A randomized multicenter trial of a chronic disease management intervention for decompensated cirrhosis. The Australian Liver Failure (ALFIE) trial.

BACKGROUND AND AIMS: Improving the care of decompensated cirrhosis is a significant clinical challenge. The primary aim of this trial was to assess the efficacy of a chronic disease management (CDM) model to reduce liver-related emergency admissions (LREA). The secondary aims were to assess model effects on quality-of-care and patient-reported outcomes. APPROACH AND RESULTS: The study design was a 2-year, multicenter, randomized controlled study with 1:1 allocation of a CDM model versus usual care. The study setting involved both tertiary and community care. Participants were randomly allocated following a decompensated cirrhosis admission. The intervention was a multifaceted CDM model coordinated by a liver nurse. A total of 147 participants (intervention=75, control=71) were recruited with a median Model for End-Stage Liver Disease score of 19. For the primary outcome, there was no difference in the overall LREA rate for the intervention group versus the control group (incident rate ratio 0.89; 95% CI: 0.53-1.50, p=0.666) or in actuarial survival (HR=1.14; 95% CI: 0.66-1.96, p=0.646). However, there was a reduced risk of LREA due to encephalopathy in the intervention versus control group (HR=1.87; 95% CI: 1.18-2.96, p=0.007). Significant improvement in quality-of-care measures was seen for the performance of bone density (p<0.001), vitamin D testing (p<0.001), and HCC surveillance adherence (p=0.050). For assessable participants (44/74 intervention, 32/71 controls) significant improvements in patient-reported outcomes at 3 months were seen in self-management ability and quality of life as assessed by visual analog scale (p=0.044). CONCLUSIONS: This CDM intervention did not reduce overall LREA events and may not be effective in decompensated cirrhosis for this end point.

Circulating cell-specific extracellular vesicles as biomarkers for the diagnosis and monitoring of chronic liver diseases.

Chronic liver diseases represent a burgeoning health problem affecting billions of people worldwide. The insufficient performance of current minimally invasive tools is recognised as a significant barrier to the clinical management of these conditions. Extracellular vesicles (EVs) have emerged as a rich source of circulating biomarkers closely linked to pathological processes in originating tissues. Here, we summarise the contribution of EVs to normal liver function and to chronic liver pathologies; and explore the use of circulating EV biomarkers, with a particular focus on techniques to isolate and analyse cell- or tissue-specific EVs. Such approaches present a novel strategy to inform disease status and monitor changes in response to treatment in a minimally invasive manner. Emerging technologies that support the selective isolation and analysis of circulating EVs derived only from hepatic cells, have driven recent advancements in EV-based biomarker platforms for chronic liver diseases and show promise to bring these techniques to clinical settings.

Impact of cardiac dysfunction on morbidity and mortality in liver transplant candidates.

The prognostic role of cardiac dysfunction in cirrhotic patients is increasingly recognized. We studied its impact on morbidity and mortality before and after liver transplantation (LT) including development of post-transplant cardiovascular disease (CVD). In this retrospective study, cirrhotic patients who underwent LT assessment from January 2010 to December 2020 were reviewed. Demographics, cardiac investigations and clinical courses were analyzed to identify the prevalence of cardiac dysfunction and its role in LT outcomes. Survival analysis was performed using Cox proportional hazard regression modelling, with LT as a time-varying covariate and as an interaction variable with cardiac dysfunction. Three hundred and eight patients (70% male) were studied. The median (interquartile range) age at LT assessment was 56 (12) years. Cardiac dysfunction was found in 178 (58%) patients (diastolic, 169; systolic, 26; both, 17) and was significantly associated with hepatorenal syndrome/acute kidney injury and peri- and post-transplant morbidity (adjusted odds ratio [aOR] 1.94, 95% CI 1.06-3.52, P < .001; aOR 2.01, 95% CI 1.06-3.82, P = .033; aOR 1.9, 95% CI 1.01-3.65, P = .023, respectively). Cardiac dysfunction was not associated with mortality before (adjusted hazard ratio [aHR] 1.01, 95% CI .99-1.01) or after LT (aHR .74, 95% CI .4-1.05. Post-transplant CVD (61% cardiac failure) occurred in 36 patients, and there was no significant association with cardiac dysfunction (P = .11). Cardiac dysfunction was common in LT candidates and was significantly associated with morbidity before and after LT. Studies on the role of advanced echocardiographic parameters to improve diagnosis of cardiac dysfunction and optimize LT outcomes are needed.

Measuring quality of hepatitis B care in a remote Australian Aboriginal community: opportunities for improvement.

BACKGROUND: Chronic hepatitis B (CHB) infection remains a significant public health issue for Indigenous Australians, in particular for remote communities. AIM: To evaluate the spectrum of hepatitis B virus (HBV) care provided to a remote Aboriginal community. Measures studied included screening, seroprevalence, vaccination rates and efficacy, and HCC risk and surveillance adherence. METHODS: A retrospective audit of HBV care received by all permanent residents currently attending a remote Aboriginal Health service. This study was endorsed by both the local Aboriginal Health service and the Aboriginal Health Council of South Australia. RESULTS: A total of 208 patients attended the clinic, of whom 52% (109) were screened for HBV. Of these, 12% (13) had CHB and 20% (22) had evidence of past infection. Similarly, of the 208 attending patients, complete vaccination was documented in 48% (99). Of the 33 patients with post-vaccination serology, 24% (8) had subtherapeutic (<10 IU/mL) levels of HBsAb. Subtherapeutic HBsAb was independently associated with higher Charlson Comorbidity scores (odds ratio = 17.1; 95% confidence interval 1.2-243.3; P = 0.036). Definitive breakthrough infection was identified in 6% (2) patients. One HBsAg positive patient was identified as needing HCC surveillance, but had not undertaken HCC surveillance. CONCLUSION: Opportunities to improve the quality of CHB care through increased HBV vaccination, screening and adherence to HCC surveillance were identified. High rates of subtherapeutic vaccine responses and documented breakthrough infection raises concerns about the effectiveness of current CHB vaccines in this population.

Nurse Led Clinics; a Novel Model of Care for Compensated Liver Cirrhosis: A Qualitative Analysis.

A nurse-led cirrhosis clinic model for management of stable, compensated cirrhotic patients is practised in our unit since 2013, wherein these patients are reviewed every six months by specialist nurses in community clinics under remote supervision of hepatologists. We evaluated the experiences of patients and healthcare providers involved in the model to understand the acceptability, strengths, and limitations of the model and obtain suggestions to improve. A qualitative design using in-depth interviews was employed, followed by thematic analysis of eight patients, one attending physician both nurse and hospital clinics, four hepatologists, and three experienced specialist nurses running the nurse-led cirrhosis clinic. Patients expressed satisfaction and a good understanding of the nurse-led cirrhosis clinic, preferring it to hospital clinics for better accessibility and the unique nurse-patient relationship. Upskilling and provision of professional care in a holistic manner were appreciated by specialist nurses. The hepatologists expressed confidence and satisfaction, although they acknowledged the difference between the medical training of specialist nurses and hepatologists. The greater availability of hospital clinic time for sick patients was welcomed. Increased specialist nurse staffing, regular forums to promote specialist nurse learning, and formalization of the referral process were suggested. No adverse experiences were reported by patients or staff. The nurse-led cirrhosis clinic model for compensated liver cirrhosis was well received by patients, hepatologists, and specialist nurses. Wider implementation of the model could be considered after further investigations in other settings.

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study.

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

Psychometric validation of the Partners in Health scale as a self-management tool in patients with liver cirrhosis.

BACKGROUND AND AIM: Liver cirrhosis is a chronic disease complicated by recurrent hospital admissions. Self-management skills could facilitate optimal disease management. At present there is no validated instrument for measuring self-management in these patients. Hence, we evaluated the internal reliability and construct validity of the Partners in Health (PIH) scale, a chronic condition self-management tool in cirrhotic patients. METHODS: In this prospective cohort study, the PIH scale was administered to 133 consenting patients within a Chronic Liver Failure Program of a tertiary hospital from February 2017 to May 2018. A Bayesian confirmatory factor analysis was used to evaluate a priori four-factor structure. Omega coefficients and 95% credible intervals (CrI) were used to assess internal reliability. Known-group validity was assessed in patients receiving active case management (n = 60) versus those without (n = 73). RESULTS: The mean (± standard deviation (SD)) age of the participants was 62 (±11) years. Model fit for the hypothesised model was adequate (posterior predictive P-value = 0.073) and all hypothesised factor loadings were substantial (>0.6) and significant (P < 0.001). Omega coefficients (95% CrI) for the PIH subscales of Knowledge, Partnership, Management and Coping were 0.88 (0.82-0.91), 0.68 (0.57-0.76), 0.92 (0.89-0.94) and 0.89 (0.85-0.92) respectively. The mean (±SD) overall PIH score was higher in patients receiving case management compared to those without case management (81 ± 12 vs 73 ± 17, P < 0.001). CONCLUSION: The dimensionality, known-group validity and reliability of the PIH scale for measuring self-management in patients with liver cirrhosis were confirmed. Its clinical predictive value requires further assessment.

Outcomes of community-based hepatitis C treatment by general practitioners and nurses in Australia through remote specialist consultation.

BACKGROUND: A unique model of care was adopted in Australia following introduction of universal subsidised direct-acting antiviral (DAA) access in 2016 in order to encourage rapid scale-up of treatment. Community-based medical practitioners and integrated hepatitis nurses initiated DAA treatment with remote hepatitis specialist approval of the planned treatment without physical review. AIMS: To evaluate outcomes of community-based treatment of hepatitis C virus (HCV) through this remote consultation process in the first 12 months of this model of care. METHODS: A retrospective chart review of patients undergoing community-based HCV treatment from general practitioners and integrated hepatitis nurse consultants through the remote consultation model in three state jurisdictions in Australia from 1 March 2016 to 28 February 2017. RESULTS: Sustained virological response at 12 weeks (SVR12) was confirmed in 383 (65.1%) of 588 subjects intended for treatment with a median follow-up time of 12 months (interquartile range 9-14 months). The SVR12 test was not performed in 159 (27.0%) of 588 and 307 (52.2%) of 588 did not have liver biochemistry rechecked following treatment. Subjects who completed follow up exhibited high SVR12 rates (383/392; 97.7%). Nurse-led treatment was associated with higher confirmation of SVR12 (73.7% vs 62.4%; P = 0.01) and liver biochemistry testing post treatment (57.5% vs 45.0%; P = 0.01). CONCLUSIONS: Community-based management of HCV through remote specialist consultation may be an effective model of care. Failure to check SVR12, recheck liver biochemistry and appropriate surveillance in patients with cirrhosis may emerge as significant issues requiring further support, education and refinement of the model to maximise effectiveness of future elimination efforts.

Validation of Knowledge Questionnaire for Patients With Liver Cirrhosis.

BACKGROUND & AIMS: There is no validated questionnaire to assess disease knowledge and self-management in patients with liver cirrhosis. We developed and validated a Cirrhosis Knowledge Questionnaire (CKQ). METHODS: We created a preliminary CKQ comprising 10 questions relevant to self-management of cirrhosis, based on publications and clinical experiences. The CKQ was given to a pilot sample of 17 patients with decompensated cirrhosis to assess its face validity. In consultation with experts, we developed a second version of CKQ, comprising 14 multiple choice questions, and administered it to 116 patients with cirrhosis participating in a Chronic Liver Failure Program. The dimensionality of the construct was assessed using exploratory factor analysis and internal consistency was assessed with Cronbach's alpha. Known-group validity of the resulting instrument was assessed by comparing the performance of the CKQ in 69 patients with decompensated cirrhosis (mean age, 62 ± 13 years; 109 responses), with (n = 42) vs without (n = 67) case management. RESULTS: A 3-factor model with 7 questions related to variceal bleeding, ascites, and hepatic encephalopathy was considered the optimal dimensionality with excellent internal consistency (Cronbach's alpha = 0.82). The mean knowledge score was higher in patients with case management (5.6 ± 1.1) than in patients without case management (4.3 ± 2.1) (P = .002). CONCLUSIONS: We developed and validated a questionnaire with 7 questions on ascites, variceal bleeding, and hepatic encephalopathy to assess knowledge and self-management in patients with liver cirrhosis. Studies are needed to confirm its dimensionality and assess association of scores with patient outcomes.

Efficacy of High-Dose, Rapid, Hepatitis A and B Vaccination Schedules in Patients With Cirrhosis.

Patients with cirrhosis have increased morbidity from hepatitis A virus (HAV) and hepatitis B virus (HBV) infections, and vaccination against these infections is an important standard of care.1,2 However, vaccination in patients with cirrhosis is hindered by immune dysfunction and there is limited high-quality literature available. The aim of this work therefore was to compare immune responses of standard dose (SD) with high-dose accelerated (HDA) vaccination in cirrhotic patients.

Hepatitis C virus infection in Australian psychiatric inpatients: A multicenter study of seroprevalence, risk factors and treatment experience.

Screening and treatment for hepatitis C virus (HCV) infection were not prioritised in psychiatric patients due to adverse neuropsychiatric effects of interferon therapy despite reports of high prevalence. However, with the safe new antiviral drugs, HCV eradication has become a reality in these patients. The aim of this study was to report HCV seroprevalence, risk factors and treatment model in an Australian cohort. This prospective study involved patients admitted to four inpatient psychiatric units, from December 2016 to December 2017. After pretest counselling and consent, HCV testing was done; information on risk factors collected. A total of 260 patients (70% male), median age 44 years (IQR 24), were studied. The HCV seroprevalence was 10.8% (28/260) with 95% CI 7-15. Independent predictors of HCV positivity were injection drug use (P < 0.001, OR 44.05, 95% CI 7.9-245.5), exposure to custodial stay (P = 0.011, OR 7.34, 95% CI 1.6-33.9) and age (P = 0.011, OR 1.09, 95% CI 1.02-1.16). Eight of the 16 HCV RNA-positive patients were treated. Hepatitis nurses liaised with community mental health teams for treatment initiation and follow-up under supervision of hepatologists. Seven patients achieved sustained viral response, one achieved end of treatment response. The remaining eight patients were difficult to engage with. In conclusion, HCV prevalence was high in our cohort of psychiatric inpatients. Although treatment uptake was achieved only in 50% patients, it was successfully completed in all, with innovative models of care. These findings highlight the need to integrate HCV screening with treatment linkage in psychiatry practice.

High rates of indeterminate interferon-gamma release assays for the diagnosis of latent tuberculosis infection in liver transplantation candidates.

BACKGROUND AND AIMS: Screening for latent tuberculosis infection (LTBI) is recommended prior to solid organ transplantation. Interferon-gamma release assays (IGRAs) are the most widely used test for LTBI screening; however, assessment of IGRA performance in patients with end-stage liver disease is limited. The purpose of this study was to evaluate the prevalence and predictors of indeterminate (INDT) IGRA results in liver transplantation candidates. METHODS: Between March 2011 and May 2018, we retrospectively analyzed 155 patients undergoing liver transplantation assessment, who underwent IGRA testing (Quantiferon-TB Gold, QFT-G) to exclude LTBI. Characteristics of patients, including age, gender, etiology of liver disease, MELD score, and absolute lymphocyte counts, were compared by QFT-G result (determinate vs INDT). RESULTS: Of the 155 patients screened, the rate of positive, negative, and INDT results were 5.2%, 69.8%, and 25%, respectively. The only variable independently associated with an indeterminate test on multivariate analysis was MELD score (odds ratio = 1.07, 95% CI = 1.01-1.14 per unit increase; P = 0.014). In 95% of INDT tests, both TB antigen tube and the positive control tube were negative and repeat testing gave the same indeterminate result, suggestive of anergy rather than laboratory error. CONCLUSIONS: Our study suggests a high rate of INDT IGRA results during screening of liver transplant candidates for LTBI, associated with severity of liver disease and anergy. Because of the high rate of INDT QFT-G testing in this setting, individualized risk assessment is required including a thorough assessment of clinical risk factors and knowledge of local TB prevalence.

Coordinated care for patients with cirrhosis: fewer liver-related emergency admissions and improved survival.

OBJECTIVES: To compare the incidence of liver-related emergency admissions and survival of patients after hospitalisation for decompensated cirrhosis at two major hospitals, one applying a coordinated chronic disease management model (U1), the other standard care (U2); to examine predictors of mortality for these patients. DESIGN: Retrospective observational cohort study. SETTING: Two major tertiary hospitals in an Australian capital city. PARTICIPANTS: Patients admitted with a diagnosis of decompensated cirrhosis during October 2013 - October 2014, identified on the basis of International Classification of Diseases (ICD-10) codes. MAIN OUTCOME MEASURES: Incident rates of liver-related emergency admissions; survival (to 3 years). RESULTS: Sixty-nine patients from U1 and 54 from U2 were eligible for inclusion; the median follow-up time was 530 days (range, 21-1105 days). The incidence of liver-related emergency admissions was lower for U1 (mean, 1.14 admissions per person-year; 95% CI, 0.95-1.36) than for U2 (mean, 1.55 admissions per person-year; 95% CI, 1.28-1.85; adjusted incidence rate ratio [U1 v U2], 0.52; 95% CI, 0.28-0.98; P = 0.042). The adjusted probabilities of transplantation-free survival at 3 years were 67.7% (U1) and 37.2% (U2) (P = 0.009). Independent predictors of reduced transplantation-free free survival were Charlson comorbidity index score (per point: hazard ratio [HR], 1.27; 95% CI, 1.05-1.54, P = 0.014), liver-related emergency admissions within 90 days of discharge (HR, 3.60; 95% CI, 1.87-6.92; P < 0.001), and unit (U2 v U1: HR, 2.54, 95% CI, 1.26-5.09; P = 0.009). CONCLUSIONS: A coordinated care model for managing patients with decompensated cirrhosis was associated with improved survival and fewer liver-related emergency admissions than standard care.

Cost-effectiveness of a chronic disease management model for cirrhosis: Analysis of a randomized controlled trial.

BACKGROUND AND AIMS: In this follow-up study to a randomized controlled trial of a chronic disease management (CDM) model in cirrhosis, our aim was to assess the relative cost-effectiveness of this model compared with usual care during the 12-month study period, using incremental costs per death avoided as the primary outcome. METHODS: Mean differences in hospitalization costs, deaths avoided, and change in Chronic Liver Disease Questionnaire (CLDQ) total scores were presented with 95% non-parametric bootstrapped confidence intervals. Results were also presented using a cost-effectiveness plane (CEP) and cost-effectiveness acceptability curve. RESULTS: The CDM intervention was more expensive, by 18 521 AUD per participant, but more effective (% of deaths at 12 months: 10% vs 15% and 0.67 units increase per patient in CLDQ total scores). The resultant incremental cost-effectiveness ratios were 370 425 AUD per death avoided (95% confidence interval: -14 564 AUD to 2 059 373 AUD) and 27 547 AUD per unit improvement in the CLDQ total score (95% CI: 7455 AUD to 143 874 AUD). The CEPs demonstrated some uncertainty around cost-effectiveness. The cost-effectiveness acceptability curves demonstrated that at willingness to pay values of 400 000 AUD per additional death avoided and 40 000 AUD per unit improvement in the CLDQ, there was at least a 70% probability of CDM being more cost-effective than usual care. At 24 months, CDM was much more effective (12% less deaths but now also cheaper by 985 AUD per patient). CONCLUSIONS: The analysis of data from a randomized controlled trial suggests that the CDM intervention used is likely to be cost-effective, relative to usual care, due to fewer patient deaths.

Hepatitis B screening before rituximab therapy: a multicentre South Australian study of adherence.

BACKGROUND: International guidelines recommend screening for hepatitis B virus (HBV) infection prior to administration of rituximab, due to high risk of HBV reactivation in at-risk patients. AIMS: To determine: (i) adherence to the South Australian (SA) protocol for HBV screening; (ii) HBV prevalence in patients receiving rituximab; and (iii) outcomes of patients at risk of HBV reactivation. METHODS: All patients commenced on rituximab at the six major SA public hospitals during a 12-month period were included in the study. Adherence was assessed by documentation of both hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) prior to initiation of rituximab. Patients were observed for a minimum of 6 months following rituximab initiation. RESULTS: Four hundred and thirty eight patients were included in the study. The main indication for rituximab therapy was haematological malignancy (76.0%). Two hundred and nine (47.7%) failed to receive appropriate HBV screening, 86 (19.6%) had neither HBsAg nor HBcAb performed, and 119 (27.2%) had only HBsAg performed. The identified prevalence of at-risk cases (either HBsAg- or HBcAb-positive) within the study population was 4.6% (20/438 cases). One case of HBV reactivation was identified, but none led to acute liver failure, transplantation or death. CONCLUSIONS: Poor adherence to HBV screening protocols suggests the need for targeted clinician education and system redesign. While the rate of reactivation was low, the prevalence of at-risk patients in this population was high and justifies further initiatives to increase adherence rates to HBV screening pre-rituximab.

Good outcomes of liver transplantation for hepatitis C at a low volume centre.

BACKGROUND AND AIMS: Concerns exist about outcomes of liver transplantation (LT) from low volume centres, especially for hepatitis C (HCV) patients. The aim of the study was to assess patient outcomes as well as their predictors post LT for HCV in a small volume Australian unit (< 25 LTs/year), comparing these with the average outcomes obtained from national and international transplant registries. Patients transplanted for HCV at the South Australian Liver Transplant Unit between 1992 and 2012 were studied. Outcomes assessed were patient and graft survival at 1,3, and 5 years. Factors independently associated with the outcomes were assessed using Cox regression model. RESULTS: 1, 3, and 5-year patient survival for HCV patients was 95.2, 82.9, and 78.2%, graft survival were 93.7, 80.1, and 75.5% respectively. The total follow-up time observed was 299.9 years amongst 61 patients in which there were 16 deaths. The expected number of deaths was 40.4 and the standardized mortality ratio 0.40 (95% CI = 0.24, 0.65). These results compared favourably to those obtained from the SRTR registry. Variables independently associated with lower patient survival: donor age (HR = 1.06, 95% CI 1.02 - 1.11; P = 0.003), and post LT cytomegalovirus (CMV) disease requiring treatment (HR = 4.03, 95% CI 1.48 - 10.92;P = 0.06). CONCLUSION: In conclusion, high rates of patient and graft survival for HCV liver transplantation can be obtained in a small volume unit. Young donor age and lack of CMV disease post-transplant were associated with better outcomes. Institutional factors may be influential determinants of outcomes.

Hepatitis C Virus Antiviral Drug Resistance and Salvage Therapy Outcomes Across Australia.

Background: Hepatitis C virus (HCV) infection can now be cured with well-tolerated direct-acting antiviral (DAA) therapy. However, a potential barrier to HCV elimination is the emergence of resistance-associated substitutions (RASs) that reduce the efficacy of antiviral drugs, but real-world studies assessing the clinical impact of RASs are limited. Here, an analysis of the impact of RASs on retreatment outcomes for different salvage regimens in patients nationally who failed first-line DAA therapy is reported. Methods: We collected data from 363 Australian patients who failed first-line DAA therapy, including: age, sex, fibrosis stage, HCV genotype, NS3/NS5A/NS5B RASs, details of failed first-line regimen, subsequent salvage regimens, and treatment outcome. Results: Of 240 patients who were initially retreated as per protocol, 210 (87.5%) achieved sustained virologic response (SVR) and 30 (12.5%) relapsed or did not respond. The SVR rate for salvage regimens that included sofosbuvir/velpatasvir/voxilaprevir was 94.3% (n = 140), sofosbuvir/velpatasvir 75.0% (n = 52), elbasvir/grazoprevir 81.6% (n = 38), and glecaprevir/pibrentasvir 84.6% (n = 13). NS5A RASs were present in 71.0% (n = 210) of patients who achieved SVR and in 66.7% (n = 30) of patients who subsequently relapsed. NS3 RASs were detected in 20 patients (20%) in the SVR group and 1 patient in the relapse group. NS5B RASs were observed in only 3 patients. Cirrhosis was a predictor of relapse after retreatment, as was previous treatment with sofosbuvir/velpatasvir. Conclusions: In our cohort, the SVR rate for sofosbuvir/velpatasvir/voxilaprevir was higher than with other salvage regimens. The presence of NS5A, NS5B, or NS3 RASs did not appear to negatively influence retreatment outcomes.

High risk of cytomegalovirus infection following solid organ transplantation despite prophylactic therapy.

Cytomegalovirus infection (CMV) in solid organ transplant recipients is a major clinical problem. The aim of this study was to evaluate the incidence of CMV infection and its association with mortality during the first year after transplantation in a large solid organ transplant cohort at the Royal Infirmary of Edinburgh between January 2006 and April 2009. Data including the use of CMV prophylaxis, nature of CMV disease, treatment and deceased date (when appropriate) was collected retrospectively using hospital databases and patient notes for all transplanted patients with detectable CMV viraemia. The outcomes between recipients of kidney and liver transplants in the four CMV donor/recipient serostatus categories (D+R+, D-R-, D+R-, D-R+) were compared. A total of 428 individuals were included. Despite the administration of valganciclovir prophylaxis, CMV disease (syndrome or end-organ involvement) was diagnosed within the year of transplantation in the D+R--group in 31.3% of liver and 19.2% of kidney recipients. All D+R- transplant recipients that received CMV-prophylaxis presented with late-onset CMV disease. Furthermore, the rate of CMV disease in the D+R+-group was markedly higher in renal graft recipients compared to liver recipients (22% vs. 5%). The highest mortality was observed among the D+R+ liver and kidney graft recipients with CMV infection. The high incidence of late-onset CMV disease in D+R- transplant recipients receiving CMV prophylaxis demonstrates that CMV disease remains an important problem after organ transplantation. Furthermore, the surprisingly high mortality in the D+R+-transplant patients with CMV viraemia highlights the need for proactive monitoring of this group.