Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.

BACKGROUND: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. METHODS: In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26. RESULTS: Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×1011 vg, 6.40×1011 vg, 8.32×1011 vg, or 1.28×1012 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels. CONCLUSIONS: Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017-000852-24 and 2017-005080-40.).

Repeated courses of transarterial embolization with polyvinyl alcohol particles: 'long life elixir' in a cirrhotic patient with unresectable hepatocellular carcinoma.

Chemoembolization improves survival in selected cirrhotic patients with hepatocellular carcinoma, but prolonged survival is unusual. In this study, a 70-year-old cirrhotic patient, who had a histologically proven hepatocellular carcinoma of 5 cm diameter, embolization with polyvinyl alcohol particles alone, without chemotherapeutic agent, has resulted in continued survival, of 5 years to date, with virtual elimination of residual hypervascularity following 10 sessions of embolization, and with continued patency of the injected branch of the hepatic artery. Provided liver function is maintained, embolization alone appears a feasible long term and effective therapy for unresectable hepatocellular carcinoma.

Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies.

BACKGROUND: Chemoembolization (TACE) improves survival in cirrhotic patients with hepatocellular carcinoma (HCC). The optimal schedule, or whether embolization (TAE) alone gives the same survival advantage, is not known. PURPOSE: To evaluate whether specific patient characteristics and/or radiological transarterial techniques result in better outcomes. METHOD: A PubMed search was carried out for cohort and randomized trials (n = 175) testing transarterial therapies; meta-analysis was performed where appropriate. RESULTS: Anticancer drugs were used as sole agent in 75% of cases (double 15% and triple 6%): doxorubicin (36%), cisplatin (31%), epirubicin (12%), mitoxantrone (8%), mitomycin (8%), and SMANCS (5%). Embolizing agents used were: gelatin sponge particles (71%), polyvinyl alcohol (PVA) particles (8%), degradable starch microspheres (DSM) (4%), and embospheres (4%). Sessions per patient were 2.5 +/- 1.5 (interval: 2 months). Objective response was 40 +/- 20%; survival rates at 1, 2, 3, and 5 years were: 62 +/- 20%, 42 +/- 17%, 30 +/- 15%, and 19 +/- 16%, respectively, and survival time was 18 +/- 9.5 months. The post-TACE complications were: acute liver failure, 7.5% (range 0-49%); acute renal failure, 1.8% (0-13%); encephalopathy, 1.8% (0-16%); ascites, 8.3% (0-52%); upper gastrointestinal bleeding; 3% (0-22%); and hepatic or splenic abscess, 1.3% (0-2.5%). Treatment-related mortality was 2.4% (0-9.5%), mainly due to acute liver failure. Our meta-analysis of nine randomized controlled trials (RCTs) confirmed that TACE improves survival; but a meta-analysis of TACE versus TAE alone (3 RCTs, 412 patients) demonstrated no survival difference. CONCLUSIONS: No chemotherapeutic agent appears better than any other. There is no evidence for benefit with lipiodol. Gelatin sponge is the most used embolic agent, but PVA particles may be better. TAE appears as effective as TACE. New strategies to reduce the risk of post-TACE complications are required.

Treatment outcomes for hepatocellular carcinoma using chemoembolization in combination with other therapies.

BACKGROUND: Although transarterial chemoembolization (TACE) improves survival in patients with hepatocellular carcinoma (HCC), it is not known if TACE combined with other treatments is beneficial. AIM: To evaluate the evidence for improved outcomes in HCC with a multimodal treatment approach involving TACE. METHOD: PubMed search for all cohort and randomized trials (n=84) evaluating TACE combined with other therapies; meta-analysis performed where appropriate. RESULTS: A meta-analysis involving 4 RCTs showed a significant decrease in mortality favouring combination treatment (TACE plus percutaneous ablation) compared to monotherapy in patients with either small (<3cm) or large HCC nodules (>3cm) (OR, 0.534; 95% CI, 0.288-0.990; p=0.046). TACE combined with local radiotherapy improved survival in patients with tumour thrombosis of the portal vein in 7 non-randomized studies. Two RCTs and 13 non-randomized studies showed that TACE prior to hepatic resection does not improve survival nor tumour recurrence. Conversely, 2 RCTs and 5 comparative studies showed that transarterial injection of chemotherapeutic drugs mixed with lipiodol (TOCE) following hepatectomy confers survival benefit and less tumour recurrence. TACE before liver transplantation is safe and reduces drop-out rate from the waiting list, but there is no current evidence of improvement in subsequent survival or recurrence rate. CONCLUSIONS: A combined approach involving TACE and percutaneous ablation improves survival. Adjuvant TOCE improves outcome after hepatectomy. TACE is useful to control tumours burden while on the waiting list for OLT. Multimodal treatment seems to be the best way to optimize TACE outcomes in HCC.

Sustained, spontaneous disappearance of serum HCV-RNA under immunosuppression after liver transplantation for HCV cirrhosis.

Immunosuppression is a main determinant for the increased Hepatitis C Virus (HCV) replication after liver transplantation and the accelerated course of recurrent HCV liver disease. We present two patients both with diabetes, renal dysfunction with proteinuria converted to sirolimus therapy, who cleared serum HCV RNA without antiviral treatment. This is a potentially important observation that should stimulate study into factors that may help viral clearance from blood.

Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation.

In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13-73) and median follow-up of 38 months (1-155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short-term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage > or = 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76-4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23-0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage.

Liver transplantation in cirrhotic patients with small hepatocellular carcinoma: an analysis of pre-operative imaging, explant histology and prognostic histologic indicators.

BACKGROUND: In recent years, liver transplantation in patients with hepatocellular cancers and cirrhosis has been restricted to those with small cancers (<5 cm for solitary and <3 cm for multifocal HCC with <3 nodules). The selection of patients for liver transplantation is based on pre-operative imaging. The accuracy of imaging correlated with explant histology and the effect of tumour stage has not been evaluated in this selected population. METHODS: In this study, prospectively collected data for 30 patients who underwent orthotopic liver transplantation for cirrhosis complicated by small hepatocellular carcinoma (HCC) at a single centre have been reviewed with the aim of correlating radiological findings, explant histology and patient outcome. Patients who underwent orthotopic liver transplantation between 1995 and 1999 had plain and contrast-enhanced dual-phase spiral CT (DCT) scans of the liver. Patients suspected of having HCC on CT scan or due to elevated serum alpha-fetoprotein underwent iodized oil CT (IOCT). Following transplantation, the explanted liver was serially sectioned at 10-mm intervals and examined by a pathologist blinded to the results of imaging. Data collected prospectively on imaging and histology were compared with outcome data. The median period of follow-up was 1,139 days (range 690-1,955 days) after transplantation. All patients were followed up by clinical assessment, assessment of serum alpha-protein levels and imaging when indicated. RESULTS: All the patients transplanted fulfilled the selective criteria on the basis of imaging (solitary HCC <5 cm in diameter or multifocal HCC <3 cm in diameter with <3 nodules). Of the 30 patients transplanted, 46 HCCs were detected on explant histology with a median size of 24 mm (range 6-75 mm). Ten patients had multifocal disease (median number of lesions 2, range 2-4). No significant difference was observed between IOCT and DCT with regards to the sensitivity (67.4 vs. 68%) and specificity (78.97 vs. 88.6%) of detecting HCCs. IOCT had a positive predictive value of 78.9% as compared to 82.8% for DCT. IOCT had an overall sensitivity of 40% as compared to 30% for DCT in detecting multifocal disease (not significant). Histological assessment of the explanted livers showed that 8 patients had well-, 17 moderate and 5 poorly differentiated HCCs. Tumour size and the presence of multifocal disease did not influence survival in this study. Microvascular invasion was more common with larger tumours (from 38% with lesions less than 40 mm in diameter to 60% with lesions >40 mm in diameter; p < 0.01) and with moderately (29.4%) or poorly differentiated (60%) HCCs than well-differentiated HCC (12.5%) (p < 0.04 and 0.01 for well- vs. moderately and poorly differentiated HCC, respectively). Microvascular invasion on explant histology was associated with poor survival. Of the 17 transplant recipients without vascular invasion, 15 were alive at 1 and 2 years in comparison to 7 of 9 with microscopic vascular invasion (p < 0.01). Four patients died in the post-transplant period due to recurrent HCC. Overall survival [after excluding early post-transplant sepsis-induced deaths (n = 4)] at 1 year was 83.3%. CONCLUSIONS: Selective criteria for transplantation of HCC in cirrhosis are associated with a 1-year and 3-year survival rate of 73.3% (including early post-transplant sepsis-induced deaths). IOCT and DCT are similar in their ability to detect unifocal or multifocal HCC. Tumour size and number are not predictive of recurrence with these selective criteria, but microscopic vascular invasion is a bad prognostic factor.

Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation.

BACKGROUND: Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described. METHODS: In 45 patients with serum creatinine more than 120 micromol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1-49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus