Liver Disease and Poor Adherence Limit Hepatitis C Cure: A Real-World Australian Treatment Cohort.

BACKGROUND AND AIMS: In 2016, direct-acting antiviral (DAA) treatment for hepatitis C (HCV) became available through Australia's universal health care system, with the aim of HCV elimination. We report real-world effectiveness of DAA HCV treatment in Australia from a clinically well-informed cohort, enriched for cirrhosis and prior HCV treatment. METHODS: 3413 patients were recruited from 26 hospital liver clinics across Australia from February 2016 to June 2020. Clinical history and sustained viral response (SVR) were obtained from medical records and data linkage to the Australian Pharmaceutical Benefits Scheme. Factors associated with SVR were assessed by multivariable logistic regression (MVR). RESULTS: At recruitment, 32.2% had cirrhosis (72.9% Child Pugh class B/C), and 19.9% were treatment experienced. Of the 2,939 with data, 93.3% confirmed SVR. 137 patients received second-line therapy. Patients with cirrhosis had lower SVR rate (88.4 vs. 95.8%; p < 0.001). On MVR, failure to achieve SVR was associated with Genotype 3 (adj-OR = 0.42, 95%CI 0.29-0.61), male gender (adj-OR = 0.49, 95%CI 0.31-0.77), fair/poor adherence (adj-OR = 0.52, 95%CI 0.28-0.94), cirrhosis (adj-OR = 0.57, 95%CI 0.36-0.88), FIB-4 > 3.25 (adj-OR = 0.52, 95%CI 0.33-0.83) and MELD score ≥ 20 (adj-OR = 0.25, 95%CI 0.08-0.80). Consistent results were seen in cirrhotic sub-analysis. CONCLUSIONS: Excellent SVR rates were achieved with DAAs in this real-world cohort of patients with chronic HCV infection. More advanced liver disease and clinician impression of poor adherence were associated with HCV treatment failure. Supports to improve liver fibrosis assessment skills for non-specialist DAA prescribers in the community and to optimize patient adherence are likely to enable more effective pursuit of HCV elimination in Australia.

Hepatitis C treatment outcomes for Australian First Nations Peoples: equivalent SVR rate but higher rates of loss to follow-up.

BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.

Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and genetic determinants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology and test mechanism-based therapies. Among several mouse models of NASH, some exhibit the key pathophysiologic as well as histopathologic criteria for human NASH, whereas others may be useful to address specific questions. Models based on overnutrition with adipose restriction/inflammation and metabolic complications, particularly insulin resistance, may be most useful to investigate critical etiopathogenic factors. In-depth pathologic description is required for all models. Some models demonstrate hepatocyte ballooning, which can be confused with microvesicular steatosis, whereas demonstration of an inflammatory infiltrate and pattern of liver fibrosis compatible with human NASH is desirable in models used for pharmacologic testing. When mice with specific genetic strains or mutations that cause overeating consume a diet enriched with fat, modest amounts of cholesterol, and/or simple sugars ("Western diet"), they readily develop obesity with liver disease similar to human NASH, including significant fibrosis. Purely dietary models, such as high-fat/high-cholesterol, Western diet, and choline-deficient, amino acid-defined, are similarly promising. We share concern about using models without weight gain, adipose pathology, or insulin resistance/hyperinsulinemia and with inadequate documentation of liver pathology. NASH-related fibrosis is a key endpoint in trials of possible therapies. When studied for this purpose, NASH models should be reproducible and show steatohepatitis (ideally with ballooning) and at least focal bridging fibrosis, while metabolic factors/disordered lipid partitioning should contribute to etiopathogenesis. Because murine models are increasingly used to explore pharmacologic therapies for NASH, we propose a minimum set of requirements that investigators, drug companies, and journals should consider to optimize their translational value.

When the liver gets stiff, the tough get moving.

Liver stiffness measurement (LSM) by FibroScan-determined transient elastography is a noninvasive approach to estimate liver fibrosis severity. In non-alcoholic fatty liver disease (NAFLD), advanced liver fibrosis is excluded by normal liver stiffness, but a wide range of cutoffs have been used to predict advanced liver fibrosis or cirrhosis. This may be partly because steatosis (measured by controlled attenuation parameter [CAP]) contributes to liver stiffness and also because LSM fluctuates in NAFLD. In a recent pivotal study, one-third of patients with liver stiffness > 12.0 kPa showed reversal after 4-6 months; these cases did not have advanced liver fibrosis on biopsy. We performed serial FibroScans 6-36 months apart in 73 NAFLD patients, 38 with LSM > 10 kPa at entry. Those who lost ≥ 1 kg of weight (n = 31) significantly reduced liver stiffness (3.6 ± 6.1 vs 0.53 ± 4.1 kPa, P < 0.05) and CAP score (39 ± 63 dB/m of loss vs 24 ± 65 dB/m of gain, P < 0.05) compared with those who did not (n = 29). Patients who reported increased physical activity (n = 25) also reduced liver stiffness (3.6 ± 6 vs 0.35 ± 6 kPa) and CAP (20 ± 71 dB/m of loss vs 32 ± 71 dB/m of gain). Overall, those with improved LSM were significantly more likely to have lost weight and/or improved physical activity. These effects of lifestyle adjustments partly explain why a single measurement of 12.0 kPa is not a reliable cutoff for advanced liver fibrosis in NAFLD. In addition to repeating the study after 6-12 months, documentation of response to lifestyle advice and weight reduction should be determined before assuming any cutoff indicates advanced liver fibrosis. Despite this reservation about diagnostic accuracy, we consider that measurement of liver stiffness and CAP score serve to motivate patients to enact lifestyle modifications that can improve NAFLD severity.

Influence of psychiatric diagnosis on treatment uptake and interferon side effects in patients with hepatitis C.

BACKGROUND AND AIM: Pegylated-interferon-α/ribavirin (PEG-IFN/RBV) treatment can cure hepatitis C virus (HCV) infection but has frequent neuropsychiatric side-effects. Patients with pre-existing psychiatric illness may not be offered therapy. We established prevalence of self-reported psychiatric comorbidity among HCV-infected patients in a hospital-liver clinic, and determined the impact of such diagnoses on uptake and tolerance to PEG-IFN/RBV. METHODS: All HCV cases referred for assessment in Australian Capital Territory/surrounding regions April 2004-March 2012 were entered into a clinical database. We conducted univariate and multivariate analyses of variables correlating with uptake of antiviral therapy and frequency of treatment-related side-effects. RESULTS: Of 773 referred patients, 235 (30%) described pre-existing psychiatric illness. Among these, 26% received antiviral therapy, compared with 30% of 538 without psychiatric comorbidity. History of depression (usually validated by liaison psychiatry) was associated with higher incidence of treatment-related neuropsychiatric side-effects (odds ratio 2.79 [1.35-5.70], P < 0.05) but did not affect treatment outcome. Twenty-seven patients reported schizophrenia: three (11%) received antiviral therapy, compared with 30% admitting depression and 20% with bipolar affective disorder (all assessed by psychiatrist). In most schizophrenia cases, the reason for not offering antiviral treatment was psychological illness, yet none of five treated (these three plus two others in a psychiatric rehabilitation facility) experienced worsening psychiatric symptoms. CONCLUSIONS: A history of depression is common with hepatitis C but does not affect initiation of antiviral treatment, despite substantially increased risk of psychiatric side-effects. In contrast, pre-existing schizophrenia appears to influence treatment decisions, despite little evidence that PEG-IFN/RBV exacerbates the psychiatric condition, and well-supervised antiviral therapy can have good outcomes.

Extreme lymphoproliferative disease and fatal autoimmune thrombocytopenia in FasL and TRAIL double-deficient mice.

To delineate the relative roles of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand in lymphocyte biology and lymphoproliferative disease, we generated mice defective in both molecules. B6.GT mice develop severe polyclonal lymphoproliferative disease because of accumulating CD3(+)CD4(-)CD8(-)B220(+) T cells, CD4(+) and CD8(+) T cells, and follicular B cells, and mice die prematurely from extreme lymphocytosis, thrombocytopenia, and hemorrhage. Accumulating lymphocytes resembled antigen-experienced lymphocytes, consistent with the maximal resistance of B6.GT CD4(+) and CD8(+) T cell to activation-induced cell death. More specifically, we show that TRAIL contributes to Fas ligand-mediated activation-induced cell death and controls lymphocyte apoptosis in the presence of interferon-gamma once antigen stimulation is removed. Furthermore, dysregulated lymphocyte homeostasis results in the production of anti-DNA and rheumatoid factor autoantibodies, as well as antiplatelet IgM and IgG causing thrombocytopenia. Thus, B6.GT mice reveal new roles for TRAIL in lymphocyte homeostasis and autoimmune lymphoproliferative syndromes and are a model of spontaneous idiopathic thrombocytopenia purpura secondary to lymphoproliferative disease.

Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground.

Nonalcoholic fatty liver disease (NAFLD) is becoming an important chronic liver disorder in Asia. Prevalence figures show regional variations but at least 10% of the general population in Asia have fatty liver. Fatty liver can develop with relatively small changes in weight (2-3 kg), often with increasing central adiposity. The metabolic syndrome may precede or follow NAFLD. Overt diabetes is present in one-third of cases but when oral glucose tolerance tests are performed, a further third of individuals have impaired glucose tolerance or diabetes. Natural history data are still scarce but cases of advanced hepatic fibrosis and hepatocellular carcinoma are now regularly reported. Many cases of cryptogenic cirrhosis are also attributable to NAFLD. Histological progression has been demonstrated for patients with NASH as well as for those with hepatic steatosis alone. Genetic factors may in part contribute to the rise in NAFLD. Polymorphisms within apolipoprotein C3 (APOC3) gene have been linked to NAFLD in lean Indian men. Although a number of other polymorphisms involving genes controlling adipose distribution, insulin signalling, adipokine responses and hepatic fibrosis have been reported, these studies have been underpowered. Transient elastography could help in detecting and monitoring hepatic fibrosis but further refinements in technique are necessary for obese individuals. Of the biomarkers, hyaluronic acid and cytokeratin-18 fragment testing show promise as markers of hepatic fibrosis and NASH, respectively. Lifestyle alterations including dietary changes and increased physical activity remain the cornerstone of management. Attention should be paid to prevention through public education of campaigns addressing the increase in both adult and childhood obesity.

Hepatic microcirculation in fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), the most common cause of steatosis, is associated with visceral obesity and insulin resistance. With more severe risk factors (obesity, type 2 diabetes [T2D], metabolic syndrome), steatosis may be complicated by hepatocellular injury and liver inflammation (steatohepatitis or NASH). NASH can lead to perisinusoidal fibrosis and cirrhosis. Fat-laden hepatocytes are swollen, and in steatohepatitis, further swelling occurs due to hydropic change (ballooning) of hepatocytes to cause sinusoidal distortion, as visualized by in vivo microscopy, reducing intrasinusoidal volume and microvascular blood flow. Involvement of other cell types (sinusoidal endothelial cells, Kupffer cells, stellate cells) and recruitment of inflammatory cells and platelets lead to dysregulation of microvascular blood flow. In animal models, the net effect of such changes is a marked reduction of sinusoidal space (approximately 50% of control), and a decrease in the number of normally perfused sinusoids. Such microvascular damage could accentuate further liver injury and disease progression in NASH. The fatty liver is also exquisitely sensitive to ischemia-reperfusion injury, at least partly due to the propensity of unsaturated fatty acids to undergo lipid peroxidation in the face of reactive oxygen species (ROS). This has important clinical consequences, particularly limiting the use of fatty donor livers for transplantation. In this review, we discuss available data about the effects of steatosis and steatohepatitis on the hepatic microvascular structure and sinusoidal blood flow, highlighting areas for future investigation.

Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice.

Administration of a methionine and choline deficient (MCD) diet to rodents causes progressive fibrosing steatohepatitis pathologically similar to human metabolic steatohepatitis. We have previously shown that the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, Wy-14,643, prevented the development of MCD diet-induced steatohepatitis. We have now tested whether Wy-14,643 ameliorates established steatohepatitis and fibrosis. Male C57BL6 mice were fed the MCD diet for 51 days to induce severe steatohepatitis. They were then treated with Wy-14,643 together with the MCD diet for 5 or 12 days; positive controls continued on the MCD diet for 5 or 12 days. After 5 days of Wy-14,643 treatment, alanine aminotransferase (ALT) levels were significantly decreased, steatohepatitis less severe, and hepatic lipoperoxides significantly reduced. After 12 days, hepatic triglycerides were normalized and there was near resolution of histological changes. MCD dietary feeding was associated with increased expression of vascular cell adhesion molecule (VCAM)-1, and increased numbers of activated macrophages in the liver. Treatment with Wy-14,643 reduced VCAM-1 expression and macrophage numbers. MCD diet-fed mice developed hepatic fibrosis with increased hepatic collagen alpha1(I), tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, and matrix metalloproteinase (MMP)-13 mRNA levels. After treatment with Wy-14,643, expression of these genes was reduced in a manner that paralleled the reduction in activated hepatic stellate cells and near resolution of liver fibrosis. In conclusion, the present study shows that MCD diet-induced fibrosing steatohepatitis can be reversed by treatment with Wy-14,643. It is likely that activation of PPARalpha reverses fibrosis indirectly by reducing stimuli, such as lipid peroxides, and activation of cells responsible for promoting hepatic fibrosis.

Factors associated with severity of hepatic fibrosis in people with chronic hepatitis C infection.

OBJECTIVE: To determine factors associated with hepatic fibrosis development in people with chronic hepatitis C virus (HCV) infection. METHODS: As a requirement for access to interferon therapy through the S100 scheme in Australia, individual pretreatment demographic and clinical information was collected on 2986 patients from 61 hospital-based liver clinics from 1 October 1994 through 31 December 1996. Patients with both a hepatic fibrosis score and an estimated duration of HCV infection (910) were divided into 540 with no or minimal hepatic fibrosis (stage 0-1) and 370 with moderate to severe hepatic fibrosis (stage 2-3). Seven factors were examined: age at HCV infection, sex, ethnicity, source of infection, duration of infection, alcohol intake, and mean ALT level. A further analysis was performed for all 1135 patients with a hepatic fibrosis score disregarding age at and duration of HCV infection. RESULTS: In multivariate analysis, four factors were significantly associated with moderate to severe hepatic fibrosis: age at infection (OR, 2.33 for age 31-40 years, 5.27 for age > 40 years, and 0.20 for age < 15 years, compared with 15-20 years); duration of infection (OR, 1.44 for 11-20 years, 2.74 for 21-30 years, and 8.71 for > 30 years, compared with < 11 years); alcohol intake in previous six months (OR, 1.51 for any intake, compared with none); and mean ALT level (OR, 1.81 for 2-3 times, 2.27 for > 3 times, compared with 1.5-2 times the upper limit of normal). In the analysis disregarding age at HCV infection and duration of HCV infection, older age was strongly associated with moderate to severe hepatic fibrosis (OR, 2.32 for age 36-40 years, 2.46 for age 41-50 years, 7.87 for age 51-60 years, and 7.15 for age > 60 years, compared with 16-30 years). There was no association in either analysis with sex or source of HCV infection. CONCLUSION: These factors may assist in targeting patients for both liver biopsy-based investigation and therapeutic intervention.