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1.
Am J Transplant ; 2024 May 21.
Article in English | MEDLINE | ID: mdl-38782187

ABSTRACT

Post-transplant diabetes mellitus (PTDM) is a prevalent complication of liver transplantation and is associated with cardiometabolic complications. We studied the consequences of genetic effects of liver donors and recipients on PTDM outcomes, focusing on the diverse genetic pathways related to insulin that play a role in the development of PTDM. 1115 liver transplant recipients without a pre-transplant diagnosis of type 2 diabetes mellitus (T2D) and their paired donors recruited from two transplant centers had polygenic risk scores (PRS) for T2D, insulin secretion, and insulin sensitivity calculated. Among recipients in the highest T2D-PRS quintile, donor T2D-PRS did not contribute significantly to PTDM. However, in recipients with the lowest T2D genetic risk, donor livers with the highest T2D-PRS contributed to the development of PTDM (OR (95% CI)=3.79 (1.10-13.1), p=0.035). Recipient risk was linked to factors associated with insulin secretion (OR (95% CI) = 0.85 (0.74-0.98), p=0.02), while donor livers contributed to PTDM via gene pathways involved in insulin sensitivity (OR (95% CI)=0.86 (0.75-0.99), p=0.03). Recipient and donor PRS independently and collectively serve as predictors of PTDM onset. The genetically influenced biological pathways in recipients primarily pertain to insulin secretion, whereas the genetic makeup of donors exerts an influence on insulin sensitivity.

2.
Aliment Pharmacol Ther ; 59(12): 1489-1509, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38693712

ABSTRACT

BACKGROUND: The increase in prevalence of liver disease globally will lead to a substantial incremental burden on intensive care requirements. While liver transplantation offers a potential life-saving intervention, not all patients are eligible due to limitations such as organ availability, resource constraints, ongoing sepsis or multiple organ failures. Consequently, the focus of critical care of patients with advanced and decompensated cirrhosis turns to liver-centric intensive care protocols, to mitigate the high mortality in such patients. AIM: Provide an updated and comprehensive understanding of cirrhosis management in critical care, and which includes emergency care, secondary organ failure management (mechanical ventilation, renal replacement therapy, haemodynamic support and intensive care nutrition), use of innovative liver support systems, infection control, liver transplantation and palliative and end-of life care. METHODS: We conducted a structured bibliographic search on PubMed, sourcing articles published up to 31 March 2024, to cover topics addressed. We considered data from observational studies, recommendations of society guidelines, systematic reviews, and meta-analyses, randomised controlled trials, and incorporated our clinical expertise in liver critical care. RESULTS: Critical care management of the patient with cirrhosis has evolved over time while mortality remains high despite aggressive management with liver transplantation serving as a crucial but not universally available resource. CONCLUSIONS: Implementation of organ support therapies, intensive care protocols, nutrition, palliative care and end-of-life discussions and decisions are an integral part of critical care of the patient with cirrhosis. A multi-disciplinary approach towards critical care management is likely to yield better outcomes.


Subject(s)
Critical Care , Critical Illness , Liver Cirrhosis , Liver Transplantation , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/therapy , Critical Illness/therapy , Critical Care/methods , Palliative Care/methods , Terminal Care/methods
3.
Liver Transpl ; 2024 May 22.
Article in English | MEDLINE | ID: mdl-38771635

ABSTRACT

BACKGROUND AND AIMS: Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and as such was assessed in a population comprised of liver transplant (LT) candidates. METHODS AND RESULTS: Fifty hospitalized, LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. ACLF grade 3, serum creatinine (SCr)>5.0 mg/dL, or MELD≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide (M&O) or norepinephrine (NorEpi) for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as ≥30% decrease in SCr with EOT SCr≤1.5, partial response (PR) as ≥30% decrease in SCr with EOT SCr>1.5, and non-response (NR) as <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p<0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. CONCLUSIONS: With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical M&O/NorEpi cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

4.
Hepatol Int ; 18(3): 876-891, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38472607

ABSTRACT

Individuals with cirrhosis experience higher morbidity and mortality rates than the general population, irrespective of the type or scope of surgery. This increased risk is attributed to adverse effects of liver disease, encompassing coagulation dysfunction, altered metabolism of anesthesia and sedatives, immunologic dysfunction, hemorrhage related to varices, malnutrition and frailty, impaired wound healing, as well as diminished portal blood flow, overall hepatic circulation, and hepatic oxygen supply during surgical procedures. Therefore, a frequent clinical dilemma is whether surgical interventions should be pursued in patients with cirrhosis. Several risk scores are widely used to aid in the decision-making process, each with specific advantages and limitations. This review aims to discuss the preoperative risk factors in patients with cirrhosis, describe and compare surgical risk assessment models used in everyday practice, provide insights into the surgical risk according to the type of surgery and present recommendations for optimizing those with cirrhosis for surgical procedures. As the primary focus is on currently available risk models, the review describes the predictive value of each model, highlighting its specific advantages and limitations. Furthermore, for models that do not account for the type of surgical procedure to be performed, the review suggests incorporating both patient-related and surgery-related risks into the decision-making process. Finally, we provide an algorithm for the preoperative assessment of patients with cirrhosis before elective surgery as well as guidance perioperative management.


Subject(s)
Liver Cirrhosis , Humans , Liver Cirrhosis/complications , Liver Cirrhosis/surgery , Risk Assessment/methods , Risk Factors , Postoperative Complications/etiology
5.
Aliment Pharmacol Ther ; 59(9): 1096-1110, 2024 May.
Article in English | MEDLINE | ID: mdl-38538967

ABSTRACT

BACKGROUND/AIMS: We examined the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) initiation on long-term Adverse Liver Outcomes (ALO) in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) cirrhosis and type 2 diabetes using real-world data from the MarketScan database. METHODS: We conducted a retrospective cohort study of patients with MASLD cirrhosis and type 2 diabetes between 2012 and 2020. Cox proportional hazard models examine the association between GLP-1RAs initiation, modelled as time-dependent, and the risk of ALO, a composite endpoint defined by the first occurrence of hepatic decompensation(s), portal hypertension, hepatocellular carcinoma (HCC) or liver transplantation (LT). We used Overlap Propensity Score Weighting (OPSW) to account for confounding. The study included 459 GLP-1RAs and 4837 non-GLP-1RAs patients. RESULTS: The non-GLP-1RAs patients presented with 1411 (29%) ALO over 7431.7 person years, while GLP-1RAs patients had 32 (7%) ALO over 586.6 person years - risk rate difference 13.5 (95% CI: 11.4-15.7) per 100 person-years. The OPSW-adjusted risk of ALO was reduced by 36% (hazard ratio [HR]: 0.64; 95% CI: 0.54-0.76) in patients with vs. without GLP-1RAs initiation. GLP-1RAs initiation was associated with significant reductions in the adjusted risk of hepatic decompensation (HR: 0.74; 95% CI: 0.61-0.88), portal hypertension (HR: 0.73; 95% CI: 0.60-0.88), HCC (HR: 0.37; 95% CI: 0.20-0.63) and LT (HR: 0.24; 95% CI: 0.12-0.43). CONCLUSION: The use of GLP-1RAs was associated with significant risk reductions in long-term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC and LT, in MASLD cirrhosis patients with type 2 diabetes.


Subject(s)
Carcinoma, Hepatocellular , Diabetes Mellitus, Type 2 , Fatty Liver , Hypertension, Portal , Liver Neoplasms , Metabolic Diseases , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/adverse effects , Glucagon-Like Peptide-1 Receptor Agonists , Carcinoma, Hepatocellular/complications , Retrospective Studies , Liver Neoplasms/complications , Fatty Liver/complications , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Metabolic Diseases/complications , Hypertension, Portal/drug therapy , Hypertension, Portal/complications
6.
Hepatol Commun ; 8(2)2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38285883

ABSTRACT

BACKGROUND: The natural history of primary sclerosing cholangitis (PSC) among African Americans (AA) is not well understood. METHODS: Transplant-free survival and hepatic decompensation-free survival were assessed using a retrospective research registry from 16 centers throughout North America. Patients with PSC alive without liver transplantation after 2008 were included. Diagnostic delay was defined from the first abnormal liver test to the first abnormal cholangiogram/liver biopsy. Socioeconomic status was imputed by the Zip code. RESULTS: Among 850 patients, 661 (77.8%) were non-Hispanic Whites (NHWs), and 85 (10.0%) were AA. There were no significant differences by race in age at diagnosis, sex, or PSC type. Inflammatory bowel disease was more common in NHWs (75.8% vs. 51.8% p=0.0001). The baseline (median, IQR) Amsterdam-Oxford Model score was lower in NHWs (14.3, 13.4-15.2 vs. 15.1, 14.1-15.7, p=0.002), but Mayo risk score (0.03, -0.8 to 1.1 vs. 0.02, -0.7 to 1.0, p=0.83), Model for End-stage Liver Disease (5.9, 2.8-10.7 vs. 6.4, 2.6-10.4, p=0.95), and cirrhosis (27.4% vs. 27.1%, p=0.95) did not differ. Race was not associated with hepatic decompensation, and after adjusting for clinical variables, neither race nor socioeconomic status was associated with transplant-free survival. Variables independently associated with death/liver transplant (HR, 95% CI) included age at diagnosis (1.04, 1.02-1.06, p<0.0001), total bilirubin (1.06, 1.04-1.08, p<0.0001), and albumin (0.44, 0.33-0.61, p<0.0001). AA race did not affect the performance of prognostic models. CONCLUSIONS: AA patients with PSC have a lower rate of inflammatory bowel disease but similar progression to hepatic decompensation and liver transplant/death compared to NHWs.


Subject(s)
Cholangitis, Sclerosing , End Stage Liver Disease , Inflammatory Bowel Diseases , Humans , Retrospective Studies , Cholangitis, Sclerosing/diagnosis , Black or African American , Delayed Diagnosis , Severity of Illness Index , Inflammatory Bowel Diseases/complications
7.
Hepatology ; 79(5): 1048-1064, 2024 May 01.
Article in English | MEDLINE | ID: mdl-37976391

ABSTRACT

BACKGROUND AND AIMS: Treatment of hepatorenal syndrome-acute kidney injury (HRS-AKI), with terlipressin and albumin, provides survival benefits, but may be associated with cardiopulmonary complications. We analyzed the predictors of terlipressin response and mortality using point-of-care echocardiography (POC-Echo) and cardiac and renal biomarkers. APPROACH: Between December 2021 and January 2023, patients with HRS-AKI were assessed with POC-Echo and lung ultrasound within 6 hours of admission, at the time of starting terlipressin (48 h), and at 72 hours. Volume expansion was done with 20% albumin, followed by terlipressin infusion. Clinical data, POC-Echo data, and serum biomarkers were prospectively collected. Cirrhotic cardiomyopathy (CCM) was defined per 2020 criteria. RESULTS: One hundred and forty patients were enrolled (84% men, 59% alcohol-associated disease, mean MELD-Na 25±SD 5.6). A median daily dose of infused terlipressin was 4.3 (interquartile range: 3.9-4.6) mg/day; mean duration 6.4 ± SD 1.9 days; the complete response was in 62% and partial response in 11%. Overall mortality was 14% and 16% at 30 and 90 days, respectively. Cutoffs for prediction of terlipressin nonresponse were cardiac variables [ratio of early mitral inflow velocity and mitral annular early diastolic tissue doppler velocity > 12.5 (indicating increased left filling pressures, C-statistic: 0.774), tissue doppler mitral velocity < 7 cm/s (indicating impaired relaxation; C-statistic: 0.791), > 20.5% reduction in cardiac index at 72 hours (C-statistic: 0.885); p < 0.001] and pretreatment biomarkers (CysC > 2.2 mg/l, C-statistic: 0.640 and N-terminal proBNP > 350 pg/mL, C-statistic: 0.655; p <0.050). About 6% of all patients with HRS-AKI and 26% of patients with CCM had pulmonary edema. The presence of CCM (adjusted HR 1.9; CI: 1.8-4.5, p = 0.009) and terlipressin nonresponse (adjusted HR 5.2; CI: 2.2-12.2, p <0.001) were predictors of mortality independent of age, sex, obesity, DM-2, etiology, and baseline creatinine. CONCLUSIONS: CCM and reduction in cardiac index, reliably predict terlipressin nonresponse. CCM is independently associated with poor survival in HRS-AKI.


Subject(s)
Acute Kidney Injury , Hepatorenal Syndrome , Male , Humans , Female , Terlipressin/therapeutic use , Vasoconstrictor Agents/therapeutic use , Hepatorenal Syndrome/diagnostic imaging , Hepatorenal Syndrome/drug therapy , Lypressin/therapeutic use , Point-of-Care Systems , Acute Kidney Injury/complications , Liver Cirrhosis/complications , Albumins/therapeutic use , Echocardiography , Biomarkers , Treatment Outcome
10.
Transplantation ; 108(3): 713-723, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-37635282

ABSTRACT

BACKGROUND: Outcomes after living-donor liver transplantation (LDLT) at high Model for End-stage Liver Disease (MELD) scores are not well characterized in the United States. METHODS: This was a retrospective cohort study using Organ Procurement and Transplantation Network data in adults listed for their first liver transplant alone between 2002 and 2021. Cox proportional hazards models evaluated the association of MELD score (<20, 20-24, 25-29, and ≥30) and patient/graft survival after LDLT and the association of donor type (living versus deceased) on outcomes stratified by MELD. RESULTS: There were 4495 LDLTs included with 5.9% at MELD 25-29 and 1.9% at MELD ≥30. LDLTs at MELD 25-29 and ≥30 LDLT have substantially increased since 2010 and 2015, respectively. Patient survival at MELD ≥30 was not different versus MELD <20: adjusted hazard ratio 1.67 (95% confidence interval, 0.96-2.88). However, graft survival was worse: adjusted hazard ratio (aHR) 1.69 (95% confidence interval, 1.07-2.68). Compared with deceased-donor liver transplant, LDLT led to superior patient survival at MELD <20 (aHR 0.92; P = 0.024) and 20-24 (aHR 0.70; P < 0.001), equivalent patient survival at MELD 25-29 (aHR 0.97; P = 0.843), but worse graft survival at MELD ≥30 (aHR 1.68, P = 0.009). CONCLUSIONS: Although patient survival remains acceptable, the benefits of LDLT may be lost at MELD ≥30.


Subject(s)
End Stage Liver Disease , Liver Transplantation , Adult , Humans , United States , Living Donors , Liver Transplantation/adverse effects , End Stage Liver Disease/diagnosis , End Stage Liver Disease/surgery , Retrospective Studies , Severity of Illness Index , Graft Survival , Treatment Outcome
11.
Transplantation ; 108(3): 693-702, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-37953470

ABSTRACT

BACKGROUND: The gap between demand and supply for solid organ transplants requires strategies to expand the donor pool. Successful use of hepatitis B virus (HBV)-positive grafts has been reported in liver transplantation. METHODS: In this United Network for Organ Sharing database (January 1999 to June 2021) retrospective cohort study, outcomes of kidney transplant (KT) or heart transplant (HT) recipients with HBV donor grafts (hepatitis B surface antigen and/or for HBV nucleic acid test-positive) were examined. Propensity score matching was performed for HBV-positive to negative graft recipients (1:5 for renal transplantation and 1:10 for HT). RESULTS: Of 448 HBV-positive donors with 896 kidneys, 352 kidneys (39.3%) and 56 hearts (12.5%) were transplanted. Of these, 312 kidneys (88.6%) and 45 hearts (80.3%) were transplanted in hepatitis B surface antigen-negative recipients. Ten-year graft survival was 47.1% and 49% (log-rank P = 0.353), and patient survival was 58% and 59% ( P = 0.999) for KT recipients. Similar figures among HT recipients were 41.9% and 38.9% for graft survival ( P = 0.471), and 54.3% and 61.2% for patient survival ( P = 0.277). Subgroup analyses in recipients with HBV nucleic acid test-positive grafts irrespective of antibodies to HBV core antigen-positive status, and recipients negative for anti-HBs (548 renal transplantation and 209 HT) were similar. CONCLUSIONS: Although we are limited by lack of available data on posttransplant anti-HBV treatment, the study observations suggest that using HBV-positive grafts is a reasonable strategy to expand the donor pool among candidates waiting for KT or HT.


Subject(s)
Heart Transplantation , Hepatitis B , Nucleic Acids , Humans , United States/epidemiology , Hepatitis B virus/genetics , Hepatitis B/diagnosis , Hepatitis B Surface Antigens , Retrospective Studies , Heart Transplantation/adverse effects , Hepatitis B Antibodies , Tissue Donors , Kidney
12.
Liver Transpl ; 30(4): 347-355, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-37801553

ABSTRACT

Hepatorenal syndrome-acute kidney injury (HRS-AKI), a serious complication of decompensated cirrhosis, has limited therapeutic options and significant morbidity and mortality. Terlipressin improves renal function in some patients with HRS-1, while liver transplantation (LT) is a curative treatment for advanced chronic liver disease. Renal failure post-LT requiring renal replacement therapy (RRT) is a major risk factor for graft and patient survival. A post hoc analysis with a 12-month follow-up of LT recipients from a placebo-controlled trial of terlipressin (CONFIRM; NCT02770716) was conducted to evaluate the need for RRT and overall survival. Patients with HRS-1 were treated with terlipressin plus albumin or placebo plus albumin for up to 14 days. RRT was defined as any type of procedure that replaced kidney function. Outcomes compared between groups included the incidence of HRS-1 reversal, the need for RRT (pretransplant and posttransplant), and overall survival. Of the 300 patients in CONFIRM (terlipressin n = 199; placebo, n = 101), 70 (23%) underwent LT alone (terlipressin, n = 43; placebo, n = 27) and 5 had simultaneous liver-kidney transplant (terlipressin, n = 3, placebo, n = 2). The rate of HRS reversal was significantly higher in the terlipressin group compared with the placebo group (37%, n = 16 vs. 15%, n = 4; p = 0.033). The pretransplant need for RRT was significantly lower among those who received terlipressin ( p = 0.007). The posttransplant need for RRT, at 12 months, was significantly lower among those patients who received terlipressin and were alive at Day 365, compared to placebo ( p = 0.009). Pretransplant treatment with terlipressin plus albumin in patients with HRS-1 decreased the need for RRT pretransplant and posttransplant.


Subject(s)
Hepatorenal Syndrome , Liver Transplantation , Humans , Terlipressin/adverse effects , Hepatorenal Syndrome/etiology , Hepatorenal Syndrome/therapy , Vasoconstrictor Agents/therapeutic use , Liver Transplantation/adverse effects , Renal Replacement Therapy/adverse effects , Albumins/adverse effects , Lypressin/adverse effects , Treatment Outcome , Liver Cirrhosis/complications
13.
Am J Gastroenterol ; 119(4): 712-718, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-37938163

ABSTRACT

INTRODUCTION: Hospitalized patients with cirrhosis can develop respiratory failure (RF), which is associated with a poor prognosis, but predisposing factors are unclear. METHODS: We prospectively enrolled a multicenter North American cirrhosis inpatient cohort and collected admission and in-hospital data (grading per European Association for the Study of Liver-Chronic Liver Failure scoring system, acute kidney injury [AKI], infections [admission/nosocomial], and albumin use) in an era when terlipressin was not available in North America. Multivariable regression to predict RF was performed using only admission day and in-hospital events occurring before RF. RESULTS: A total of 511 patients from 14 sites (median age 57 years, admission model for end-stage liver disease [MELD]-Na 23) were enrolled: RF developed in 15%; AKI occurred in 24%; and 11% developed nosocomial infections (NI). At admission, patients who developed RF had higher MELD-Na, gastrointestinal (GI) bleeding/AKI-related admission, and prior infections/ascites. During hospitalization, RF developers had higher NI (especially respiratory), albumin use, and other organ failures. RF was higher in patients receiving albumin (83% vs 59%, P < 0.0001) with increasing doses (269.5 ± 210.5 vs 208.6 ± 186.1 g, P = 0.01) regardless of indication. Admission for AKI, GI bleeding, and high MELD-Na predicted RF. Using all variables, NI (odds ratio [OR] = 4.02, P = 0.0004), GI bleeding (OR = 3.1, P = 0.002), albumin use (OR = 2.93, P = 0.01), AKI (OR = 3.26, P = 0.008), and circulatory failure (OR = 3.73, P = 0.002) were associated with RF risk. DISCUSSION: In a multicenter inpatient cirrhosis study of patients not exposed to terlipressin, 15% of patients developed RF. RF risk was highest in those admitted with AKI, those who had GI bleeding on admission, and those who developed NI and other organ failures or received albumin during their hospital course. Careful volume monitoring and preventing nosocomial respiratory infections and renal or circulatory failures could reduce this risk.


Subject(s)
Acute Kidney Injury , Cross Infection , End Stage Liver Disease , Humans , Middle Aged , Inpatients , End Stage Liver Disease/complications , Severity of Illness Index , Liver Cirrhosis/complications , Acute Kidney Injury/etiology , Acute Kidney Injury/complications , Albumins
15.
Transplantation ; 2023 Nov 13.
Article in English | MEDLINE | ID: mdl-37953481

ABSTRACT

BACKGROUND: In 2015, the United Network for Organ Sharing implemented a policy introducing a 6-mo waiting period before granting model for end-stage liver disease exception points to liver transplant (LT) candidates with hepatocellular carcinoma (HCC). This study analyzes the policy impact on post-LT HCC recurrence. METHODS: This was a United Network for Organ Sharing retrospective cohort study of patients with HCC who underwent LT from January 1, 2010, to May 31, 2019. HCC-specific data included alpha-fetoprotein, tumor characteristics, locoregional therapy (LRT), and explant data used to calculate the Risk Estimation of Tumor Recurrence After Transplant score. The primary exposure was pre-/post-policy era, divided on October 8, 2015. Survival analysis techniques were used to evaluate the unadjusted and sequentially adjusted association between policy era and HCC recurrence, accounting for competing risks. RESULTS: A total of 7940 patients were included, 5879 (74.0%) pre-policy era and 2061 (26.0%) post-policy era. Post-policy patients were older, received more LRT, and had lower alpha-fetoprotein levels and smaller tumor sizes at transplant. Incidence rates of HCC recurrence were 19.8 and 13.7 events per 1000 person-years for pre- and post-policy eras, respectively. Post-policy era was associated with an unadjusted 35% reduction in the risk of HCC recurrence (P < 0.001). After adjusting for recipient, donor, and tumor characteristics at listing this association remained (subhazard ratio 0.69; 95% confidence interval, 0.55-0.86; P = 0.001); however, after additionally adjusting for LRT episodes and Risk Estimation of Tumor Recurrence After Transplant score, there was no longer a statistically significant association (subhazard ratio 0.77; 95% confidence interval, 0.59-1.00; P = 0.054). CONCLUSIONS: We observed a significant reduction in post-LT HCC recurrence after policy implementation. This may be due to waitlist selection of healthier patients, increased LRT utilization, and potential selection of favorable tumor biology.

16.
Contemp Clin Trials Commun ; 36: 101211, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37953795

ABSTRACT

Background: Hepatorenal syndrome-acute kidney injury (HRS-AKI) carries significant morbidity and mortality among those with end-stage liver disease. Bolus terlipressin for treatment of HRS-AKI received FDA approval in September 2022. US implementation of terlipressin, however, is hindered by the paucity of local data on the optimal patient population and administration mode, as well as the effect on transplant priority. The INFUSE study is designed to evaluate the use of continuous terlipressin infusion among transplant candidates with advanced liver disease and HRS-AKI. Methods: Fifty prospective patients with HRS-AKI will receive a single bolus of terlipressin 0.5 mg followed by continuous infusions of terlipressin from 2 to 8 mg/day for up to 14 days. The cohort will be enriched with those listed, in evaluation, or eligible for liver transplantation, while those with ACLF grade 3, MELD ≥35, and serum creatinine >5.0 mg/dL will be excluded. Fifty patients who received midodrine plus octreotide or norepinephrine for HRS-AKI will serve as a retrospective comparator cohort. Conclusion: The INFUSE study aims to assess the safety and efficacy of continuous terlipressin infusion among largely transplant-eligible patients with HRS-AKI, and to provide US-based data on transplant outcomes. This novel study design simultaneously mitigates terlipressin adverse events while providing renal benefits to patients, thus addressing the unmet medical need of those with HRS-AKI who have limited treatment options and are awaiting liver transplantation in the US.

17.
Expert Rev Gastroenterol Hepatol ; 17(11): 1067-1079, 2023.
Article in English | MEDLINE | ID: mdl-37856367

ABSTRACT

INTRODUCTION: Kidney is the most common extra-hepatic organ involved in patients with advanced liver cirrhosis and acute-on-chronic liver failure. Hepatorenal syndrome-acute kidney injury (HRS-AKI) accounts for most hospitalizations, and liver transplantation (LT) remains the ultimate and long-term treatment in such patients. However, HRS-AKI, being a functional renal failure, has a fair chance of reversal, and as such, patients who achieve reversal of HRS-AKI have better outcomes post-LT. AREAS COVERED: In this review, we discuss the pharmacokinetics, pharmacodynamics and evidence to support the use of terlipressin in HRS-AKI while we also address predictors of response and the associated adverse events. Further, we discuss the role of terlipressin in the context of LT. EXPERT OPINION: The recommended treatment for HRS-AKI reversal includes a vasoconstrictor in addition to volume expansion with albumin. The three vasoconstrictor regimens generally used to treat HRS-AKI include octreotide plus midodrine, noradrenaline, and terlipressin. Of these, terlipressin is a widely used drug and has been recently approved by US Food and Drug Administration (USFDA) for HRS-AKI. Terlipressin is the most effective drug for HRS-AKI reversal and is associated with a decreased need for renal replacement therapy pre- and post-transplant. Furthermore, terlipressin responders have improved transplant-free and post-transplant survival.


Subject(s)
Acute Kidney Injury , Hepatorenal Syndrome , Midodrine , Humans , Adult , Terlipressin/adverse effects , Hepatorenal Syndrome/drug therapy , Hepatorenal Syndrome/etiology , Vasoconstrictor Agents/adverse effects , Midodrine/therapeutic use , Acute Kidney Injury/drug therapy
18.
Viruses ; 15(10)2023 09 29.
Article in English | MEDLINE | ID: mdl-37896803

ABSTRACT

A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child-Turcotte-Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3-4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated.


Subject(s)
Hepatitis C, Chronic , Hepatitis C , Adult , Humans , Sofosbuvir/adverse effects , Ribavirin/adverse effects , Hepacivirus/genetics , Antiviral Agents/adverse effects , Treatment Outcome , Hepatitis C/drug therapy , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/drug therapy , Genotype , Drug Therapy, Combination
19.
PLoS One ; 18(9): e0290889, 2023.
Article in English | MEDLINE | ID: mdl-37656704

ABSTRACT

A care cascade is a critical tool for evaluating delivery of care for chronic infections across sequential stages, starting with diagnosis and ending with viral suppression. However, there have been few data describing the hepatitis B virus (HBV) care cascade among people living with HIV infection who have HBV coinfection. We conducted a cross-sectional study among people living with HIV and HBV coinfection receiving care between January 1, 2012 and December 31, 2016 within 13 United States and Canadian clinical cohorts contributing data to the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). We evaluated each of the steps in this cascade, including: 1) laboratory-confirmed HBV infection, 2) tenofovir-based or entecavir-based HBV therapy prescribed, 3) HBV DNA measured during treatment, and 4) viral suppression achieved via undetectable HBV DNA. Among 3,953 persons with laboratory-confirmed HBV (median age, 50 years; 6.5% female; 43.8% were Black; 7.1% were Hispanic), 3,592 (90.9%; 95% confidence interval, 90.0-91.8%) were prescribed tenofovir-based antiretroviral therapy or entecavir along with their antiretroviral therapy regimen, 2,281 (57.7%; 95% confidence interval, 56.2-59.2%) had HBV DNA measured while on therapy, and 1,624 (41.1%; 95% confidence interval, 39.5-42.6) achieved an undetectable HBV DNA during HBV treatment. Our study identified significant gaps in measurement of HBV DNA and suppression of HBV viremia among people living with HIV and HBV coinfection in the United States and Canada. Periodic evaluation of the HBV care cascade among persons with HIV/HBV will be critical to monitoring success in completion of each step.


Subject(s)
Acquired Immunodeficiency Syndrome , Coinfection , HIV Infections , Hepatitis B , Female , Humans , Middle Aged , Male , Hepatitis B virus , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Coinfection/epidemiology , Cross-Sectional Studies , DNA, Viral , Canada/epidemiology , Hepatitis B/complications , Hepatitis B/drug therapy , Hepatitis B/epidemiology , Tenofovir/therapeutic use
20.
J Viral Hepat ; 30(11): 879-888, 2023 11.
Article in English | MEDLINE | ID: mdl-37488783

ABSTRACT

Hepatitis delta virus (HDV) infection increases the risk of liver complications compared to hepatitis B virus (HBV) alone, particularly among persons with human immunodeficiency virus (HIV). However, no studies have evaluated the prevalence or determinants of HDV infection among people with HIV/HBV in the US. We performed a cross-sectional study among adults with HIV/HBV coinfection receiving care at eight sites within the Center for AIDS Research Network of Integrated Clinical Systems (CNICS) between 1996 and 2019. Among patients with available serum/plasma specimens, we selected the first specimen on or after their initial HBV qualifying test. All samples were tested for HDV IgG antibody and HDV RNA. Multivariable log-binomial generalized linear models were used to estimate prevalence ratios (PRs) with 95% CIs of HDV IgG antibody-positivity associated with determinants of interest (age, injection drug use [IDU], high-risk sexual behaviour). Among 597 adults with HIV/HBV coinfection in CNICS and available serum/plasma samples (median age, 43 years; 89.9% male; 52.8% Black; 42.4% White), 24/597 (4.0%; 95% CI, 2.4%-5.6%) were HDV IgG antibody-positive, and 10/596 (1.7%; 95% CI, 0.6%-2.7%) had detectable HDV RNA. In multivariable analysis, IDU was associated with exposure to HDV infection (adjusted PR = 2.50; 95% CI, 1.09-5.74). In conclusion, among a sample of adults with HIV/HBV coinfection in care in the US, 4.0% were HDV IgG antibody-positive, among whom 41.7% had detectable HDV RNA. History of IDU was associated with exposure to HDV infection. These findings emphasize the importance of HDV testing among persons with HIV/HBV coinfection, especially those with a history of IDU.


Subject(s)
Coinfection , HIV Infections , Hepatitis B , Humans , Adult , Male , United States/epidemiology , Female , Hepatitis Delta Virus/genetics , HIV , Prevalence , Cross-Sectional Studies , HIV Infections/complications , HIV Infections/epidemiology , Hepatitis B/complications , Hepatitis B/epidemiology , Hepatitis B virus/genetics , RNA , Hepatitis Antibodies , Immunoglobulin G
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