Community-based provision of direct-acting antiviral therapy for hepatitis C: study protocol and challenges of a randomized controlled trial.

BACKGROUND: To achieve the World Health Organization hepatitis C virus (HCV) elimination targets, it is essential to increase access to treatment. Direct-acting antiviral (DAA) treatment can be provided in primary healthcare services (PHCS), improving accessibility, and, potentially, retention in care. Here, we describe our protocol for assessing the effectiveness of providing DAAs in PHCS, and the impact on the HCV care cascade. In addition, we reflect on the challenges of conducting a model of care study during a period of unprecedented change in HCV care and treatment. METHODS: Consenting patients with HCV infection attending 13 PHCS in Australia or New Zealand are randomized to receive DAA treatment at the local tertiary institution (standard care arm), or their PHCS (intervention arm). The primary endpoint is the proportion commenced on DAAs and cured. Treatment providers at the PHCS include: hepatology nurses, primary care practitioners, or, in two sites, a specialist physician. All PHCS offer opioid substitution therapy. DISCUSSION: The Prime Study is the first real-world, randomized, model of care study exploring the impact of community provision of DAA therapy on HCV-treatment uptake and cure. Although the study has faced challenges unique to this period of time characterized by changing treatment and service delivery, the data gained will be of critical importance in shaping health service policy that enables the elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT02555475 . Registered on 15 September 2015.

The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3.

BACKGROUND: The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. AIM: We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. METHODS: HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. RESULTS: Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV-1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. CONCLUSIONS: The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.

Australian Aboriginal people and Torres Strait Islanders have an atherogenic lipid profile that is characterised by low HDL-cholesterol level and small LDL particles.

AIM: To characterise lipid profiles for Australian Aboriginal people and Torres Strait Islanders. METHODS: Community-based, cross-sectional surveys in 1995-1997 including: 407 female and 322 male Australian Aboriginal people and 207 female and 186 male Torres Strait Islanders over 15 years old. A comparator of 78 female (44 with diabetes) and 148 male (73 with diabetes) non-indigenous participants recruited to clinical epidemiological studies was used. Lipids were determined by standard assays and LDL diameter by gradient gel electrophoresis. RESULTS: Diabetes prevalence was 14.8% and 22.6% among Aboriginal people and Torres Strait Islanders, respectively. LDL size (mean [95% CI (confidence interval)]) was smaller (P<0.05) in non-diabetic Aboriginal (26.02 [25.96-26.07] nm) and Torres Strait Islander women (26.01 [25.92-26.09] nm) than in non-diabetic non-indigenous women (26.29 [26.13-26.44] nm). LDL size correlated (P<0.0005) inversely with triglyceride, WHR, and fasting insulin and positively with HDL-cholesterol. HDL-cholesterol (mean [95% CI] mmol/L) was lower (P<0.0005) in indigenous Australians than in non-indigenous subjects, independent of age, sex, diabetes, WHR, insulin, triglyceride, and LDL size: Aboriginal (non-diabetic women, 0.86 [0.84-0.88]; diabetic women, 0.76 [0.72-0.80]; non-diabetic men, 0.79 [0.76-0.81]; diabetic men, 0.76 [0.71-0.82]); Torres Strait Islander (non-diabetic women, 1.00 [0.95-1.04]; diabetic women, 0.89 [0.83-0.96]; non-diabetic men, 1.00 [0.95-1.04]; diabetic men, 0.87 [0.79-0.96]); non-indigenous (non-diabetic women, 1.49 [1.33-1.67]; diabetic women, 1.12 [1.03-1.21]; non-diabetic men, 1.18 [1.11-1.25]; diabetic men, 1.05 [0.98-1.12]). CONCLUSIONS: Indigenous Australians have a dyslipidaemia which includes small LDL and very low HDL-cholesterol levels. The dyslipidaemia was equally severe in both genders. Strategies aimed at increasing HDL-cholesterol and LDL size may reduce high CVD risk for indigenous populations.

Albuminuria in Australian Aboriginal people: prevalence and associations with components of the metabolic syndrome.

AIMS/HYPOTHESIS: To examine the prevalence and associations with the metabolic syndrome of albuminuria among Australian Aboriginal people. METHODS: Early-morning urine specimens were collected as part of community-based risk factor surveys assessing the prevalence of diabetes and cardiovascular disease in eight remote communities, with a sample size of 1,075 people. Microalbuminuria was defined as urinary albumin : creatinine ratio 3.4-33.9 mg/mmol, macroalbuminuria as albumin: creatinine ratio equal to or greater than 34 mg/mmol. RESULTS: There were high prevalences of microalbuminuria (men 22.2 %, women 26.9 %) and of macroalbuminuria (men 10.4%, women 13.5%). There were highly statistically significant linear associations of microalbuminuria and macroalbuminuria with increasing number of coexisting components of the metabolic syndrome (hypertension, glucose intolerance, dyslipidaemia, insulin resistance, abdominal obesity): among people with zero, one, two and three to five of these conditions, respectively, prevalence of microalbuminuria was 16%, 20%, 36% and 32% (p < 0.001); prevalence of macroalbuminuria was 2%, 6%, 12% and 32% (p < 0.001). There were independent associations of microalbuminuria with hypertension (odds ratio, 95% confidence interval = 2.36, 1.63-3.42) and diabetes (2.10, 1.28-3.45): macroalbuminuria was independently associated with hypertension (6.39, 3.93-10.4), diabetes (3.49, 1.93-6.28) and abdominal obesity (4.56, 2.40-8.64) and had a weaker association with insulin resistance (1.99, 1.12-3.54). Dyslipidaemia and impaired glucose tolerance were neither independently associated with microalbuminuria or macroalbuminuria, nor was insulin resistance or abdominal obesity independently associated with microalbuminuria. CONCLUSION/INTERPRETATION: There was a strong clustering of albuminuria with components of the metabolic syndrome. Diabetes, hypertension and abdominal obesity are major contributors to high rates of albuminuria among Australian Aboriginal people.

Has westernization influenced serum cholesterol levels in Bougainvillian males?

This study was performed to see if there was any difference in cholesterol levels between three socioeconomic groups of Bougainvillian males, each with different levels of exposure to western influences. Serum cholesterol levels were measured in 50 subjects from each of 1) village people leading a traditional lifestyle, 2) town dwellers exposed to western influences, and 3) mine workers who regularly dined in the company mess. Mean cholesterol levels were significantly higher in the mine workers (5.3 +/- SD 0.9 mmol/l) and the town dwellers (4.8 +/- SD 0.8 mmol/l) than in the village people (3.7 +/- SD 1.0 mmol/l). There was a positive correlation between serum cholesterol level and age in two groups, the town dwellers and the village people, even though the latter group had a low mean cholesterol level. There was a significant correlation between body mass index (BMI) and serum cholesterol level for the entire group as well as the town dwellers and mine workers. The higher mean cholesterol levels in the mine workers and town dwellers than in the village people may reflect a difference in lifestyle, particularly in diet, between these groups, and may represent an increased risk for ischaemic heart disease.