Treatment Of Chronic Hepatitis C Virus Infection Research Articles

PP87 Glecaprevir/pibrentasvir (Maviret®) Remains A Cost-effective Treatment For Chronic Hepatitis C Virus Infection After Changes To The Treated Population

IntroductionThe first direct-acting antiviral (DAA) therapies for chronic Hepatitis C virus (HCV) infection were reimbursed via Australia’s Pharmaceutical Benefits Scheme (PBS) in March 2016. This was based on the recommendation from the Pharmaceutical Benefits Advisory Committee (PBAC) that the regimens would be acceptably cost-effective at an incremental cost-effectiveness ratio (ICER) of AUD15,000/quality-adjusted life-year (QALY). Broad access to DAA therapies has been a key strategy in driving a national health goal to eliminate viral hepatitis as a major health threat by 2030. Since the initial PBS listings for DAA therapies and subsequent listings of newer DAA treatments such as Maviret, the demographics and disease characteristics of currently treated patients have markedly changed. The aim of our analysis was to reassess the cost-effectiveness of Maviret, accounting for the changes of the treated population characteristics and retreatment in first-line failures and reinfected individuals.MethodsTo assess the cost-effectiveness six years after initial listing of Maviret, an update was made to the Markov model used to achieve PBS reimbursement for Viekira-Pak® in May 2016. Amendments to the Viekira-Pak model include: changes to baseline age and fibrosis distribution of treated patients, and incorporation of retreatment of first-line failures (those not achieving a sustained virologic response (SVR)) and reinfected individuals. Treatment-related inputs including SVR response rates, adverse events, treatment-related disutility and discontinuations were sourced from pivotal glecaprevir/pibrentasvir clinical trials.ResultsUsing the published price of Maviret, the ICER is above AUD15,000/QALY but well below the commonly used ICER threshold in other chronic diseases (AUD45,000/QALY). When the confidential effective price is used, the ICER is under the AUD15,000/QALY cost-effectiveness threshold set by the PBAC for DAA therapies.ConclusionsDespite substantial changes to the population seeking treatment in Australia since reimbursement in 2016, Maviret remains a cost-effective treatment for chronic HCV infection.

Alfosbuvir plus Daclatasvir for Treatment of Chronic Hepatitis C Virus Infection in China.

A pan-genotypic and effective treatment regimen for patients with chronic hepatitis C virus (HCV) infection remains an unmet medical need in China. Alfosbuvir is a novel potent HCV NS5B polymerase inhibitor in development for the treatment of chronic HCV infection. We conducted a phase 3 study to evaluate the efficacy and safety of alfosbuvir in combination with daclatasvir in Chinese patients with HCV infection. All patients received 600mg alfosbuvir tablets plus 60mg daclatasvir tablets once daily for 12weeks. The primary endpoint was sustained virological response 12weeks after the end of treatment (SVR12). A follow-up visit was done at week 4 and 12, and those who achieved SVR12 were followed up at post-treatment week 24. Of the 326 patients who received at least one dose of the study drug, 320 (98.2% [95% confidence interval (CI): 96.5%-99.5%]) achieved sustained virological response at post-treatment week 12 (SVR12), which was superior to the historical SVR12 rate of 88% (p < 0.0001). The SVR12 rates were similar regardless of most baseline characteristics. The most common adverse event (AE) (≥ 10%) was hypercholesterolemia. Serious adverse events (SAEs) were reported in 25 (7.7%) patients, none of which was judged to be related to the study drug. The majority of AEs were mild to moderate in severity. Alfosbuvir plus daclatasvir for 12weeks was highly effective and safe in Chinese patients infected with HCV genotype 1, 2, 3, or 6, suggesting that this regimen could be a promising option for HCV treatment in China irrespective of genotype. ClinicalTrial.gov identifier, NCT04070235.

The results of real-world practice with glecaprevir/pibrentasvir for the treatment of chronic hepatitis C virus infection genotypes 1 and 3 in adolescents aged 12 to 17 years in the Moscow region

Rationale: The first direct anti-viral agents (DAVA) for the treatment of adolescents with chronic hepatitis C virus (HCV) infection have been approved quite recently, i. e. in 2017 worldwide and in 2019 in Russia. Currently, only few adolescents are treated worldwide, their proportion in the Russian Federation not exceeding 9 to 15%. The results of real-world practice with various DAVA regiments in adolescents aged 12 to 17 years could be useful to choose the strategies for local healthcare bodies.&#x0D; Aim: To evaluate the efficacy and safety of the fixed combination of glecaprevir and pibrentasvir (GLE/PIB) in adolescents aged 12 to 17 years with HCV infection genotypes (GT) 1 and 3 in the Moscow region.&#x0D; Materials and methods: We retrospectively analyzed the results of treatment of 32 adolescents (gender ratio 1:1) who were treated for HCV infection (GT1, 49.9% of the cases, GT3, 53.1%; F1 fibrosis according to the METAVIR scale, 37.5% of the patients, F2, 9.4%) with GLE/PIB during 2019 to 2022 within the Program of State-guaranteed free medical care to the citizens of the Moscow region. The treatment course lasted for 8 weeks in 31 treatment-nave patients and 16 weeks in one patient who had failed on interferon treatment. The information was extracted from medical files of the patients treated on the outpatient basis and from discharge letters from the day care unit. Concomitant diseases were diagnosed in 75% of the adolescents.&#x0D; Results: At week 4 of GLE/PIB treatment, HCV RNA was undetectable in 90.6% (95% confidence interval (CI) 75.098.0) of the patients, and alanine aminotransferase activity reached the reference interval in all patients (100%). The rate of sustained viral response at 12 week of therapy was 96.9% (95% CI 83.899.9), including 100% (95% CI 78.2100) in the GT1 patients and 94.1% (95% CI 71.399.9) in the GT3 patients. At week 24 after the GLE/PIB treatment had been finished, the rate of liver fibrosis according to METAVIR decreased from 46.9% to 12.5% (p 0.001). The lack of response to GLE/PIB in one patient with GT1 HCV appeared to be due to missed doses of the drug. GLE/PIB-related adverse events (headache, fatigue, nausea, and diarrhea) were rare and were recorded in 9.4% (95% CI 1.925.0) of the patients, whereas unrelated adverse events (acute respiratory infection symptoms) in 15.6% (95% CI 5.332.8) of the patients. All adverse events were mild, occurred at 23 weeks of the treatment and did not require additional pharmacological intervention.&#x0D; Conclusion: The results obtained indicate a high efficacy and safety profile of GLE/PIB for the treatment of chronic HCV infection in adolescents aged 12 to 17 years. They can be used by local healthcare authorities to choose the treatment regimens effective for all genotypes and most suitable for children.

Hepatitis C Guidance 2023 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection.

The Infectious Diseases Society of America and the American Association for the Study of Liver Diseases have collaboratively developed evidence-based guidance regarding the diagnosis, management, and treatment of hepatitis C virus (HCV) infection since 2013. A panel of clinicians and investigators with extensive infectious diseases or hepatology expertise specific to HCV infection periodically review evidence from the field and update existing recommendations or introduce new recommendations as evidence warrants. This update focuses on changes to the guidance since the previous 2020 published update, including ongoing emphasis on recommended universal screening; management recommendations for incomplete treatment adherence; expanded eligibility for simplified chronic HCV infection treatment in adults with minimal monitoring; updated treatment and retreatment recommendations for children as young as 3 years old; management and treatment recommendations in the transplantation setting; and screening, treatment, and management recommendations for unique and key populations.

Safety and efficacy of sofosbuvir-velpatasvir: A meta-analysis.

Introduction:The sofosbuvir-velpatasvir single-tablet regimen (Epclusa) is a newly FDA-approved inhibitor of hepatitis C virus (HCV). This meta-analysis aimed to investigate the safety and efficacy of velpatasvir-sofosbuvir in the treatment of chronic HCV infection.Methods:A comprehensive literature search of PubMed, Cochrane CENTRAL, EMBASE and Web of Science was conducted. Data from eligible studies were pooled in a fixed-effect meta-analysis model, using Open-Meta and RevMan software’s.Results:Pooled data showed that velpatasvir-sofosbuvir achieved sustained virological response (SVR12) rates of 94.2% (95% CI 90.7–97.7%, P < .001) in 1277 patients. The addition of ribavirin did not significantly increase the SVR12 (RR = 1.03, 95%CI [0.95, 1.11]) in HCV genotype-1 patients and the SVR12 (RR = 1.09, 95%CI [0.86, 1.38]) in HCV genotype-2 patients. However, adding ribavirin significantly increased SVR12 (RR = 1.13, 95% CI [1.04, 1.23]) in genotype-3 patients.Conclusion:In conclusion, the 12-week regimen of sofosbuvir-velpatasvir was highly effective in HCV patients. Except for genotype-3, adding ribavirin was not associated with significant improvements in SVR12 rates.

POS-090 A STUDY ON CLINICAL PROFILE OF PATIENTS WITH ESRD V D WITH HEPATITIS C INFECTION AND THEIR RESPONSE TO TREATMENT WITH DIRECTLY ACTING ANTIVIRAL AGENTS

Hepatitis C virus (HCV) infection is one of the most common viral infections affecting the patients on maintenance hemodialysis (MHD). Nosocomial transmission of infection and multiple transfusions during HD appears to be the primary reason for this increased prevalence. Treatment of chronic HCV infection in advanced CKD includes a combination of Elbasvir/ Grazoprevir, Glecaprevir/ Pibrentasvir, Dasabuvir/ Ombitasvir and Paritaprevir/ Ritonavir which are not available in many countries including India.

Efficacy and safety of sofosbuvir/velpatasvir with or without ribavirin in hepatitis C genotype 3 compensated cirrhosis: A meta-analysis

BACKGROUNDHepatitis C virus (HCV) is a leading cause of liver cirrhosis and hepatocellular carcinoma globally. Sofosbuvir/velpatasvir (SOF/VEL) is an effective pan-genotypic direct-acting antiviral combination for treatment of chronic HCV infection. While the addition of ribavirin (RBV) to SOF/VEL improved sustained virological response (SVR12) in genotype 3 (GT3) decompensated cirrhosis patients, the benefits of RBV in GT3 compensated cirrhosis patients receiving SOF/VEL remains unclear. AIMTo evaluate the efficacy and safety of SOF/VEL, with or without RBV in GT3 compensated cirrhosis patients. METHODSWe searched four electronic databases (PubMed/Medline, Embase, Cochrane Library and Web of Science) from inception up to June 2021 using both free text and MeSH terms. There was no restriction on language, geography, publication dates and publication status (full text or abstracts). All GT3 compensated cirrhosis patients treated with 12 wk of SOF/VEL, with or without RBV, were included, regardless of age, gender or prior treatment experience. The primary outcome was sustained virological response 12-wk post-treatment (SVR12). The secondary outcome was treatment-related adverse events, as defined by symptomatic anemia requiring transfusion or a drop in hemoglobin beyond 2 g/dL. The pooled relative risk (RR), 95%CI and heterogeneity (I2) were estimated using Review Manager version 5.3.RESULTSFrom 1752 citations, a total of seven studies (2 randomized controlled trials, 5 cohort studies) with 1088 subjects were identified. The SVR12 was similar in GT3 compensated cirrhosis patients, regardless of the use of RBV, for both the intention-to-treat RR 1.03, 95%CI: 0.99-1.07; I2 = 0%) and the per-protocol analysis (RR: 1.03, 95%CI: 0.99-1.07; I2 = 48%). The overall pooled rate of treatment-related adverse events was 7.2%. Addition of RBV increased the pooled risk of treatment-related adverse events in GT3 compensated cirrhosis patients receiving SOF/VEL (RR: 4.20, 95%CI: 1.29-13.68; I2 = 0%). Subgroup analysis showed that RBV was associated with a higher SVR12 in GT3 compensated cirrhosis patients with baseline resistance-associated substitutions. However, addition of RBV did not significantly increase the SVR12 among treatment-experienced GT3 compensated cirrhosis patients. CONCLUSIONRibavirin was not associated with higher SVR12 in GT3 compensated cirrhosis patients receiving SOF/VEL. Our findings suggest a limited role for RBV as routine add-on therapy to SOF/VEL in GT3 compensated cirrhosis patients.

Key Role of Multidisciplinary Collaboration towards Global Elimination of HCV Infection.

The elimination of HCV (hepatitis C virus) infection is, according to WHO (World Health Organization), of international interest. With new diagnostic tools and treatment possibilities, one major challenge for the elimination is to involve infected patients, especially those from socially excluded subpopulations, into HCV infection-treatment programs. The key question is how to help people who inject drugs (PWID) to engage in HCV infection-treatment programs and improve communication between PWID and hepatologists or other medical professionals involved in the treatment of chronic HCV infection. Furthermore, the medical professionals have to accept the changing spectrum of patients with chronic viral hepatitis. Without close interdisciplinary cooperation, it would be extremely difficult to achieve the WHO goal of global viral hepatitis C elimination. Here, we try to encourage our colleagues as well as addictologists and social workers to play their crucial part in the viral hepatitis C eradication process. It is extremely important for the healthcare providers to be able to communicate with addicted clients, inform PWID about the latest developments in the diagnosis and HCV infection treatment, and get them motivated to engage with specialized treatment programs.

Efficacy and Safety of Sofosbuvir and Velpatasvir Combination for the Treatment of Chronic Hepatitis C in Patients With or Without Cirrhosis.

Background and aimFor years, interferon-based treatment has been offered to patients with chronic hepatitis C virus (HCV) infection; however, the complexity of the treatment, efficacy, and adverse effects were the primary concerns. All these concerns were addressed with the introduction of directly acting antivirals (DAAs) to treat chronic HCV. Sofosbuvir and velpatasvir are second-generation DAAs used in combination for the treatment of chronic HCV infection. The aim of our study was to determine and compare the efficacy and safety profile of the sofosbuvir and velpatasvir combination in treating patients with chronic hepatitis C with or without cirrhosis.Materials and methodsThis descriptive study was conducted at the Department of Medicine, Khyber Teaching Hospital, Peshawar, from March 15th to September 15th, 2021 after approval from the Institution Research and Ethical Review Board (IREB). Diagnosis of HCV was based on the detection of hepatitis C ribonucleic acid (RNA) fragments by reverse transcription-polymerase chain reaction (RT-PCR). Liver status was assessed with liver function tests and imaging. Sofosbuvir (400 mg) and velpatasvir (100 mg) were administered once daily for 12 weeks, followed by polymerase chain reaction (PCR) for HCV RNA after 12 weeks of completion of treatment for determination of sustained virologic response at 12 weeks (SVR12). Patients with cirrhosis also received weight-based ribavirin. Adverse events experienced by the study participants during the course of treatment were recorded. Data were collected regarding patients' demographics, laboratory parameters, SVR12, and adverse events, and were then analyzed using SPSS, version 22 (IBM SPSS Statistics, Armonk, NY).ResultsA total of 58 patients with cirrhosis and 58 patients without cirrhosis with chronic HCV were enrolled. The rate of SVR12 in patients with cirrhosis was 89.7% (52 patients achieved SVR12), compared to 98.3% in patients without cirrhosis (57 patients achieved SVR12). Subgroup analysis of patients with cirrhosis revealed that patients who have failed to achieve SVR12 were mostly males, had prolonged disease duration, and low hemoglobin at baseline; however, the association of these factors with SVR12 was not significant. The incidence of adverse events among all study participants was 46.5%. Among the cirrhotic cohort, 37 (63.8%) patients experienced adverse events, while only 17 (29.3%) patients among the non-cirrhotic cohort had adverse events. A total of 24 patients with cirrhosis (41.37%) reported mild complaints. The most commonly reported adverse event was gastrointestinal (GI) upsets (46.2%), followed by fatigue (33.9%), while 19.9% developed miscellaneous adverse events such as headaches, rash, and insomnia.ConclusionThe combination of sofosbuvir and velpatasvir is highly effective and safe in patients with HCV with or without cirrhosis. However, this combination's efficacy was slightly higher in non-cirrhotic patients (98.3%) than in cirrhotic patients (89.7%).

Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV).

The standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID. INTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals. Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment. Integrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV. ClinicalTrials.gov.no NCT03155906.

Evaluation of the Renal Safety of Direct Acting Antivirals in Chronic Hepatitis C Patients

Objective:Direct acting antivirals (DAA) is a class of antivirals that hasbeen extensively used in chronic hepatitis C virus (HCV) patients over the past 6 years.Despite the excellent therapeutic benefits of DAA, there is a knowledge gap regardingthe safety of this class. Several reports of possible renal toxicity associated with DAAadministration can be found in the literature. The aims of this study are: to assess therenal safety of DAA used for the treatment of chronic HCV infection and to quantify the odds ofdeveloping renaltoxicityin patients withchronicHCV viralinfection.&#x0D; Study Design: Disproportionalityanalysiswasusedtodetectsignalsofpotentialsideeffects.&#x0D; Place andDuration: Amman –Jordan,One year study since September 2017 to march 2018.&#x0D; Methods: The method that was applied in the current study is obtaining the data from United States (US) food and drug administration(FDA)adverseeventreportingsystem(FAERS).DatabetweenJuly,2014andSeptember,2017werecombinedandexplored.Disproportionalityanalysiswasconducted to reports from chronic HCV patients to explore possible association betweenDAA administrationand renalsideeffects.&#x0D; Results: This study showed that a total of 3,837,418 safety reports were available in the period between July,2014 and September, 2017. Patients with chronic HCV infection represent 22,022 cases.When considering all DAA as drug of interest, the use of DAA alone or in combinationwith interferon and/or ribavirin did not increase the risk of having renal side effects.Exploring individual DAA demonstrated a significant association between the incidenceofrenalsideeffectsandtheadministrationoftelapreviranddasabuvir.ConsideringrenalsideeffectsindividuallyshowedasignificantassociationbetweenDAAadministrationand chronickidney disease.&#x0D; Conclusions: In this study, we reported a significant association between DAA administration andchronic kidney disease and between telaprevir or dasabuvir and renal side effect. Thesefindings are used for hypothesis generation rather than testing.

Spontaneous Clearance After Relapse Following Direct-Acting Antiviral Treatment for Chronic HCV Infection

Direct-acting antivirals (DAAs) cure most cases of chronic hepatitis C virus (HCV) infection. However, a small percentage of patients relapse with reappearance of viremia after a full course of therapy. Although most who relapse require retreatment, some patients spontaneously clear HCV without additional therapy. We studied patients who relapsed with detectable HCV RNA after a full course of DAA therapy and then spontaneously cleared the HCV infection without retreatment. We performed a case-control study of patients who spontaneously cleared chronic HCV infection following a documented relapse after DAA therapy at the Toronto Centre for Liver Disease, from January 2014 through December 2017. We collected clinical information at baseline, 12 weeks after treatment, and 6 months after relapse and compared data among spontaneous clearers, patients with persistent relapse, and patients who achieved a sustained virologic response to therapy 12 weeks after treatment (SVR12). The strength and breadth of interferon gamma cytokine secretion by HCV-specific T cells from peripheral blood were quantified using the ELISPOT assay. Of the 1032 individuals with chronic HCV infection who were treated with DAAs, 93 patients had a documented relapse. Of these patients, 12 patients (13%) spontaneously cleared HCV within 6 months after the documented relapse without additional therapy. The spontaneous clearers had low levels of HCV RNA (<4 log IU/mL in 11 of 12) and normal levels of alanine aminotransferase at the time of relapse, much like patients with an SVR12. There was no significant difference between the spontaneous clearance group and the SVR12 group in magnitude and breadth of HCV-specific T cell responses. In a case-control study of patients who spontaneously cleared chronic HCV infection following a relapse after DAA therapy, we found that it is important to confirm viremia prior to retreatment after the relapse-particularly for individuals with low levels of HCV RNA and normal or near-normal levels of alanine aminotransferase after treatment.

COMBINED NS5A & NS5B NUCLEOTIDE INHIBITOR THERAPY FOR PATIENTS WITH CHRONIC HEPATITIS C WITH STAGE 5 CHRONIC KIDNEY DISEASE ON HEMODIALYSIS.

Hepatitis C virus (HCV) infection is the most common hepatotropic viral infection affecting the patients on maintenance hemodialysis. Treatment of chronic HCV infection in stage 4 and 5 CKD includes a combination of elbasvir/grazoprevir and glecaprevir/pibrentasvir, which are not available in many countries. Hence, we have conducted this study to look for the safety and efficacy of sofosbuvir combination therapy in this difficult to treat population. We conducted a single-center, prospective, open-label study in which Stage 5 CKD patients on maintenance hemodialysis with HCV infection. Total of 18 patients was included. sofosbuvir with daclatasvir or ledipasvir was used according to genotype for 12 weeks. HCV RNA, genotype, transient elastography (TE) was considered for every patient. HCV RNA was quantified at 4th week, 12th week and 12 weeks post-treatment to look for sustained virologic response (SVR 12). Infection due to genotype 1 was seen in 12 (66.7%) patients followed by genotype 3 in 4 (22.3%) with each patient of genotype 2 and 5. The median value of HCV RNA was 2,35,000 IU/mL. On TE, all had liver stiffness of <9.4 KPa. All patients had HCV RNA of <15 IU/mL at 4th and 12th week of treatment and 12 weeks post-treatment. No significant change in hemoglobin, eGFR and liver stiffness was observed. Full dose sofosbuvir i.e. 400 mg, in combination with NS5A inhibitors daclatasvir or ledipasvir is found to be safe and effective in patients with end stage renal disease, who are on maintenance hemodialysis.

USE OF NEW HEPATITIS C DRUGS IN MEDICARE: PERSISTENT URBAN-RURAL DISPARITIES AND POTENTIAL INTERVENTIONS

Chronic hepatitis C virus (HCV) infection, whose prevalence is concentrated among older adults, can bring serious health impacts and high financial burden. With the availability of highly effective and well tolerated direct-acting antiviral (DAA) therapy, treatment of chronic HCV infection has rapidly evolved, making HCV treatment less burdensome. However, the high cost of DAA and lack of clinical expertise are still important barriers for providing DAA therapy to rural patients, highlighting the urban-rural disparities in managing many chronic diseases for aging populations. Telehealth could serve as effective care-model to improve management of HCV infection for older, rural populations. This talk will present work that examines multi-level factors affecting HCV DAA treatment (focusing on urban-rural disparities), evaluates changes in urban-rural disparities in DAA utilization over time, and explores the role of a telehealth-based intervention in reducing urban-rural disparities in HCV DAA treatment in Medicare patients.

RESOLUTION OF HEPATOPULMONARY SYNDROME WITH SUCCESSFUL TREATMENT OF CHRONIC HEPATITIS C INFECTION

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Hepatopulmonary syndrome (HPS) is a serious complication of liver disease where pulmonary vasculature dilates causing hypoxia and dyspnea. The following case describes a patient had reversal of their HPS after successful treatment of their chronic hepatitis C virus (HCV) infection. CASE PRESENTATION: A 49-year-old female presented to the St. Paul Hospital in Saskatoon, Canada for hypoxemia. Her past medical history includes untreated human immunodeficiency virus (HIV) and HCV genotype 3 with associated cirrhosis. At presentation, the patient had a SpO2 of 78% on room air which improved to 88% with administration of 5L supplemental oxygen. HPS was suspected and a thoracic CT was performed which demonstrated enlargement of the pulmonary arterioles in the lower lung zones. The diagnosis of HPS was confirmed with a contrast echo demonstrating bubbles in the left atrium after approximately 4 cardiac cycles suggesting a large shunt. For symptomatic management , the patient was started on 4L of home O2 and referred to infectious diseases for management of the patients HIV and HCV. The patient was started immediately on emtricitabine, tenofovir alafenamide and dolutegravir for her HIV, developing undetectable viral loads and a CD4 count of 80 within 3 months of treatment. For her HCV, the patient was later started on a 12-week course of sofosbuvir, velpatasvir and ribavarin, which was confirmed to have eliminated her HCV infection at 24 weeks post-treatment. Following eradication of the patients HCV infection, the patient's hypoxia had also resolved with a measured SpO2 of 94% on room air. A follow-up contrast echo demonstrated few bubbles in the left atrium following 10 cardiac cycles, therefore suggesting successful treatment of HPS. DISCUSSION: HPS is characterized by hypoxia secondary to intrapulmonary vascular dilatations which cause an apparent right to left intrapulmonary shunt1. The syndrome leads to progressive hypoxemia and significant morbidity. There is currently no effective medical therapy for HPS, and liver transplantation is the only definitive treatment available2,3. Globally HCV infection is a major contributor to chronic liver disease, and therefore HPS. There has also been evidence of HPS occurring in non-cirrhotic patients with chronic viral hepatitis 4. With the introduction of direct-acting antivirals (DAAs), treatment of HCV has become more efficacious and well tolerated. The potential for successful treatment with DAAs to resolve HPS could lead to significant medical advances for the treatment of HPS. CONCLUSIONS: In conclusion this case report describes the successful reversal of HPS following the treatment of chronic HCV infection. These findings suggests that further research may discover a role for the use of DAAs in treatment of HPS. Reference #1: Grilo-Bensusan, I., & Pascasio-Acevedo, J. M. (2016). Hepatopulmonary syndrome: What we know and what we would like to know. World journal of gastroenterology, 22(25), 5728. Reference #2: Gupta, S., et al. (2010). Improved survival after liver transplantation in patients with hepatopulmonary syndrome. American Journal of Transplantation, 10(2), 354-363. Reference #3: Tzovaras, N., et al. (2006). Reversion of severe hepatopulmonary syndrome in a non cirrhotic patient after corticosteroid treatment for granulomatous hepatitis: a case report and review of the literature. World journal of gastroenterology: WJG, 12(2), 336. DISCLOSURES: No relevant relationships by Adam Bloom, source=Web Response Advisory Committee Member relationship with Gilead Please note: $1001 - $5000 Added 03/23/2019 by Kris Stewart, source=Web Response, value=Consulting fee Speaker/Speaker's Bureau relationship with Gilead Please note: $1001 - $5000 Added 03/23/2019 by Kris Stewart, source=Web Response, value=Honoraria Grant relationship with Gilead Please note: $20001 - $100000 Added 03/23/2019 by Kris Stewart, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Abbvie Please note: $1001 - $5000 Added 03/23/2019 by Kris Stewart, source=Web Response, value=Consulting fee grant relationship with Abbvie Please note: $5001 - $20000 Added 03/23/2019 by Kris Stewart, source=Web Response, value=Grant/Research Support Grant relationship with Viiv Please note: $1001 - $5000 Added 03/23/2019 by Kris Stewart, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Merck Please note: $1001 - $5000 Added 03/23/2019 by Kris Stewart, source=Web Response, value=Consulting fee Grant relationship with Merck Please note: $5001 - $20000 Added 03/23/2019 by Kris Stewart, source=Web Response, value=Grant/Research Support No relevant relationships by Chung Chun Tyan, source=Web Response

Frequency of baseline NS5A resistance-associated substitutions in patients infected with genotype 1 of hepatitis C virus in Croatia

The backbone of current treatment for chronic Hepatitis C virus (HCV) infection are direct-acting antivirals targeting viral nonstructural proteins (NS3, NS4A, NS5A, NS5B). To date, there are six NS5A inhibitors approved for treatment of chronic HCV infection. The presence of drug-associated resistance substitutions is mainly due to fast error-prone replication, showing differential frequency between genotypes and subtypes. The aim of this study was to determine the frequency of baseline resistance to NS5A protein inhibitors in patients with genotype 1 HCV in Croatia. Resistance-associated substitutions (RAS) were detected by Sanger sequencing of HCV NS5A region amplified from 84 patients followed by phylogenetic analysis and analysis with Geno2Pheno algorithm. The frequency of NS5A RAS was 14.3% and highly dependent on viral subtype. The overall frequency of NS5A RAS was higher in patients infected with HCV subtype 1b (24.2%) than in those infected with HCV subtype 1a (7.8%). Overall, three resistance-conferring mutations were detected (Q30R, M28T and Y93H) along with two mutations (M28V and L31I) that cause reduced susceptibility to NS5A inhibitors. Analysis of the sequences showed two distinct subtype 1a clades with RAS detected in 4.3% (1/23) clade I and 10.7% (3/28) clade II sequences. Only a few distinct NS5A RAS were detected suggesting a high degree of homogeneity of the viral population. High frequency of clinically relevant NS5A RAS in Croatia suggest that the analysis of frequency and patterns of resistance mutations in local populations and evaluation of their possible clinical impact could be beneficial.

Viral Hepatitis C Therapy: Pharmacokinetic and Pharmacodynamic Considerations: A 2019 Update.

It has been estimated by the World Health Organization (WHO) that over 71 million people were infected with the hepatitis C virus (HCV) in 2015. Since then, a number of highly effective direct-acting antiviral (DAA) regimens have been licensed for the treatment of chronic HCV infection: sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, elbasvir/grazoprevir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir. With these treatment regimens, almost all chronic HCV-infected patients, even including prior DAA failures, can be treated effectively and safely. It is therefore likely that further development of DAAs will be limited. In this descriptive review we provide an overview of the clinical pharmacokinetic characteristics of currently available DAAs by describing their absorption, distribution, metabolism, and excretion. Potential drug–drug interactions with the DAAs are briefly discussed. Furthermore, we summarize what is known about the pharmacodynamics of the DAAs in terms of efficacy and safety. We briefly discuss the relationship between the pharmacokinetics of the DAAs and efficacy or toxicity in special populations, such as hard to cure patients and patients with liver cirrhosis, liver transplantation, renal impairment, hepatitis B virus or HIV co-infection, bleeding disorders, and children. The aim of this overview is to educate/update prescribers and pharmacists so that they are able to safely and effectively treat HCV-infected patients even in the presence of underlying co-infections or co-morbidities.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00774-0) contains supplementary material, which is available to authorized users.

Observed Changes in Natural Killer and T cell Phenotypes with Evaluation of Immune Outcome in a Longitudinal Cohort Following Sofosbuvir-Based Therapy for Chronic Hepatitis C Infection.

BackgroundChronic hepatitis C virus (HCV) infection diminishes immune function through cell exhaustion and repertoire alteration. Direct acting antiviral (DAA)-based therapy can restore immune cell subset function and reduce exhaustion states. However, the extent of immune modulation following DAA-based therapy and the role that clinical and demographic factors play remain unknown.MethodsWe examined natural killer (NK) cell, CD4+, and CD8+ T cell subsets along with activation and exhaustion phenotypes across an observational study of sofosbuvir-based treatment for chronic HCV infection. Additionally, we examined the ability of clinical variables and duration of infection to predict 12 weeks of sustained virologic response (SVR12) immune marker outcomes.ResultsWe show that sofosbuvir-based therapy restores NK cell subset distributions and reduces chronic activation by SVR12. Likewise, T cell subsets, including HCV-specific CD8+ T cells, show reductions in chronic exhaustion markers by SVR12. Immunosuppressive CD4+ regulatory T cells decrease at 4-weeks treatment and SVR12. We observe the magnitude and direction of change in immune marker values from pretreatment to SVR12 varies greatly among participants. Although we observed associations between the estimated date of infection, HCV diagnosis date, and extent of immune marker outcome at SVR12, our regression analyses did not indicate any factors as strong SVR12 outcome predictors.ConclusionOur study lends further evidence of immune changes following sofosbuvir-based therapy. Further investigation beyond SVR12 and into factors that may predict posttreatment outcome is warranted.

Ceruloplasmin as a Predictor for Responsiveness to Direct Antiviral Drugs in Treatment of Chronic HCV Infection

Background: Hepatitis C virus (HCV) is one of the major globally cause of death and morbidity. The appearance of direct-acting antiviral agents (DAAs), which specifically target HCV proteins, has provided insights into the current situation Ceruloplasmin (Cp), where its serum levels tend to be high in myocardial infarction, neoplastic and inflammatory conditions. Objective: The aim of the current work was to evaluate the prognostic value of serum ceruloplasmin in chronic hepatitis C before and after treatment by direct-acting antiviral agents and possibility of using it as a marker for hepatitis C virus treatment response. Patients and methods: This intervention prospective study was conducted on one hundred subjects attending at the Hepatology Clinic at the Hepatology Clinic at Algalaa Military Hospital and Kopri Elkopa Military Hospital and Al-Hussein university Hospital, from December 2016 till June 2017. The associations between serum Ceruloplasmin levels in chronic HCV patients before receiving DAAS and three months after was investigated. Results: showed that serum Ceruloplasmin levels were slightly higher after receiving DAAS and so it can be used as a marker for responsiveness to direct acting antiviral drugs. Conclusion: It could be concluded that ceruloplasmin can be used as a marker for responsiveness to direct acting antiviral drugs

Induction of HCV-specific cell response in vitro by dendritic cells generated with interferon-α

The induction of a strong multi-epitope T-cell response against hepatitis C virus (HCV) plays an important role in eliminating the virus, whereas adoptive response deficiency contributes to chronic and rapid progression of HCV-infection. Since dendritic cells (DCs) are capable of priming naive T lymphocytes and induce an effective immune response, the use of DC-based vaccines to enhance the HCV-specific T cell response is considered as a new approach to treatment of chronic hepatitis C (CHC). The ability of DCs generated from monocytes in the presence of interferon- and loaded with recombinant HCV proteins Core (1120) and NS3 (11921457) to induce an antigen-specific cellular response in healthy donors and patients with CHC was investigated. The immune response was assessed by proliferative activity and Th1 (IFN)/Th2 (IL-4, IL-6) production in mononuclear cells (MNC) cultures, and activation of cytotoxic T-lymphocytes in the degranulation test. We demonstrated that the primary antigen-specific response in MNC cultures of seronegative donors was detected better by stimulation of DCs, loaded with both antigens (DCCore /NS3) than when loaded with a single protein. DCCore/NS3 induced the proliferative response and degranulation of CD8+ T cells in MNC cultures of all tested donors, and in 50% (5/10) cases IFN production. Similarly to donor DCs, DCCore/NS3 of patients with CHC induced a proliferative response in most cases (86%) and IFN production in 57% cases. At the same time, the activation of cytotoxic T cells in patients was less frequent (patients vs donors 57 and 100%, respectively), which could be partly due to increased spontaneous degranulation of CD8+ T cells in some patients. The obtained data testify the possibility of using vaccines based on interferon--induced DCs for the prevention and treatment of chronic HCV infection.