Use Of Direct-acting Antivirals Research Articles

The Beginning of Ending Hepatitis C Virus: A Summary of the 26th International Symposium on Hepatitis C Virus and Related Viruses.

Hepatitis C virus (HCV) infects ~71 million people worldwide, and 399,000 people die annually due to HCV-related liver cirrhosis and hepatocellular carcinoma. The use of direct-acting antivirals results in a sustained virologic response in >95% of patients with chronic HCV infection. However, several issues remain to be solved to eradicate HCV. At the 26th International Symposium on Hepatitis C Virus and Related Viruses (HCV2019) held in Seoul, South Korea, October 5–8, 2019, virologists, immunologists, and clinical scientists discussed these remaining issues and how we can achieve the elimination of HCV.

Possible risk of dysglycaemia with use of direct-acting antivirals

Possible risk of dysglycaemia with use of direct-acting antivirals

Effect of direct-acting antivirals on corrected QT interval and cardiac functions in patients with chronic hepatitis C virus infection

BackgroundHepatitis C virus (HCV) infection is a major public health problem in Egypt. The use of direct-acting antivirals (DAAs) in such patients has been shown to be highly effective. The cardiac safety of such antivirals remains uncertain. This study aimed to assess the effect of the novel DAAs on corrected QT (QTc) interval and on cardiac function using trans-thoracic echocardiography.ResultsThis was a prospective cohort study performed on 100 patients suffering from chronic HCV infection. Patients were into two equal groups according to the presence of liver cirrhosis. The group without liver cirrhosis received a daily combination of sofosbuvir 400 mg and daclatasvir 60 mg for 12 weeks while that with liver cirrhosis (Child-Pugh score A or B) received a daily combination of sofosbuvir 400 mg, daclatasvir 60 mg, and ribavirin 600 mg for 12 weeks. Surface ECG and trans-thoracic echocardiography were performed prior to the start of treatment and after 12 weeks of treatment.At the end of treatment, no changes were observed in QTc interval in those with (p = 0.48) or without (p = 0.048) liver cirrhosis. In patients without liver cirrhosis, right ventricular global longitudinal strain (RV GLS) decreased from 22 (−30 to −17) to −21 (−27–18), p = 0.024. In patients with liver cirrhosis, lateral mitral E’ velocity was reduced from 14.38 ± 3.59 to 13.62 ± 3.21 cm/s, p = 0.02 and indexed left atrial volume (LAVI) was increased from 25.96 ± 3.96 to 26.86 ± 4.12 ml/m2, p = 0.032. There were no changes in both groups regarding left ventricular (LV) dimensions, ejection fraction, trans-mitral E/A ratio, E/E’ ratio, deceleration time, right ventricular (RV) systolic pressure, mean pulmonary artery pressure, RV fractional area change, tricuspid annular plane systolic excursion, and LV GLS.ConclusionThe current national protocol of HCV infection treatment with direct-acting antiviral agents used in Egyptian patients has a good cardiac safety profile. Such treatments have no effect on QTc interval, left and right ventricular functions except for a decrease in RV GLS in those with no liver cirrhosis and a reduction in lateral mitral E’ velocity in those with liver cirrhosis both remained within the normal reference range.

Effect of Recipient Hepatitis C Status on Outcomes of Deceased Donor Kidney Transplantation

Hepatitis C virus (HCV) infection has been deemed detrimental to kidney transplantation (KT) outcomes. Breakthrough HCV treatment with direct-acting antiviral (DAA) medications improved the probability of HCV+ kidney use for KT even in noninfected (HCV-) recipients. We hypothesized that recipient HCV infection influences deceased donor KT outcomes, and this effect could be modified by donor HCV status and use of DAAs. We conducted a retrospective cohort study based on data from the Organ Procurement and Transplantation Network as of September 2018. A mate kidneys analysis was performed with HCV+ and HCV- recipients of solitary adult KT from ABO-compatible deceased donor between January 1994 and June 2018. We selected donors where 1 KT recipient was HCV+ and the mate kidney recipient was HCV-. Both HCV- and HCV+ donors were identified and analyzed separately. Outcomes, including survival of patients, grafts, and death-censored grafts, were compared between the groups. Four-hundred and twenty-five HCV+ and 5,575 HCV- donor mate kidneys were transplanted in HCV-discrepant recipients. HCV+ recipients of HCV- donor had worse patient and graft survival (adjusted hazard ratio 1.28; 95% CI, 1.19 to 1.37 and adjusted hazard ratio 1.26; 95% CI 1.18 to 1.34, respectively) and death-censored grafts (adjusted hazard ratio 1.24; 95% CI, 1.15 to 1.34) compared with HCV- recipients. Comparable patient and graft survival and death-censored grafts were found in recipients of HCV+ donors, regardless of recipient HCV status. The risk associated with HCV positivity in donors or recipients in the pre-DAA era (before December 2013) was no longer statistically significant in the post-DAA era. Given comparable outcomes between HCV+ and HCV- recipients in post-DAA era or when receiving HCV+ donor kidneys, broader use of HCV+ kidneys regardless of the recipient's HCV status should be advocated, and allocation algorithm for HCV+ kidneys should be revised.

Successful Allogenic and Autologous Transplant with Concurrent Usage of Direct-Acting Antivirals for Hepatitis C in Children with Hematological Malignancies

Background Transfusion related hepatitis C(HCV) is rare in the west, in the developing world, it remains a challenge. Children with hematological malignancies are especially vulnerable due to large number of blood components received. They often develop active hepatitis due to immunocompromised status and concurrent hepatic insults from chemotherapy and iron overload. Stem cell transplant(SCT) further increases hepatic risk due to veno-occlusive disease(VOD) and hepatic graft versus host disease(GVHD). Direct acting antivirals(DAA) have revolutionized treatment of HCV. DAAs are currently not approved for children Results We describe allogenic and autologous SCT in two children while on DAA. An 8 year old girl with relapsed AML and baseline viral load(VL) of >10^6 IU/ml (genotype 1b) presented with transaminitis and refractory thrombocytopenia. Sofosbuvir 200mg and velpatasvir 50mg once daily were started with salvage chemotherapy(FLAG-IDA). VL was undetectable after 5 weeks when allogeneic SCT(Cy/Bu) was initiated while continuing DAAs. Neutrophils and platelet engraftment occurred at day + 11 and + 14 respectively. DAAs were continued for 3 months post SCT(until withdrawal of immunosuppression). There was no evidence of VOD or liver GVHD. A 9 year old girl with relapsed lymphoblastic lymphoma, had a baseline VL of >10^6 IU/ml with genotype1b. She was started on the same DAAs and taken for auto SCT(Cy/TBI). G-CSF and plerixafor were used for mobilization and a stem cell dose of 10 × 10^6 cells/ kg was collected. Neutrophils and platelet engraftment occurred on day +10 and day + 16 respectively. No hepatic toxicity was noted. DAAs were continued for 3 months post SCT and VL remained undetectable. Conclusion Use of DAAs is feasible during allogeneic and autologous SCT and does not interfere with mobilization or engraftment. This could decrease the risk of hepatic adverse events during SCT.

Inhibitory Activity of a Scorpion Defensin BmKDfsin3 against Hepatitis C Virus.

Hepatitis C virus (HCV) infection is a major worldwide health problem which can cause chronic hepatitis, liver fibrosis and hepatocellular carcinoma (HCC). There is still no vaccine to prevent HCV infection. Currently, the clinical treatment of HCV infection mainly relies on the use of direct-acting antivirals (DAAs) which are expensive and have side effects. Here, BmKDfsin3, a scorpion defensin from the venom of Mesobuthus martensii Karsch, is found to dose-dependently inhibit HCV infection at noncytotoxic concentrations and affect viral attachment and post-entry in HCV life cycle. Further experimental results show that BmKDfsin3 not only suppresses p38 mitogen-activated protein kinase (MAPK) activation of HCV-infected Huh7.5.1 cells, but also inhibits p38 activation of Huh7.5.1 cells stimulated by tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) or lipopolysaccharide (LPS). BmKDfsin3 is also revealed to enter into cells. Using an upstream MyD88 dimerization inhibitor ST2345 or kinase IRAK-1/4 inhibitor I, the inhibition of p38 activation represses HCV replication in vitro. Taken together, a scorpion defensin BmKDfsin3 inhibits HCV replication, related to regulated p38 MAPK activation.

Complementary and Alternative Medicines for the Treatment of Hepatitis C: Perspectives of Users and CAM Practitioners.

Background Despite substantial progress in the treatment of hepatitis C through the use of direct-acting antivirals which have been shown to cure the disease, complementary and alternative medicines (CAM) are popular among patients as a substitute or complement of allopathic medicines. This study aimed to explore the perspectives of patients and CAM practitioners on the use of CAM for the treatment of hepatitis C in Pakistan. Methods A cross-sectional design was adopted. Participants (CAM practitioners and patients) were recruited from the capital and two provinces: Khyber Pakhtunkhwa and Punjab of Pakistan. A survey using paper-based questionnaires, each specific for patients and CAM practitioners, was conducted to gather information pertaining to demography, disease status, treatment history, and participants' perspectives (about the disease, reasons to switch to CAM, and referring source). Results A total of 417 respondents (n = 284 patients, n = 133 practitioners) were recruited. Of the total patients, 170 (59.9%) had started CAM during the previous three months. There were 168 (59.2%) of the total patients who had used allopathic treatments for hepatitis C prior to their use of CAM. The confidence in CAM (24.6%), high cost (19%), and unbearable side effects (52.1%) of allopathic medicines were the main reasons to switch to CAM treatment. Majority (49.3%) of the patients were referred to CAM on the recommendations of relatives or care givers (17.3%) whereas only 9.5% were referred by health care professionals. Out of 133 practitioners, 48 (36.1%) were practicing herbal medicines. From practitioners' perspectives, club-moss (Lycopodium clavatum) was the best treatment option for hepatitis C. The majority, 73 (54.9%), of the patients had chosen to use CAM because of the side effects of allopathic medicines. Patients who had previous “good experience” with CAM were the most common referral source (56.4%) for CAM use in hepatitis C. Conclusions Patients' beliefs in CAM, side effects of allopathic therapy, high cost of allopathic medicines, and referrals from previous CAM users are key factors in the switching of hepatitis C patients to CAM.

Decreased risk of hepatocellular carcinoma recurrence with direct-acting antivirals compared with no treatment for hepatitis C: a meta-analysis.

BackgroundStudies investigating the association between direct-acting antivirals (DAAs) and the recurrence of hepatocellular carcinoma (HCC) related to hepatitis C (HCV) have yielded conflicting results. The objective of this meta-analysis was to define the short- and long-term recurrence rates of HCC after DAA treatment.MethodsA search of multiple databases was performed, including Scopus, Cochrane, MEDLINE/PubMed and abstracts from gastroenterology meetings. Only studies reporting the recurrence of HCC in patients receiving DAA treatment, compared to HCV controls without DAA treatment, were evaluated. A meta-analysis was completed using the Mantel-Haenszel model.ResultsA comprehensive literature search resulted in 32 abstracts and papers. Six papers met our inclusion criteria and were included in the analysis. Follow up ranged from 1.25-4 years. Analysis of these 6 studies found a >60% lower risk of HCC recurrence in patients exposed to DAA compared to controls (odds ratio [OR] 0.36, 95% confidence interval [CI] 0.27-0.47; P<0.001; I2=88%). A sensitivity analysis, which excluded studies showing the lowest recurrence rate to reduce heterogeneity, showed that patients receiving DAA still had a 60% lower risk of developing HCC (OR 0.4, 95%CI 0.26-0.61; P<0.0001; I2=39%) and a 66% lower risk of developing HCC beyond 1 year (OR 0.34, 95%CI 0.22-0.54; P<0.00001; I2=0%) compared to controls.ConclusionsThe use of DAA is associated with a significantly lower risk of HCC development compared to DAA-untreated patients, both overall and beyond 1 year of treatment. Further studies are needed to assess the impact of DAAs on early recurrence.

Can hepatitis C virus core antigen replace quantitative RNA in the assessment of a sustained virologic response?

BackgroundThe widespread use of direct-acting antivirals (DAAs) in the treatment of hepatitis C virus (HCV) infection has reduced the need for monitoring HCV-RNA levels because viral kinetics do not predict a sustained virologic response (SVR). However, the performance of cheaper tests, such as the assay to quantify hepatitis C virus core antigen (HCV Ag), has not been determined. Our aim was to assess the accuracy of the HCV core Ag test in predicting the achievement of SVR and its predictive value as a monitoring test in the course of treatment.Patients and methodsThis prospective study was carried out on 90 patients, chronically infected with HCV, who received DAA therapy. Blood samples were collected and the levels of HCV core Ag and HCV-RNA were measured at baseline and at 12 weeks after the end of treatment. We compared the ability of these assays to predict which patients would achieve SVR12.ResultsThe baseline level of HCV-RNA was 1 688 529.6±994 697.3 IU/ml (range: 312 700–3 491 100 IU/ml) and HCV core Ag was 179.2±83.5 pg/ml (range: 33.5–315.6 pg/ml). HCV Ag became undetectable in 92.2% 12 weeks after the end of treatment, whereas HCV-RNA became undetectable in 87.8% at the end of treatment (P<0001). Seventy-nine out of 90 (87.8%) patients achieved SVR12; the test for HCV Ag identified 63.6% of these patients.ConclusionMeasurement of HCV core Ag can monitor the efficacy of DAA therapy for HCV infection. Thus, it can be applied in clinical practice.

Impact of Direct Acting Antivirals on Survival in Patients with Chronic Hepatitis C and Hepatocellular Carcinoma

With the increasing use of direct-acting antivirals (DAA) for treatment of chronic hepatitis C virus (HCV) infection, we looked at the impact of DAA use and 12-week sustained viral response (SVR12) in patients with hepatocellular carcinoma (HCC) and HCV. This is a retrospective analysis of 969 HCC patients diagnosed from 2005 to 2016 at an urban tertiary-care hospital. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to assess survival. Median overall survival of the cohort was 24.2 months. 470 patients had HCV (56%). 123 patients received DAA therapies for HCV (26.2%), 83 of whom achieved SVR12 (67.4%). HCV-positive and HCV-negative patients had similar survival, 20.7 months vs 17.4 months (p = 0.22). Patients receiving DAA therapy had an overall survival of 71.8 months vs 11.6 months for patients without (p < 0.0001). DAA patients who achieved SVR12 had an overall survival of 75.6 months vs. 26.7 months in the non SVR12 group (p < 0.0001). Multivariable analysis revealed AJCC, Child-Pugh Score, MELD, tumor size, tumor location, cancer treatment type, receiving DAA treatment and achieving SVR12 had independent influence on survival (p < 0.05). This suggests DAA therapy and achieving SVR12 is associated with increased overall survival in HCV patients with HCC.

From the Editor’s Desk…: December 2019

From the Editor’s Desk…: December 2019

Racial/Ethnic and Socioeconomic Disparities in Use of Direct-Acting Antivirals Among Medicare Beneficiaries with Chronic Hepatitis C, 2014-2016.

New hepatitis C virus (HCV) drugs-direct-acting antivirals (DAAs)-are highly effective but costly, which raises a concern about limited access to DAAs by vulnerable populations. Previous studies of disparities in DAA use across patient groups showed mixed results, but their generalizability was limited due to using data from commercial insurers or from 2014 only-the first year DAAs were available. Disparities in DAA use in a national cohort in the years when more DAAs were available is unknown. To examine whether disparities in DAA use by patient race/ethnicity and socioeconomic status in Medicare changed between 2014 and 2016. The study population was made up of chronic hepatitis C patients in fee-for-service Medicare with Part D between 2014 and 2016. We used multinomial logistic regression to estimate adjusted odds ratios (aOR) of using DAAs by patient race/ethnicity and socioeconomic status. We estimated the model separately for 2014 and 2014-2016. Of 281,810 Medicare patients who were followed to the end of 2016, a total of 90,419 (32.1%) filled prescriptions for DAAs. In the 2014 analysis, blacks were less likely to use DAAs than whites (aOR = 0.95; 95% CI = 0.91-0.99). However, in the 2014-2016 analysis, blacks had higher odds of using DAAs than whites (aOR = 1.24; 95% CI = 1.22-1.27). No significant Hispanic-white gap existed during the study period. Income was positively associated with DAA use in both periods. Between 2014 and 2016, patients who received a Part D low-income subsidy had lower odds of using DAAs than patients who did not (aOR = 0.90; 95% CI = 0.88-0.92), and patients in areas with the higher income tertiles were more likely to initiate DAAs than those in areas with the lowest income tertile. DAA use among Medicare patients remained far below the level needed to eradicate HCV. The black-white gap in HCV treatment was closed by 2016, but disparities by patient socioeconomic status remained. DAA use also varied by patient age and health risk, as well as across geographic regions. Continued efforts to improve DAA uptake in all HCV patients are needed to eradicate HCV. This study was supported by the National Institute on Aging (1 R01 AG055636-01A1) and National Institute of Child Health & Human Development (R24 HD04025). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Feldman owns stock in Gilead Sciences and Abbvie. No other potential competing interest exists.

288. Hepatitis B Virus Reactivation in Patients with Hematologic Malignancies after Anticancer Therapy Which Included Ibrutinib

BackgroundSeveral cases of severe bacterial, fungal, and viral infections have been reported following ibrutinib therapy. Here, we report a case of a patient with non-Hodgkin lymphoma who developed hepatitis B virus (HBV)–associated liver failure after anti-cancer treatment most recently with ibrutinib. We also review reported cases of HBV reactivation (HBVr) after ibrutinib.MethodsWe searched the Medline and Embase databases and identified 5 patients with HBVr related to ibrutinib for a total of 6 study patients, including our case (figure). HBV-related outcomes were defined according to the 2018 AASLD HBV guidance document.ResultsAll 6 patients were men and most (5 or 83%) had chronic lymphocytic leukemia and past HBV infection (table). Three patients (50%) developed HBV-related hepatitis and 2 of them progressed to liver failure. Four patients (67%) had a remote history (≥24 months) of other potential risk factors besides ibrutinib that could contribute to HBVr, including the use of direct-acting antivirals for hepatitis C co-infection (1 pt), hematopoietic cell transplant (HCT) (1 pt) and rituximab use (4 patients). HBVr occurred at least 6 months after initiation of ibrutinib in most patients (4 or 67%), with a median of 9.7 months (range, 1.5–42). In all 4 patients pretreated with rituximab, that treatment was completed at least 24 months before HBVr. Two of these patients received anti-HBV prophylaxis that was stopped 12 months after the completion of rituximab; the other 2 patients were only monitored without antivirals. The HCT recipient received anti-HBV prophylaxis per guidelines. None of the 6 patients treated with ibrutinib were receiving anti-HBV prophylaxis at the time of HBVr, but 5 patients were started on anti-HBV drugs at the first sign of HBVr. Four received entecavir and 1, tenofovir. All treated patients recovered from HBVr. No pt died of HBVr.ConclusionLife-threatening HBVr can occur following ibrutinib therapy in patients with past or chronic HBV infection. The temporal association between ibrutinib therapy and reactivation indicates that ibrutinib is the likely cause of the HBVr, and clinicians should be aware of the risk of HBVr in these patients. A provisional approach could be HBV monitoring at regular intervals with initiation of antiviral therapy at the earliest sign of HBV reactivation. Disclosures All authors: No reported disclosures.

1042 Direct-Acting Antivirals for the Treatment of Hepatitis C Genotypes 1 to 5 in Sub-Saharan Africa

INTRODUCTION: The use of direct-acting antivirals (DAAs) for the treatment of hepatitis C virus infection (HCV) has exposed the possibility of global elimination of the virus worldwide. However, a large number of HCV-infected individuals reside in resource-limited settings such as sub-Saharan Africa (SSA). There is very limited knowledge of the use of DAAs in SSA METHODS: We developed a single-arm prospective study to assess response to DAAs in 164 individuals infected with HCV genotypes 1 to 5 in Addis Ababa, Ethiopia. The majority of patients were treated with Ledipasvir/Sofosbuvir (LDP/SOF) with or without Ribavirin (RBV) or Sofosbuvir with Ribavirin (SOF/RBV). Before initiation of treatment, every patient underwent an abdominal ultrasound, evaluation of liver function markers and calculation of aspartate transaminase to Platelet Ratio Index (APRI) to determine fibrosis status. HCV RNA levels were determined at baseline and 12 weeks after end of treatment. RESULTS: HCV treatment with DAAs was completed by all 164 enrolled individuals. The median age of patients was 52 years (IQR 42-60) and 55% of them were females. Seventy-six percent of individuals had genotype 4, 14% genotype 2, 6% genotype 1, 2.5% genotype 5 and 1.5% genotype 3. The median HCV RNA level before treatment was 1.300.555 IU/L (IQR: 649825-3182800), and the median APRI score was 1.49 (IQR 1.13-2.24) with 19 % of participants showing evidence of cirrhosis on imaging. Sixty-seven percent of patients were treated using LDP/SOF, 18.5% using LDP/SOF/RBV and 14.6% using SOF/RBV, all for a total of 12 weeks. The sustained virologic response (SVR) rate across all genotypes was 98.8%. In those individuals with cirrhosis, SVR was 93.5% and in non-cirrhotics 100% regardless of APRI-based fibrosis level. Two patients failed to achieve SVR. Both showed evidence of decompensated cirrhosis and one had failed previous therapy with interferon. Among reported side effects, fatigue was the most commonly reported at 11%, followed by nausea in 1.2% of subjects. All side effected subsidized after end of treatment. CONCLUSION: Our study demonstrates for the first time successful treatment of HCV with DAAs among different viral genotypes in Sub-Saharan Africa, demonstrating the feasibility of HCV elimination in resource-limited settings.

SUSTAINED VIROLOGIC RESPONSE RATE IN CHRONIC HEPATITIS C PATIENTS THROUGH DIRECT-ACTING ANTIVIRALS THERAPY.

In recent years the management of hepatitis C virus infection and the possibility of its eradication have been researched due to the importance that they represent in the health of the world population. Obtaining data that help to cope with this pathology improves the quality of life of those affected by it. The present study evaluated the effectiveness of direct-acting antiviral therapies provided by the Brazilian Ministry of Health in accordance to the Clinical Protocol and Therapeutic Guidelines of 2015. To evaluate the epidemiological profile of patients with chronic hepatitis C and the rate of sustained virologic response using direct-acting antivirals of all individuals that attended the referral service for the treatment of chronic hepatitis C at the Hospital of the Federal University of Rio Grande. This was an observational, retrospective/prospective study with all patients with chronic hepatitis C who had their treatments available from December 2015 to August 2017 according to the criteria of the Clinical Protocol and Therapeutic Guidelines of 2015. In the first phase, the clinical and demographic variables of all individuals enrolled in a treatment for hepatitis C were selected and collected from the Reference Service database. In the second phase, treatment data were collected. The outcome variable, sustained virologic response, was defined as an undetectable viral load on the blood test three months after the end of treatment. The descriptive and bivariate analyzes were performed with Pearson's chi-square and Fisher's Exact test, adopting a P value ≤0.05 in the SPSS 20 software. Of the 252 participants in the study, 228 (90.5%) had a sustained virologic response, 55.2% were male with an average age of 58.6 years (SD±9.1). Genotype 1 was the most prevalent, observed in 54.4% of the participants, and 87.4% of the patients had moderate/advanced hepatic fibrosis. After the statistical analysis, it was observed that the individuals with genotype 3 and moderate/advanced hepatic fibrosis had lower sustained virologic response rate (P=0.05 and P=0.04, respectively). It was observed that the use of direct-acting antivirals, in comparison to previous therapeutic regimens, increases the sustained virologic response, reaching all patients with mild fibrosis. This study provides information that helps in the hepatitis C treatment by showing that prescribing early treatment for patients without hepatic fibrosis and/or genotype 3 virus could increase therapeutic effectiveness.

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

Efficacy of Direct-acting Antivirals for Chronic Hepatitis C Virus Infection in People Who Inject Drugs or Receive Opioid Substitution Therapy: A Systematic Review and Meta-analysis.

Treatment uptake for hepatitis C virus (HCV) infection in people who inject drugs (PWID) and patients on opioid substitution therapy (OST) is still low despite treatment guidelines that advocate the use of direct-acting antivirals (DAAs) in all patients. Our aim in this review was to investigate treatment outcomes among PWID and patients on OST in comparison to control cohorts. A search of Embase, Medline, PubMed, and Web of Science (from October 2010 to March 2018) was conducted to assess sustained virologic response (SVR), discontinuation rates, adherence, and HCV reinfection in PWID and patients on OST. We identified 11 primary articles and 12 conference abstracts comprising 1702 patients on OST, 538 PWID, and 19 723 patients who served as controls. Among patients on OST, the pooled SVR was 90% (95% confidence interval [CI], 87% to 93%) and pooled treatment discontinuation rate was 7% (95% CI, 4% to 11%). Similarly, the pooled SVR was 88% (95% CI, 80% to 93%) in PWID and the pooled treatment discontinuation rate was 9% (95% CI, 5% to 15%). There was no significant difference regarding pooled rates of SVR, adherence, and discontinuation between patients on OST and controls as well as between PWID and controls. HCV reinfection rates among patients on OST ranged from 0.0 to 12.5 per 100 person-years. HCV treatment outcomes in PWID and patients on OST are similar to those in patients without a history of injecting drugs, supporting current guideline recommendations to treat HCV in these patient populations.

Baseline resistance associated substitutions in HCV genotype 1 infected cohort treated with Simeprevir, Daclatasvir and Sofosbuvir in Brazil

The World Health Organization estimates that 1% of the world population (71 million) is infected with hepatitis C virus (HCV). In 2015, three direct-acting antivirals (DAAs), simeprevir (SMV), sofosbuvir (SOF) and daclatasvir (DCV) were included in the Brazilian protocol for the treatment of chronic hepatitis C. Despite the fact that the use of these drugs is associated with higher treatment response rates and with lower incidence of side effects, studies have shown the association between the presence of viral resistance mutations and the failure of pharmacological treatment. This way, this study aimed to evaluate the safety and effectiveness of treatment for HCV genotypes 1a and 1b infected patients with these DAAs, also analyzing the occurrence and prevalence of baseline resistance associated substitutions (RAS), observing the impact of these mutations into the treatment success. Clinical data were collected from all the 262 HCV infected patients included for comparative analysis, while serum samples collected from 144 of these individuals, before treatment, were submitted to molecular biology approaches for mutation analysis into NS3, NS5A and NS5B regions. Regarding the treatment regimens, 49.6% of the patients received SOF+DCV±ribavirin and 50.4% used SOF+SMV±ribavirin. The sustained virological response at 12 weeks post-treatment (SVR12) rate was 92.7% (93.9% for SOF plus DCV and 91.7% for SOF plus SMV). No clinical or laboratorial factor was statistically associated with SVR. The most common adverse reactions were haematological events, nausea/vomiting, headache and asthenia. Out of 144 blood samples, 70 (48.6%) had detected RAS, 34.8% treated with SOF+DCV±ribavirin and 61.3% SOF+SMV±ribavirin. The resistance mutations against SMV were detected into NS3: substitutions G122S (28%), I170V (22.7%), Y56F (17.3%) and V132I (14.7%). The mutations against DCV R30Q (9.1%), P58H (6.1%) and Q62E (6.1%) were observed into NS5A, and for SOF the mutations A421V (10.6%), L159F (6.4%) and C316N (6.4%) were present inside NS5B viral protein. Four patients did not reach SVR, three of them presented viruses carrying RAS (1 treated with SOF+DCV and 2 with SOF+SMV). Some of these mutations, like R30Q (present in relapsing samples) and L159F, are well known by their influence on antiviral resistance, while others, like C316N, have a compensatory effect on viral fitness, maintaining these baseline RAS. The use of treatment regimens composed of SOF and DCV or SOF and SMV showed a high SVR rate, despite of a high rate of RAS, and a good tolerability profile in patients with HCV genotype 1. However, the high occurrence of baseline RAS observed in this casuistic is still a concern and studies like this show the necessity to understand how they are maintained in the population and to direct more efficiently the use of DAAs.

Provider Attitudes and Practice Patterns for Direct-Acting Antiviral Therapy for Patients With Hepatocellular Carcinoma

Direct-acting antivirals (DAAs) are effective against hepatitis C virus and sustained virologic response is associated with reduced incidence of hepatocellular carcinoma (HCC). However, there is controversy over the use of DAAs in patients with active or treated HCC and uncertainty about optimal management of these patients. We aimed to characterize attitudes and practice patterns of hepatology practitioners in the United States regarding the use of DAAs in patients with HCC. We conducted a survey of hepatology providers at 47 tertiary care centers in 25 states. Surveys were sent to 476 providers and we received 279 responses (58.6%). Provider beliefs about risk of HCC recurrence after DAA therapy varied: 48% responded that DAAs reduce risk, 36% responded that DAAs do not change risk, and 16% responded that DAAs increase risk of HCC recurrence. However, most providers believed DAAs to be beneficial to and reduce mortality of patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy to patients with early-stage HCC who received curative treatment. However, fewer providers recommended DAA therapy for patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Timing of DAA initiation varied among providers based on HCC treatment modality: 49.1% of providers reported they would initiate DAA therapy within 3 months of surgical resection whereas 45.9% and 5.0% would delay DAA initiation for 3-12 months and >1 year post-surgery, respectively. For patients undergoing transarterial chemoembolization (TACE), 42.0% of providers would provide DAAs within 3 months of the procedure, 46.7% would delay DAAs until 3-12 months afterward, and 11.3% would delay DAAs more than 1 year after TACE. Based on a survey sent to hepatology providers, there is variation in provider attitudes and practice patterns regarding use and timing of DAAs for patients with HCC. Further studies are needed to characterize the risks and benefits of DAA therapy in this patient population.

Therapy with Direct-Acting Antiviral Agents in Transplanted Patients with HCV Recurrence: A Retrospective Analysis

: The recurrence of HCV infection after liver transplantation was the main cause of mortality and loss of graft in transplanted patients until the use of direct-acting antivirals (DAAs). We performed a monocentric retrospective study from November 2014 to September 2017 at “Ospedali Riuniti”, Ancona, Italy, to evaluate the outcome and tolerability of DAAs after liver transplantation. In total, 55 patients with HCV recurrence after liver transplantation treated with DAAs were included. The most frequent genotype was genotype 1a (36%), followed by genotype 3a (27%). The majority of the patients presented a mild or moderate hepatic fibrosis (METAVIR score of F0 - F1 in 20% and F2 in 27%). The patients received sofosbuvir + daclatasvir, sofosbuvir + ribavirin, sofosbuvir + simeprevir, sofosbuvir + ledipasvir, and sofosbuvir + velpatasvir in 54%, 18%, 13%, 13%, and 2% of the cases, respectively, for 12 or 24 weeks. The SVR 12 rate was 89% overall, without a statistically significant relationship with genotypes, fibrosis stage, and therapy. Moreover, 52% of the patients modified the dosage of tacrolimus in the first three months of therapy with DAAs, without statistical significance compared to the group that not changed tacrolimus dosage. The most frequent adverse events were anemia associated with ribavirin. IFN-free treatment with DAAs is highly effective for HCV relapse after liver transplantation and it showed high tolerability in our patients.