Abstract
Background
In 2019, about 58 million individuals were chronically infected with hepatitis C virus. Some experts have proposed challenge trials for hepatitis C virus vaccine development.
...Methods
We modeled incremental infections averted through a challenge approach, under varying assumptions regarding trial duration, number of candidates, and vaccine uptake. We computed the benefit-risk ratio of incremental benefits to risks for challenge versus traditional approaches. We also benchmarked against monetary costs of achieving incremental benefits through treatment.
Results
Our base case assumes 3 vaccine candidates, each with an 11% chance of success, corresponding to a 30% probability of successfully developing a vaccine. Given this probability, and assuming a 5-year difference in duration between challenge and traditional trials, a challenge approach would avert an expected 185 000 incremental infections with 20% steady-state uptake compared to a traditional approach and 832 000 with 90% uptake (quality-adjusted life-year benefit-risk ratio, 72 000 & 323 000). It would cost at least $92 million and $416 million, respectively, to obtain equivalent benefits through treatment. BRRs vary considerably across scenarios, depending on input assumptions.
Conclusions
Benefits of a challenge approach increase with more vaccine candidates, faster challenge trials, and greater uptake.
Peginterferon-α (PegIFNα) is of limited utility during immunotolerant (IT) or immune active (IA) phases of chronic hepatitis B infection but is being explored as part of new cure regimens. Low/absent ...levels of IFNα found in some treated patients are associated with limited/no virological responses.
To determine if sera from participants inhibit IFNα activity and/or contain therapy-induced anti-IFNα antibodies.
Pre-, on- and post-treatment sera from 61 IT trial participants on PegIFNα/ entecavir therapy and 88 IA trial participants on PegIFNα/tenofovir therapy were screened for anti-IFNα antibodies by indirect ELISA. The neutralization capacity of antibodies was measured by pre-incubation of sera +/- recombinant-human IFNα (rhIFNα) added to Huh7 cells with measurement of interferon stimulated gene (ISG)-induction by qPCR. Correlations between serum-induced ISG inhibition, presence, and titer of anti-IFNα antibodies and virological responses were evaluated.
Pre-incubation of on-treatment serum from 26 IT (43%) and 13 IA (15%) participants with rhIFNα markedly blunted ISG-induction in Huh7 cells. Degree of ISG-inhibition correlated with IFNα antibody titer (p<0.0001; r=0.87). On-treatment development of anti-IFNα neutralizing antibodies (nAbs) was associated with reduced qHBsAg and qHBeAg declines (p<0.05) and inhibited IFNα bioactivity to 240 weeks after PegIFNα cessation. Children developed anti-IFNα nAbs more frequently than adults (p=0.004) but nAbs in children had less impact on virological responses.
The development of anti-IFNα nAbs during PegIFNα treatment diminishes responses to antiviral therapy. Understanding how and why anti-IFNα antibodies develop may allow for optimization of IFN-based therapy, which is critical given its renewed use in HBV-cure strategies.
Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. ...However, because of treatment‐limiting side effects and its additive toxicity with interferon, the search for interferon‐ and ribavirin‐free regimens has been underway. The recent approvals of all‐oral direct acting antivirals (DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co‐administered with all‐oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all‐oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups.
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•HCC incidence varies markedly by etiology of cirrhosis.•THRI is simple to use, has good predictive ability, and has been externally validated.•THRI may help to refine HCC ...surveillance guidelines for patients with cirrhosis.
Current guidelines recommend biannual surveillance for hepatocellular carcinoma (HCC) in all patients with cirrhosis, regardless of etiology. However, HCC incidence is not well established for many causes of cirrhosis. We aimed to assess the disease-specific incidence of HCC in a large cohort of patients with cirrhosis and to develop a scoring system to predict HCC risk.
A derivation cohort of patients with cirrhosis diagnosed by biopsy or non-invasive measures was identified through retrospective chart review. The disease-specific incidence of HCC was calculated according to etiology of cirrhosis. Factors associated with HCC were identified through multivariable Cox regression and used to develop a scoring system to predict HCC risk. The scoring system was evaluated in an external cohort for validation.
Of 2,079 patients with cirrhosis and ≥6months follow-up, 226 (10.8%) developed HCC. The 10-year cumulative incidence of HCC varied by etiologic category from 22% in patients with viral hepatitis, to 16% in those with steatohepatitis and 5% in those with autoimmune liver disease (p<0.001). By multivariable Cox regression, age, sex, etiology and platelets were associated with HCC. Points were assigned in proportion to each hazard ratio to create the Toronto HCC Risk Index (THRI). The 10-year cumulative HCC incidence was 3%, 10% and 32% in the low-risk (<120points), medium-risk (120–240) and high-risk (>240) groups respectively, values that remained consistent after internal validation. External validation was performed on a cohort of patients with primary biliary cirrhosis, hepatitis B viral and hepatitis C viral cirrhosis (n=1,144), with similar predictive ability (Harrell’s c statistic 0.77) in the validation and derivation cohorts.
HCC incidence varies markedly by etiology of cirrhosis. The THRI, using readily available clinical and laboratory parameters, has good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis.
HCC incidence varies markedly depending on the underlying cause of cirrhosis. Herein, using readily available clinical and laboratory parameters we describe a risk score, THRI, which has a good predictive ability for HCC in patients with cirrhosis, and has been validated in an external cohort. This risk score may help to guide recommendations regarding HCC surveillance among patients with cirrhosis.
•Interferon has been the backbone of therapy for hepatitis C virus (HCV) infection for 20years.•Oral direct-acting antivirals will eventually largely replace interferon-based therapy.•Peginterferon ...may be used in QUAD therapy for prior null responders and patients with multi-DAA resistant HCV.•Peginterferon may also be used to contain costs by limiting the number or duration of antivirals.•With similar efficacy but reduced toxicity, peginterferon lambda may replace peginterferon alpha.
Interferon has been the backbone of therapy for hepatitis C virus (HCV) infection for over 20years. Initial response rates were poor, however they have slowly but steadily improved, such that with the addition of the nucleotide analogue ribavirin and the pegylation of interferon, over 50% of infected individuals could be cured with a course of therapy. However, interferon therapy is not ideal, requiring up to a year of weekly injections and associated with numerous systemic side effects. Advances in understanding of the HCV lifecycle have led to the development of numerous highly effective, well-tolerated oral direct acting antivirals (DAAs). Although the first DAAs were combined with peginterferon and ribavirin, with the rapid progress in the field, it is likely that interferon-free therapy will be available for most patients in the relatively near future. In the short term, peginterferon will be required with either the protease inhibitor simeprevir, or the nucleotide analogue polymerase inhibitor, sofosbuvir, for the treatment of genotype 1 infection. Peginterferon also appears to be a useful adjunct to sofosbuvir and ribavirin for patients with genotype 3 infection, particularly those with cirrhosis. In the future, once combination DAA therapies are available, peginterferon will serve a smaller and smaller role. Peginterferon may be useful as part of QUAD therapy with 2 DAAs and ribavirin in prior null responders or in patients who fail DAA regimens with multi-drug resistant HCV. Peginterferon may also have a role in resource-limited regions to reduce the number and/or duration of DAAs required. Ultimately, although peginterferon will remain a salvage therapy, its days as a mainstay of therapy are definitely numbered.
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide ...clinical trials aiming to ‘cure’ HBV. Agreement among the conference participants was reached on some key points. ‘Functional’ but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV ‘functional cure’, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
Abstract Background & Aims Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) following 12 weeks of treatment with the nucleotide polymerase ...inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). Methods In 2 phase 3, open-label trials, patients with HCV infection who had not previously been treated with a direct-acting antiviral agent were randomly assigned to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the non-inferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a non-inferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups to a performance goal of 83%. Results In POLARIS-2, 95% (95% CI, 93%–97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish non-inferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%–99%; difference in the stratum-adjusted Mantel-Haenszel proportions of 3.4%; 95% CI, –6.2% to –0.6%). The difference in the efficacy was primarily due to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%–99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportions of patients who discontinued treatment owing to adverse events were low (0–1%). Conclusions In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was non-inferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800 and POLARIS-3, NCT02639338
There has been a major focus on the clinical translation of emerging technologies for diagnosing patients with infectious diseases, cancer, heart disease, and diabetes. However, most developments ...still remain at the academic stage where researchers use spiked target molecules to demonstrate the utility of a technology and assess the analytical performance. This approach does not account for the biological complexities and variabilities of human patient samples. As a technology matures and potentially becomes clinically viable, one important intermediate step in the translation process is to conduct a full clinical validation of the technology using a large number of patient samples. Here, we present a full detailed clinical validation of Quantum Dot (QD) barcode technology for diagnosing patients infected with Hepatitis B Virus (HBV). We further demonstrate that the detection of multiple regions of the viral genome using multiplexed QD barcodes improved clinical sensitivity from 54.9-66.7% to 80.4-90.5%, and describe how to use QD barcodes for optimal clinical diagnosis of patients. The use of QDs in biology and medicine was first introduced in 1998 but has not reached clinical care. This study describes our long-term systematic development strategy to advance QD technology to a clinically feasible product for diagnosing patients. Our "blueprint" for translating the QD barcode research concept could be adapted for other nanotechnologies, to efficiently advance diagnostic techniques discovered in the academic laboratory to patient care.
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