclusively for HIV-HCV coinfected patients were matched to characteristics of identified eligible patients: sofosbuvir-velpatasvir ASTRAL-1 , glecaprevir-pibrentasvir EXPEDITION-2 . These are the first 2 pan-genotypic regimens approved for the treatment of chronic HCV infection in the United States. Complete inclusion and exclusion criteria were extracted from the study protocols and utilized to create a database grid to which the criteria were matched to patient characteristics and data including labs.
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