Background & Aims There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. Methods In this phase 2, open-label study, we ...assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). Results We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%–89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%–98% of patients without cirrhosis or with compensated cirrhosis, by 85%−88% of patients with moderate hepatic impairment, by 60%–75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. Conclusion The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.
Vascular, autoimmune hepatitis, and malignant causes of acute-on-chronic liver failure are rare but important to consider and investigate in patients with underlying liver disease who present with ...acute deterioration and other more common etiologies have been excluded. Vascular processes including Budd-Chiari syndrome and portal vein thrombosis require imaging for diagnosis and anticoagulation is the mainstay of therapy. Patients may require advanced interventional therapy including transjugular intrahepatic portosystemic shunt or consideration of liver transplantation. Autoimmune hepatitis is a complex disease entity that requires a high degree of clinical suspicion and can present heterogeneously.
Background
Thrombocytopenia is the most common hematologic complication associated with chronic liver disease (CLD) with important clinical implications. While the mechanisms for thrombocytopenia are ...multifactorial, platelet sequestration in the spleen and decreased thrombopoietin (TPO) production are the main mechanisms in patients with CLD.
Aim
This review outlines the current treatment options for thrombocytopenia in patients with CLD, explores their limitations, and proposes a revised treatment algorithm for the management of thrombocytopenia in this patient group.
Methods
A PubMed search of the literature was undertaken with search terms focused on CLD and thrombocytopenia.
Results
Until now, the standard-of-care treatment in these patients has been the use of platelet transfusions either prophylactically or periprocedurally to control bleeding. Treatment options, such as splenic artery embolization and splenectomy, are invasive, and their utility is limited by significant complications. The US Food and Drug Administration recently approved 2 s-generation TPO-receptor agonists, avatrombopag and lusutrombopag, as safe and effective therapies for the treatment of thrombocytopenia in patients with CLD scheduled to undergo a procedure.
Conclusions
The addition of avatrombopag and lusutrombopag offers physicians an alternative to platelet transfusions in patients with CLD who have to undergo medical/dental procedures that could potentially put them at an increased risk of bleeding. There are several other drugs in the research pipeline at various stages of development, including a new class of monoclonal antibodies that can bind to and activate TPO-receptor agonists. The outlook for treatment choices for thrombocytopenia in patients with liver disease is promising.
To determine the clinical and biologic effects of bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in unresectable hepatocellular carcinoma (HCC).
Adults with ...organ-confined HCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month progression-free survival (PFS) rate from 40% to 60%. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients' plasma to support angiogenesis via an in vitro assay.
The study included 46 patients, of whom six had objective responses (13%; 95% CI, 3% to 23%), and 65% were progression free at 6 months. Median PFS time was 6.9 months (95% CI, 6.5 to 9.1 months); overall survival rate was 53% at 1 year, 28% at 2 years, and 23% at 3 years. Grade 3 to 4 adverse events included hypertension (15%) and thrombosis (6%, including 4% with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11% of patients, including one fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma.
We observed significant clinical and biologic activity for bevacizumab in nonmetastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11% of patients. Further evaluation is warranted in carefully selected patients.
Assessment of liver fibrosis is important as the range of liver disease management has expanded, rendering biopsy both imperfect and impractical in many situations. Noninvasive tests of fibrosis ...leverage laboratory, imaging and elastography techniques to estimate disease extent, often with the goal of identifying advanced fibrosis. This review attempts to summarize their utility across a broad range of possible clinical scenarios while considering the central tenets of health care quality: access, quality, and cost. For each test, it also discusses the caveats whereby each test may have reduced effectiveness and how to consider each in a typical clinical setting.
Living donor liver transplantation (LDLT) is a vital tool to address the growing organ shortage in the United States caused by increasing numbers of patients diagnosed with end‐stage liver disease. ...LDLT still only makes up a very small proportion of all liver transplantations performed each year, but there are many innovations taking place in the field that may increase its acceptance among both transplant programs and patients. These innovations include ways to improve access to LDLT, such as through nondirected donation, paired exchange, transplant chains, transplant of ABO‐incompatible donors, and transplants in patients with high Model for End‐Stage Liver Disease scores. Surgical innovations, such as laparoscopic donor hepatectomy, robotic hepatectomy, and portal flow modulation, are also increasingly being implemented. Policy changes, including decreasing the financial burden associated with LDLT, may make it a more feasible option for a wider range of patients. Lastly, center‐level behavior, such as ensuring surgical expertise and providing culturally competent education, will help toward LDLT expansion. Although it is challenging to know which of these innovations will take hold, we are already seeing LDLT numbers improve within the past 2 years.
Decisions about patient candidacy for liver transplant (LT) can mean the difference between life and death. We surveyed LT centers across the United States to assess their perceptions of and barriers ...to second-opinion referrals for inpatients declined for transplant. The medical and surgical directors of 100 unique US LT programs that had done >20 LTs in 2021 were surveyed with a 33-item questionnaire including both multiple-choice and free-response questions. The response rate was 60% (60 LT centers) and included 28 larger-volume ( ≥100 LTs in 2021) and 32 smaller-volume (<100 LTs in 2021) programs. The top 3 reasons for inpatient denial for LT included lack of social support (21%), physical frailty (20%), and inadequate remission duration from alcohol use (11%). Twenty-five percent of the programs reported "frequently" facilitating a second opinion for a declined inpatient, 52% of the programs reported "sometimes" doing so, and 7% of the programs reported never doing so. One hundred percent of the programs reported that they receive referrals for second opinions. Twenty-five percent of the programs reported transplanting these referrals frequently (over 20% of the time). Neither program size nor program location statistically impacted the findings. When asked if centers would be in favor of standardizing the evaluation process, 38% of centers would be in favor, 39% would be opposed, and 23% were unsure. The practices and perceptions of second opinions for hospitalized patients evaluated for LT varied widely across the United States. Opportunities exist to improve equity in LT but must consider maintaining individual program autonomy.
We sought to develop a "Model Of Recurrence After Liver transplant" (MORAL) for hepatocellular carcinoma (HCC).
The Milan criteria are used to allocate livers to patients with HCC requiring liver ...transplantation (LT) but do not include objective measures of tumor biology. Biological markers including the neutrophil-lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) have been associated with recurrence risk.
Prospective cohort study of adults undergoing LT for HCC between January 2001 and December 2012.
A total of 339 patients were included. On multivariable Cox regression analysis, 3 preoperatively available factors were independent predictors of worse recurrence-free survival (RFS), namely, an NLR ≥ 5 (P < 0.0001, hazard ratio, HR: 6.2), AFP > 200 (P < 0.0001, HR: 3.8), and Size >3 cm (P < 0.001, HR: 3.2). The Pre-MORAL score was constructed from the hazard ratios and assigning patients points in an additive fashion, with a minimum of 0 points (no factors) and a maximum of 13 points (all 3 factors). The highest risk patients in the Pre-MORAL had a 5-year RFS of 17.9% compared with 98.6% for the low risk group (P < 0.0001). The post-MORAL was constructed similarly using the 4 postoperatively available independent predictors of worse RFS, grade 4 HCC's (P < 0.0001, HR: 5.6), vascular invasion (P = 0.019, HR: 2.0), size >3 cm (P < 0.0001, HR: 3.2) and number >3 (P = 0.048, HR: 1.8). The pre- and post-MORAL were superior to Milan at predicting recurrence with c-statistics of 0.82 and 0.87, compared with 0.63, respectively. We then combined the scores to produce a combo-MORAL, with a c-statistic of 0.91 for predicting recurrence.
The MORAL score provides a simple, highly accurate tool for predicting recurrence and risk-stratification pre- and postoperatively.
Liver transplantation is a life-saving therapy to correct liver failure, portal hypertension and hepatocellular carcinoma arising from hepatitis C infection. But despite the successful use of living ...donors and improvements in immunosuppression and antiviral therapy, organ demand continues to outstrip supply and recurrent hepatitis C with accelerated progression to cirrhosis of the graft is a frequent cause of graft loss and the need for retransplantation. Appropriate selection of candidates and timing of transplantation, coupled with better pre- and post-transplant antiviral therapy, are needed to improve outcomes.
PDF
