Administration Of Direct-acting Antivirals Research Articles

Long term changes in thrombocytopenia and leucopenia after HCV eradication with direct-acting antivirals

BackgroundThrombocytopenia due to hypersplenism is a major complication of hepatitis C virus (HCV)-associated cirrhosis. HCV eradication improves these complications in some patients, but the long-term effects of HCV eradication on these complications remain unclear, especially in patients treated with direct acting antivirals (DAAs). The aim was to evaluate long term changes in thrombocytopenia and leucopenia after HCV eradication with DAAs.MethodsThe present multicenter study retrospectively evaluated changes over 5 years in thrombocytopenia and leukocytopenia, as well as changes in liver fibrosis markers and spleen size, in 115 patients with HCV-cirrhosis treated with DAAs.ResultsThrombocytopenia and leukocytopenia were improved 4 weeks after DAA administration, with thrombocytopenia show further gradual improvement over the next year. Fib-4 index was markedly reduced 1 year after DAA, followed by subsequent gradual reduction over the next 4 years. Spleen size showed gradual annual reductions, with patients experiencing spleen size reduction characterized at baseline by bilirubinemia.ConclusionsRapid DAA-associated HCV eradication might lead to rapid disappearance of liver inflammation and bone marrow suppression due to HCV infection. HCV eradication may gradually improve portal hypertension, reducing spleen size.

Serum Angiopoietin-2 Predicts the Occurrence and Recurrence of Hepatocellular Carcinoma after Direct-Acting Antiviral Therapy for Hepatitis C.

Progressive liver fibrosis after anti-HCV treatment is a risk factor for HCC. Angiopoietin-2 (Ang2) is associated with non-regression of liver fibrosis after direct-acting antiviral (DAA). This study evaluated the predictive value of serum Ang2 levels for HCC occurrence or recurrence after DAA administration. In this retrospective study, 310 HCV-infected patients treated with DAAs in 2014-2020 were screened and evaluated for HCC occurrence or recurrence every three-six months. Multivariate Cox regression analysis revealed that age ≥ 75 years (HR: 2.92, 95% CI: 1.34-6.33; p = 0.007) and baseline Ang2 level ≥ 464 pg/mL (HR: 2.75, 95% CI: 1.18-6.37; p = 0.019) were significantly associated with HCC occurrence after DAA therapy. A high or low risk of HCC after DAA therapy could be distinguished by the combination of age and baseline Ang2 level. The cumulative incidences of de-novo HCC at two and four years were 0.8% and 3.8% in the low-risk group and 22.6% and 27.1% in the high-risk group, respectively. Baseline Ang2 level ≥ 402 pg/mL was significantly associated with HCC recurrence in patients who achieved sustained virological response with DAAs (HR: 3.68). In conclusion, serum Ang2 levels can predict HCC occurrence and recurrence after successful HCV eradication by DAAs.

Impact of Direct-Acting Antivirals on the Outcome of HIV/HCV Coinfected Patients with Non-Hodgkin Lymphomas in the Modern Anti-Retroviral Therapy Era: A Retrospective Multicenter Study of 74 Cases

Impact of Direct-Acting Antivirals on the Outcome of HIV/HCV Coinfected Patients with Non-Hodgkin Lymphomas in the Modern Anti-Retroviral Therapy Era: A Retrospective Multicenter Study of 74 Cases

Serum α-fetoprotein level at treatment completion is a useful predictor of hepatocellular carcinoma occurrence more than one year after hepatitis C virus eradication by direct-acting antiviral treatment.

Direct-acting antivirals (DAAs) have recently been developed to treat hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved liver function of HCV patients. The risk of hepatocellular carcinoma (HCC) occurrence following HCV eradication has been previously reported, but HCC may have been missed following imaging diagnosis before DAA administration in previous studies. Therefore, the present study aimed to identify definite predictors of HCC occurrence ≥1year after DAA treatment. Among 956 patients receiving DAAs for HCV infection, 567 patients who achieved sustained virologic response with no history of HCC treatment were enrolled in this study between September 2014 and July 2021. The incidence of HCC in HCV-infected patients ≥1year following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinical characteristics and blood test results. In the present study, 25 patients developed HCC. The incidence of HCC was 1.4%, 3.2%, 4.9% and 6.8% at 2, 3, 4 and 5years, respectively, from the end of treatment with DAAs. Multivariate logistic analysis revealed serum α-fetoprotein level at end of treatment (EOT-AFP) >3.8ng/ml ≥1year following treatment with DAAs (HR, 9.7; p<.0001) as an independent factor that may contribute to HCC occurrence following DAA treatment. In conclusion, serum EOT-AFP level may serve an important role in determining the risk of HCC occurrence ≥1year after DAA treatment. Regular examinations are required even if serum EOT-AFP level is low at treatment completion.

Postoperative direct-acting antiviral treatment after liver resection in patients with hepatitis C virus-related hepatocellular carcinoma.

We investigated effects of direct-acting antiviral (DAA)-induced sustained virological response (SVR) after liver resection in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) for postoperative recurrence and survival. Surgical outcomes in 18 patients with postoperative DAA-induced SVR (HCC-DAA group) were compared with those in 23 patients with preoperative DAA-induced SVR (DAA-HCC group) and those in 10 patients who did not receive DAA therapy (control group). Patients who received DAA therapy >1year after surgery and those with recurrence <1year after surgery were excluded. Serum concentrations of aminotransferases improved 1year after surgery in both the HCC-DAA and DAA-HCC groups. The number of HCC-DAA patients with albumin-bilirubin (ALBI) grade 1 increased from 11 to 15. The disease-free survival rate did not differ between HCC-DAA group (3years, 60%) and the other two groups (DAA-HCC group, 92% and control group, 60%). The 3-year overall survival rates were better in the DAA-HCC group (84%) and HCC-DAA group (100%) than in the control group (46%; all ps<0.05 according to Holm's test). Multivariable analysis revealed that tumor stage was an independent risk factor for postoperative recurrence, and ALBI grade at 1year after surgery was predictive of postoperative survival, but DAA-induced SVR was neither. Although postoperative DAA-induced SVR itself may not suppress postoperative recurrence, improvement in liver function as a result of DAA administration after surgery may prolong postoperative survival.

The oral microbiome of treated and untreated chronic HCV infection: A preliminary study.

Chronic hepatitis C virus (HCV) infection is a debilitating disease that is lately treated using direct-acting antivirals (DAAs). Changes in the oral microbiome were detected in other liver diseases; however, oral microbiome was never investigated in patients having chronic HCV infection, whether pre- or post-treatment. This case-control preliminary study enrolled three equal groups: Group (I): untreated HCV patients; group (II): HCV patients who achieved viral clearance after DAA administration; and group (III): healthy controls. For each participant, a buccal swab was harvested and its 16S rRNA was sequenced. The oral microbiome of chronic HCV patients had a significantly distinct bacterial community compared to healthy controls, characterized by high diversity and abundance of certain pathogenic species. These changes resemble that of oral lichen planus patients. After treatment by DAAs, the oral microbiome shifted to a community with partial similarity to both the diseased and the healthy ones. Chronic HCV is associated with dysbiotic oral microbiome having abundant pathogenic bacteria. With HCV clearance by DAAs, the oral microbiome shifts to approach the healthy composition.

Long-term assessment of recurrence of hepatocellular carcinoma in patients with chronic hepatitis C after viral cure by direct-acting antivirals.

Background and AimEarly hepatocellular carcinoma (HCC) recurrence is common, even after achieving hepatitis C virus (HCV) cure. This study was carried out to assess the long‐term trends and predictors of recurrence after HCV cure by direct‐acting antivirals (DAAs).MethodsThis retrospective, multicenter cohort study enrolled 365 consecutive patients with chronic hepatitis C who required HCC treatment following sustained viral response (SVR) by DAA administration. Patients with HCC recurrence before SVR were excluded. Late HCC recurrence and its predictors beyond the post‐treatment early phase (24 weeks after SVR) were evaluated.ResultsThe data of 326 patients were available for the final analysis. The median follow‐up duration from SVR determination was 2.7 years. Median age was 74, and 220 (67.5%) were 70 or over. The corresponding 5‐year cumulative HCC recurrence rates of previous curative and palliative treatment groups were 45.4% and 65.7%, respectively (log‐rank test: P < 0.001). Cox regression multivariable analysis revealed that cirrhosis (hazard ratio [HR] 1.85, P = 0.021), the number of HCC nodules (≥ 2) (HR 1.52, P = 0.031), and previous palliative HCC treatment (HR 1.71, P = 0.012) were independent predictors of late recurrence, in addition to the predictors of early recurrence; AFP > 7 ng/mL at 12 weeks after DAA administration, time from HCC complete response (CR) to DAA initiation (< 1 year), and the number of HCC treatments necessary to achieve CR (≥ 2).ConclusionsThe evaluation of fibrosis and characteristics of the previous HCC would allow for better HCC recurrence stratification, which would be helpful for developing long‐term surveillance strategies.

Changes of esophageal varices in hepatitis C patients after achievement of a sustained viral response by direct-acting antivirals.

ObjectivesThe changes in portal hypertension after achieving a sustained viral response (SVR) by direct‐acting antivirals (DAAs) have not been fully elucidated. Consequently, noninvasive and inexpensive predictors need to be investigated. We therefore explored factors associated with the progression of EVs after the achievement of an SVR with DAAs in patients with chronic hepatitis C.MethodsEighty‐nine patients, who had achieved an SVR with DAAs and could have their esophagogastroduodenoscopy (EGD) findings compared between before DAAs administration and after achieving an SVR achievement were enrolled in this study. We compared the patients with and without EVs progression. Furthermore, the cumulative progression rates of EVs were also analyzed.ResultsThe fibrosis‐4 index (FIB‐4) before DAAs administration was the only significant factor for the progression of EVs after an SVR (odds ratios: 1.2, 95% confidence intervals: 1.05–1.38, p = 0.01). In a receiver operating characteristics analysis, the cut‐off of FIB‐4 for the progression of EVs was 8.41 (sensitivity: 0.63, specificity: 0.86, positive predictive value: 0.31, negative predictive value: 0.96), namely EVs of those with more than 8.41 of FIB‐4 progressed and those with less than 8.41 of FIB‐4 did not.ConclusionsAs patients with FIB‐4 ≥ 8.41 may have progressions of EVs, periodic surveillance by EGD should be continued in such cases, even after an SVR is achieved.

Well tolerability and highly effective treatment response for hepatitis C virus-human immunodeficiency virus-coinfected patients treated by all-oral direct-acting antivirals.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) coinfection is common because the two pathogens share their transmission route. Studies have suggested that coinfection is associated with accelerated hepatic fibrosis, increased hepatic decompensation, and hepatocellular carcinoma development. Historically, the sustained virological response (SVR) rates for patients undergoing pegylated interferon (PEG-IFN)-based therapy are poor owing to advanced liver disease, immune dysfunction, and poor medical adherence. This study aimed to investigate the efficacy and safety of oral direct-acting antivirals (DAAs) in HCV-HIV-coinfected patients. Between January 2017 and February 2020, 52 consecutive HCV-HIV-coinfected patients treated with oral DAAs (paritaprevir/ritonavir, ombitasvir, and dasabuvir: 7; daclatasvir and asunaprevir: 1; glecaprevir and pibrentasvir: 15; and sofosbuvir-based drugs: 29) were enrolled. The DAA regimen was selected based on the genotype/subtypes, patient characteristics, potential drug-drug interaction profiles, and health insurance reimbursement criteria. SVR12 was defined as undetectable HCV RNA (<15 IU/mL) at the end of therapy and 12 weeks after therapy completion. The mean age of the enrolled patients was 42 ± 10.2 years; 92.3% of the patients were male and 32.7% had advanced fibrosis or cirrhosis. Nine (17.3%) patients had failed previous IFN therapy. The genotype distribution was as follows: 1a: 8; 1b: 23; 2: 14; 3: 1; and 6: 6. The baseline HCV RNA level before DAA administration was 6.56 ± 0.9 log10 IU/mL, and 67.3% of patients had baseline HCV RNA >2 000 000 IU/mL. After posttreatment follow-up, all 52 patients (100%) achieved SVR12. Subjective and laboratory adverse events during therapy were generally mild, and none of the patients terminated therapy early. A highly effective treatment response and good tolerability were achieved using the oral DAAs for the HCV-HIV-coinfected patient population, which has been considered difficult to treat using IFN-based therapy in the past with urgent unmet medical needs.

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.

Prognosis of late elderly patients with chronic hepatitis C after achieving a sustained viral response by direct-acting antivirals.

Background and AimWe investigated the prognosis of late elderly patients (≥75 years old) after the achievement of a sustained viral response (SVR) by direct‐acting antivirals (DAAs).MethodsOne hundred and four late elderly patients and 251 young patients (≤74 years old) who had achieved an SVR were included. We compared the cumulative hepatocellular carcinoma (HCC) incidence rates and survival rates after DAA administration. Furthermore, the factors associated with HCC incidence and the causes of death after DAA administration were also investigated.ResultsThe cumulative HCC incidence rates for 1 and 3 years were 2.9% and 11.7% in the late elderly patients and 2.4% and 5.4% in the young patients, respectively. The cumulative survival rates for 1 and 3 years were 100% and 95.6% in the late elderly patients and 100% and 96.4% in the young patients, respectively, with no significant differences in those rates noted (P = 0.133, P = 0.322, respectively). In the late elderly patients, only a history of HCC was a significant factor associated with HCC incidence after DAA administration. Five late elderly patients died after achieving an SVR, and malignant liver tumor was the cause of death in three of those patients.ConclusionsThe prognosis did not differ markedly between late elderly patients and young patients. The factor most strongly influencing the prognosis of late elderly patients was likely liver disease, including HCC. DAAs should be introduced even in late elderly patients who can be expected to have a relative long‐term survival.

Acute interstitial nephritis following treatment with direct-acting antiviral agents in hepatitis C virus-infected patients: A case series.

Hepatitis C virus (HCV) infection has been associated with several extrahepatic adverse clinical outcomes, including an accelerated rate of loss of kidney function in patients with chronic kidney disease (CKD) and an increased mortality in patients with CKD and kidney failure on hemodialysis. Clinical trials using direct-acting antiviral (DAA) agents have uniformly achieved sustained viral response at 12weeks (SVR12) rates of >90% in the general population as well as in patients with CKD/kidney failure on hemodialysis. Sofosbuvir is a DAA prodrug that is phosphorylated into the active metabolite GS-461203, with subsequent dephosphorylation into the inactive metabolite GS-331007. The kidneys clear both sofosbuvir and GS-331007, and its use has been associated with worsening kidney function in some studies. In the HCV-TARGET study, patients with an estimated glomerular filtration rate (eGFR) < 30 mL/min at the initiation of sofosbuvir-based therapy had higher rates of deterioration of kidney function compared to patients with higher eGFR [1]. However, based on recent data demonstrating safety in patients with advanced CKD, the US Food and Drug Administration (FDA) approved the use of sofosbuvir-containing regimens in patients with CKD 4/5 (eGFR of less than 30 mL/min/1.73m2) and end-stage renal disease (ESRD) in late 2019. The current report describes 8 HCV-infected patients who developed acute kidney injury (AKI) with biopsy-proven acute interstitial nephritis (AIN) temporally associated with the use of DAAs. The mean age of the group was 61.3 (±6 years). The most common HCV genotype (GT) was 1a (n=7). The DAA formulations were sofosbuvir/ledipasvir (n=5), elbasvir/grazoprevir (n=2), and sofosbuvir/simeprevir (n=1). All patients achieved an SVR12. The mean serum creatinine at the initiation of DAA treatment was 1.5 mg/dL (± 0.6) and increased to 2.03 mg/dL (± 0.7) by the last day of DAA administration. The kidney biopsies were performed at a mean of 320 days (± 247) after achieving an SVR12, at which point the mean creatinine had increased to 2.3 mg/dL (± 1.4). All patients received a course of high-dose corticosteroids after the diagnosis of AIN was confirmed by biopsy. Serum creatinine levels at 3 and 6months following the completion of steroid therapy were 2.8 (±1.2) and 3.1mg/dL (±1.5), respectively. Three patients had worsening CKD and progressed to kidney failure requiring hemodialysis. These results are consistent with earlier studies demonstrating the efficacy of the DAAs in HCV-infected CKD patients. Of note, the demonstration of AIN in these patients may explain some of the AKI events reported with the use of DAAs in patients with CKD.

Commercial insurance delays direct-acting antiviral treatment for hepatitis C kidney transplantation into uninfected recipients.

The advent of direct-acting antivirals (DAAs) has created an avenue for transplantation of hepatitis C virus (HCV)-infected donors into uninfected recipients (D+/R-). The donor transmission of HCV is then countered by DAA administration during the post-operative period. However, initiation of DAA treatment is ultimately dictated by insurance companies. A retrospective chart review of 52 D+/R- kidney recipients who underwent DAA treatment post-transplant was performed. Patients were grouped according to their prescription coverage plans, managed by either commercial or government pharmacy benefit managers (PBMs). Thirty-nine patients had government PBMs and 13 had commercial PBMs. Demographics were similar between the two groups. All patients developed HCV viremia, but cleared the virus after treatment with DAA. Patients with government PBMs were treated earlier compared to those with commercial PBMs (11days vs 26days, P=.01). Longer time to DAA initiation resulted in higher peak viral loads (β=0.39, R2 =.15, P=.01) and longer time to HCV viral load clearance (β=0.41, R2 =.17, P=.01). D+/R- transplantation offers patients an alternative strategy to increase access. However, treatment can be profoundly delayed by a third-party payer authorization process that may be subjecting patients to unnecessary risks and worsened outcomes.

Surgical outcomes for hepatocellular carcinoma detected after hepatitis C virus eradiation by direct-acting antivirals.

To investigate the postoperative recurrence of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after liver resection in patients with and without the achievement of sustained virologic response (SVR) through the administration of direct-acting antivirals (DAA). Among 28 patients with HCC detected after DAA-SVR (DAA group) and 197 patients with HCC who did not receive treatment for HCV infection or who did not achieve an SVR (control group) between January 2000 and July 2019, we performed propensity score matching (PSM) to avoid confounding differences between the two groups. After PSM, 28 patients in each group were selected for analysis. The DAA-SVR patients showed improved liver function at operation and at recurrence in comparison to the control group. The disease-free survival rate at 3 years after surgery was 69% in the DAA group and 35% in the control group, respectively (P = .021). In the DAA group, all three patients with recurrence met the Milan criteria and could be managed by curative treatments and none died of liver failure during the follow-up period. SVR status suppresses postoperative recurrence of HCV-related HCC detected after DAA-SVR. Improved liver function may contribute to the successful treatment and prevention of liver failure.

P0281THE EFFECT OF DIRECT ANTIVIRAL AGENTS ON GLOMERULAR FILTRATION RATE

Abstract Background and Aims HCV infects 170 million individuals approximately worldwide. The kidney is a major component of the HCV clinical syndrome. This viral infection imposes itself as a cause of kidney disease, a major risk in hemodialysis units and a significant threat in kidney transplantation. In 2011, direct acting antivirals (DAA) had been developed, which represented a huge boom in the treatment of HCV. Some doubtful data suggest possibility of association between some DAA administration and AKI occurrence, but larger prospective studies are recommended for confirming this suggestion. Method Retrospective cohort study of 118 adult HCV infected patients with normal baseline kidney functions (GFR ≥ 60ml/min) were included. Patients coinfected with HBV and those with impaired kidney functions at beginning of treatment were excluded. Patients were divided into 3 groups according to their DAA-combination treatment regimen. Patients’ eGFR were measured at baseline, at the end of treatment and one year later. Results Our results showed that patients who received Sofosbuvir/Daclatasvir/Ribavirin, their pre-treatment eGFR Mean ± SD. was (86.15±16.37). Post treatment eGFR showed an insignificant change after end of treatment (84.73±17.41) and 1 year after treatment (82.0±18.07) (P-value: 0.998 and 0.220 respectively). Those who received Sofosbuvir/Daclatasvir, their pretreatment eGFR Mean ± SD was (94.60±19.32). Post treatment eGFR showed an insignificant change after end of treatment (89.39±18.39) and 1 year after treatment (89.17±20.27). (P-value: 0.156 and 0.097 respectively). As for patients who received Sofosbuvir/Simeprevir, their pretreatment eGFR Mean ± SD was (92.71±15.11). Post treatment eGFR showed an insignificant change after end of treatment (88.36±16.27) and 1 year after treatment (89.01±15.72). (P-value: 0.620 and 0.676 respectively). Conclusion The new direct antiviral agents (sofosbuvir, daclatasvir and simeprevir) are effective and safe regarding glomerular filtration rate in patients with normal renal function. However, a meticulous monitoring of kidney function is mandatory during the use of these medications to early detect any untoward side effects.

Simple scoring system for prediction of hepatocellular carcinoma occurrence after hepatitis C virus eradication by direct-acting antiviral treatment: All Kagawa Liver Disease Group Study.

Direct acting antivirals (DAA) have recently been developed to treat patients with hepatitis C virus (HCV) infection, and interferon-free DAA treatment has improved the cure rate of patients. However, the occurrence rate of hepatocellular carcinoma (HCC) following HCV eradication remains unknown. Therefore, the present study aimed to identify predictors of HCC occurrence following DAA treatment. Among 1,454 patients infected with HCV, 1,088 patients who achieved sustained virologic response and who had no history of HCC treatment were recruited between September 2014 and November 2018. The incidence of HCC in patients infected with HCV following DAA treatment, and the predictors contributing to HCC occurrence were identified using clinicopathological characteristics and blood test results. During the present study, 26 patients developed HCC. The incidence of HCC was 0.61, 1.88, 2.82 and 3.71% at 6, 12, 18 and 24 months after treatment with DAA, respectively. The results of multivariate analysis identified age [hazard ratio (HR), 1.0729; P=0.0044] and α-fetoprotein (AFP) level after DAA treatment (HR, 1.0486; P=0.0486) as independent factors that may contribute to HCC occurrence following DAA treatment. By using these two factors, a novel scoring system (0–2 points) was established to predict HCC occurrence following HCV eradication by DAA treatment. The incidence of HCC at 2 years was 0.3% in the 0 points group, 6.27% in the 1 point group and 18.37% in the 2 points group. In conclusion, AFP level after DAA treatment and age at DAA administration were identified as independent predictors of HCC occurrence in patients that were treated with DAA. The scoring system that was established in the present study is simple and easy, and using pre-treatment factors may be a convenient tool to predict the risk of HCC occurrence in HCV-free patients following DAA treatment.

Hepatitis C virus infection suppresses hepatitis B virus replication via the RIG-I-like helicase pathway

Mechanisms of hepatitis B virus (HBV) reactivation after hepatitis C virus (HCV) elimination by direct-acting antiviral (DAA) treatment in HBV/HCV-co-infected patients remain unclear. We examined RIG-I-like helicase (RLH) pathway activation by HBV mono-infection, HCV mono-infection or HBV/HCV co-infection and interference between HBV and HCV in primary human hepatocytes. Interference between HBV and HCV and HBV reactivation after DAA treatment in humanized-liver mice were assessed. HCV infection activated RLH pathway, as evidenced by RIG-I, ISG15 and ISG56 expression induction; HBV caused only RIG-I induction in vitro. RLH activation was also found in HBV/HCV-co-infected cells, and HBV replication were suppressed in HBV/HCV-co-infected than in HBV-mono-infected cells. siRNA-mediated double knockdown of ISG15 and ISG56 increased HBV replication in HBV/HCV-co-infected cells. HCV infection activated RLH pathway and suppressed HBV replication in humanized-liver mice. Subsequent elimination of HCV by DAA administration downregulated RLH pathway and upregulated HBV replication in mice. RLH pathway was activated in livers of chronic hepatitis C patients compared to those of chronic hepatitis B or non-B, non-C patients. The RLH pathway activation was downregulated by HCV elimination. In conclusion, HCV infection activated RLH pathway and suppressed HBV replication in human hepatocytes. HCV elimination upregulated HBV replication, probably through RLH pathway downregulation.

Management of Hepatitis C in the Older Adult

OBJECTIVE: To provide a review of the epidemiology, clinical presentation, screening, diagnosis, treatment, and prevention of hepatitis C with an emphasis on older adults. DATA SOURCES: PubMed and Google Scholar were searched for relevant literature using a combination of the following terms: hepatitis C, epidemiology, hepatitis C virus (HCV), diagnosis, treatment, direct-acting antivirals (DAAs), and older adults. In addition, websites of the hepatitis C guidelines, Centers for Disease Control and Prevention (CDC), and manufacturers of DAAs were also reviewed for relevant information. (The authors reviewed the literature through May 2019. STUDY SELECTION/DATA EXTRACTION: The key resources reviewed were the CDC website, American Association for the Study of Liver Diseases/Infectious Diseases Society of America hepatitis C guidelines, prescribing information of DAAs, and pivotal clinical trials of DAAs. DATA SYNTHESIS: Hepatitis C disproportionately affects baby boomers and people who inject drugs (PWID). CDC recommends screening adults born from 1945 to 1965 and high-risk patients for the presence of hepatitis C antibody. The goal of therapy is to achieve sustained virologic response, defined as undetectable HCV ribonucleic acid 12 weeks after treatment completion. Treatment for those who are treatment-naive with or without compensated cirrhosis consists of administration of DAAs orally for 8 to 12 weeks. Regimen selection depends on HCV genotype, presence or absence of cirrhosis, comorbid conditions, and concurrent medications. Currently recommended DAAs are highly effective, well tolerated, and can be associated with significant drug interactions particularly in older adults. Access to DAAs remains an obstacle for many patients. CONCLUSION: Hepatitis C is common among baby boomers and PWID. Screening is recommended in these patient populations. Treatment with DAAs is curative and well tolerated.

Ruptured hepatocellular carcinoma in a patient with chronic hepatitis C and a sustained viral response

Hepatitis C virus (HCV) is one of the most common causes of chronic liver disease in the world (1). The goal of chronic hepatitis C therapy is to prevent cirrhosis of the liver and hepatocellular carcinoma (HCC) by achieving a sustained virologic response (SVR). It has been reported that telaprevir-based triple therapy enabled 60%–70% SVR in genotype 1 (G1) patients (2,3). The 74-year-old male patient was diagnosed with chronic hepatitis C 6 years ago, and peginterferon (P) + ribavirin (R) therapy was initiated. As HCV-RNA positivity continued in the 24th week of treatment, the patient was considered unresponsive, and his treatment was concluded. With the introduction of telaprevir into the therapy approximately one year later, the G1b patient was started on a triple therapy (telaprevir, PR) for 12 weeks followed by a 36-week course of double therapy (PR); thereby, his treatment was completed in a total of 48 weeks. The patient, who now had SVR, has been followed up in the 4 years since the completion of his therapy by carrying out tests on his HCV-RNA and alpha-fetoprotein (AFP) levels, alongside abdominal ultrasonography (ABD USG) performed every 6 months. The patient, who presented to the emergency department with a complaint of severe abdominal pain reflecting on his right shoulder about 4 months after his latest follow-up, had a heterogeneous solid mass about 6 cm in size in his eighth liver segment alongside free fluid in the perihepatic and pelvic areas, as revealed by ABD USG. The results of testing showed that the patient had a high AFP level of 36 ng/mL (0–8.1). The results of all abdominal computed tomography scans carried out in view of these findings showed that the patient’s liver was of a normal size with no pronounced undulation of the contours. A heterogeneous solid mass lesion about 67 × 73 × 68 mm in size growing toward the subdiaphragmatic space in liver segment 8 was observed to reveal a hyperdense, possibly arterial contrasting image; the presence of high-density fluid around the mass in the subdiaphragmatic space was also visualized. Consequently, the rapidly contrasting arterial mass on the hepatic dome was diagnosed as HCC (?), hepatic adenoma (?), and a ruptured mass, and it was recommended that the patient undergo dynamic magnetic resonance (MR). A T1A hypointense, T2A mildly hyperintense heterogeneous solid mass, 63 × 70 mm in size with fine borders and irregular contours, was visualized on the dome level of the eighth segment of the right lobe (Figure 1). As a result, the patient was diagnosed with spontaneous rupture of the mass because of his high AFP levels, the presence of a solid mass concordant with HCC, contour irregularity neighboring the superior, and signs of hemoperitoneum observed in the perihepatic area. The patient was taken into surgery and died in the perioperative period. The risk of HCC development in patients with SVR through direct-acting antiviral (DAA) has proven to be a controversial issue (4,5). Patients with SVR through DAA administration should be followed up every 6 months with regards to ABD USG results and AFP levels.

305. Using Big Data to Re-Engage Hepatitis C-infected Persons: A UK Operational Delivery Network’s Experience

BackgroundThe prevalence of hepatitis C (HCV) varies across different risk groups in the UK. In England, responsibility for the co-ordination and administration of DAAs (direct-acting antivirals) to HCV PCR positive patients is with 22 regional “Operational Delivery Networks” (ODNs). To attempt to eliminate Hepatitis C before 2030, Public Health England (PHE) and NHS England (NHSE) are attempting to re-engage previously diagnosed infected persons. To this end, ODNs have been supplied with historical antibody result data to target and reengage individuals for PCR testing and intervention if required.A study was designed to evaluate these data to help with informing ODN decisions. This study aimed to ensure that the data accurately identified patients that were PCR positive for HCV and thus fit the current criteria for receiving DAAs.MethodsThe regional ODN for the West Midlands was provided with 4540 patients with historical positive HCV antibody results, collected by a PHE surveillance system, to target for DAA intervention. DAA-treated patients had been excluded. Patient details were cross-referenced with all PCR results from January 1, 1996 up to January 1, 2019 at several regional laboratories (Public Health England Birmingham, the Queen Elizabeth Hospital, City and Sandwell Hospital) and national treatment data.ResultsPCR data were found for 988, 276 (28%) of whom had received treatment. Of the 712 persons untreated, 347 (49%) were PCR negative and thus would not fit the criteria for receiving DAAs. 365 (51%) had a positive PCR result without a record of treatment would be eligible for DAAs (see Figure 1).ConclusionOur study suggests approximately one-third of patients identified by cross-referencing NHSE treatment and PHE epidemiological HCV antibody databases will be PCR-positive and suitable for re-engagement. Epidemiological data needs to be accurately curated when implementing public health control measures. Using “Big Data” to target interventions has several limitations but can be useful. DAAs for HCV are not without risk and administration should be clinically justified. Re-testing individuals prior to intervention is essential and other methods of elimination, for example “test and treat,” may be more efficient and accurate. Disclosures All authors: No reported disclosures.