Monitoring hepatitis C treatment uptake in Australia: Issue #13, July 2023

A total of 105,024 individuals have initiated direct acting antiviral (DAA) treatment for chronic hepatitis C virus (HCV) infection in Australia, including 100,684 individuals through Pharmaceutical Benefits Scheme (PBS) during 2016 to 2022, and an estimated 4,340 individuals through early DAA access avenues in 2014-15. In 2022, 5,205 individuals initiated treatment (first course), increasing from 1,141 in the first quarter to 1,432 in the last quarter of 2022. The recent increase in treatment uptake could be explained by enhanced HCV testing programs implemented in the community and prisons in several jurisdictions. Among individuals initiating DAA treatment during 2016 to 2022 (n=100,684), 68% were men, and median age was 47 years (quartiles 1-3: 38-57). Since August 2018 when both pan-genotypic regimens were available (i.e., sofosbuvir/velpatasvir and glecaprevir/pibrentasvir), 53% of individuals have been initiated on sofosbuvir/velpatasvir, 41% on glecaprevir/pibrentasvir, and 6% on other regimens. Most individuals initiating DAA treatment received their prescriptions from general practitioners (GPs; 46%), followed by gastroenterologists (35%). Overall, 52% of individuals were initiated on treatment by specialists, and 48% by non-specialists (i.e., GPs and nurse practitioners). A total of 2,048 individuals were initiated on treatment by nurse practitioners, increasing from 92 in 2017 to 535 in 2022. Among individuals initiating DAA treatment during 2016 to 2022, 8.6% discontinued treatment, including 4.0% early discontinuation (i.e., dispensed 28 days of treatment) and 4.6% late discontinuation (i.e., dispensed at least 56 days of treatment, but not all recommended duration). The proportion of early discontinuation increased from >3% in 2016 to 8.5% in mid-2021 followed by a plateau phase and then slight decrease in 2022. Among individuals who discontinued treatment, 26% received re-treatment. Among individuals initiating DAA treatment during 2016 to 2022, 8.5% received at least one course of re-treatment. Among re-treatment initiations, an estimated 57% were for HCV re-infection and 43% for treatment failure. The number of re-treatment initiations for treatment failure increased during the second quarter of 2019, corresponding to sofosbuvir/velpatasvir/voxilaprevir availability through PBS (April 2019), and has decreased since. The number of re-treatment initiations for HCV re-infection increased until mid-2020, stabilised during 2020-21, and increased again in 2022. This latest increase could be the result of enhanced HCV testing programs implemented in several jurisdictions through which many individuals with HCV re-infection were diagnosed and linked to clinical care

Monitoring hepatitis C treatment uptake in Australia: Issue #14, July 2024

A total of 105,947 individuals have initiated direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection in Australia through the Pharmaceutical Benefits Scheme during 2016 to 2023. The number of new treatment initiations decreased between 2016 to 2022. An increase in treatment initiations was observed in 2023.The proportion of people who did not complete a full course of treatment has increased, over time, most notably among women. Retreatment has accounted for an increasing proportion of all DAA prescriptions over time. By end 2023, 10567 (10%) of the treated population had been retreated at least once. The total number of retreatments prescribed during this period was 13465. Over the past five years retreatment for reinfection has increased, while retreatment for treatment failure has stabilised. HCV prescriber patterns and the population treated have changed over time. Between 2016 to 2023, the median age of those treated declined from 52 to 44 years. During 2016 to 2023 the proportion of people treated by gastroenterologists declined (50% to 19%), whereas the proportion of people treated by general practitioners increased (31% to 55%). During 2019 to 2023, prescribing of treatment, and notably retreatment, by nurse practitioners increased. By 2023, 11% of treatment and 19% of retreatment was prescribed by nurse practitioners

Prevalence and determinants of diabetes mellitus among Iranian patients with chronic liver disease

BACKGROUND: Alterations in carbohydrate metabolism are frequently observed in cirrhosis. We conducted this study to define the prevalence of diabetes mellitus (DM) and impaired glucose tolerance (IGT) in Iranian patients with chronic liver disease (CLD), and explore the factors associated with DM in these patients. METHODS: One hundred and eighty-five patients with CLD were enrolled into the study. Fasting plasma glucose and two-hour plasma glucose were measured in patients' sera. DM and IGT were diagnosed according to the latest American Diabetes Association criteria. RESULTS: The subjects included 42 inactive HBV carriers with a mean age of 42.2 ± 12.0 years, 102 patients with HBV or HCV chronic hepatitis with a mean age of 41.2 ± 10.9 years, and 41 cirrhotic patients with a mean age of 52.1 ± 11.4 years. DM and IGT were diagnosed in 40 (21.6%) and 21 (11.4%) patients, respectively. Univariate analysis showed that age (P = 0.000), CLD status (P = 0.000), history of hypertension (P = 0.007), family history of DM (P = 0.000), and body mass index (BMI) (P = 0.009) were associated with DM. Using Multivariate analysis, age (OR = 4.7, 95%CI: 1.8–12.2), family history of DM (OR = 6.6, 95%CI: 2.6–17.6), chronic hepatitis (OR = 11.6, 95%CI: 2.9–45.4), and cirrhosis (OR = 6.5, 95%CI: 2.4–17.4) remained as the factors independently associated with DM. When patients with cirrhosis and chronic hepatitis were analyzed separately, higher Child-Pugh's score in cirrhotic patients (OR = 9.6, 95%CI: 1.0–88.4) and older age (OR = 7.2, 95%CI: 1.0–49.1), higher fibrosis score (OR = 59.5, 95%CI: 2.9–1211.3/ OR = 11.9, 95%CI: 1.0–132.2), and higher BMI (OR = 30.3, 95%CI: 3.0–306.7) in patients with chronic hepatitis were found to be associated with higher prevalence of DM. CONCLUSIONS: Our findings indicate that patients with cirrhosis and chronic hepatitis are at the increased risk of DM occurrence. Older age, severe liver disease, and obesity were associated with DM in these patients

Increasing national trend of direct-acting antiviral discontinuation among people treated for HCV 2016-2021

Background: Direct-acting antiviral (DAA) treatment discontinuation may negatively impact HCV elimination efforts. In Australia, DAA therapy is pharmacy dispensed, generally in 4-week amounts, with the approved duration (8-24 wk) and volume dispensed reported in pharmaceutical administrative data. This analysis assessed national HCV treatment discontinuation. Methods: Individuals commencing DAAs between 2016 and 2021 were assessed for treatment discontinuation. Individuals with a single dispensation of their entire treatment course were excluded. Treatment discontinuation was defined as ≥ 4 weeks of approved treatment duration not dispensed. Factors associated with treatment discontinuation were assessed using Cox regression. Factors associated with retreatment following treatment discontinuation were assessed using logistic regression. Results: Of 95,275 individuals who were treated, 88,986 were included in the analysis of whom 7532 (9%) discontinued treatment. Treatment discontinuation increased from 6% in the first half of 2016 to 15% in 2021. Longer treatment durations (vs. 8 wk) were associated with increased discontinuation risk (12 wk: adjusted HR = 3.23; 95% CI: 2.90, 3.59; p < 0.001, 16-24 wk: adjusted HR = 6.29; 95% CI: 5.55, 7.14; p < 0.001). Of individuals discontinuing treatment, 24% were retreated. Early discontinuation (4 wk treatment dispensed) increased the likelihood of retreatment (adjusted OR = 3.91; 95% CI: 3.44, 4.44; p < 0.001). Those with early discontinuation of glecaprevir/pibrentasvir 8 weeks (vs. sofosbuvir/velpatasvir 12 wk) had a lower likelihood of retreatment (adjusted OR = 0.62; 95% CI: 0.49, 0.79; p < 0.001). Initial treatment discontinuation was associated with an increased risk of retreatment discontinuation (adjusted HR = 4.41; 3.85, 5.05; p < 0.001). Conclusions: DAA treatment discontinuation increased over time corresponding to increasing treatment uptake through primary care among people who inject drugs. The use of simplified, short-duration therapies may reduce treatment discontinuation. Access to adherence support and retreatment will be essential for HCV elimination

National trends in retreatment of HCV due to reinfection or treatment failure in Australia

Background & Aims: Population-level uptake of direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection, including retreatment, can be estimated through administrative pharmaceutical dispensation data. However, the reasons for retreatment are not captured in these data. We developed a machine learning model to classify retreatments as reinfection or treatment failure at a national level. Methods: Retreatment data from the REACH-C cohort (n = 10,843 treated with DAAs; n = 320 retreatments with known reason), were used to train a random forest model. Nested cross validation was undertaken to assess model performance and to optimise hyperparameters. The model was applied to data on DAA retreatment dispensed during 2016-2021 in Australia, to identify the reason for retreatment (treatment failure or reinfection). Results: Average predictive accuracy, precision, sensitivity, specificity and F1-score for the model were 96.3%, 96.5%, 96.3%, 96.3% and 96.3%, respectively. Nationally, 95,272 individuals initiated DAAs, with treatment uptake declining from 32,454 in 2016 to 6,566 in 2021. Of those treated, 6,980 (7%) were retreated. Our model classified 51.8% (95% CI 46.7–53.6%; n = 3,614) of cases as reinfection and 48.2% (95% CI 46.4–53.3%; n = 3,366) as treatment failure. Retreatment for reinfection increased steadily over the study period from 14 in 2016 to 1,092 in 2020, stabilising in 2021. Retreatment for treatment failure increased from 73 in 2016 to 1,077 in 2019, then declined to 515 in 2021. Among individuals retreated for treatment failure, 50% had discontinued initial treatment. Conclusions: We used a novel methodology with high classification accuracy to evaluate DAA retreatment patterns at a national level. Increases in retreatment uptake for treatment failure corresponded to the availability of pangenotypic and salvage regimens. Increasing retreatment uptake for reinfection likely reflects increasing reinfection incidence. Impact and implications: This study used machine learning methodologies to analyse national administrative data and characterise trends in HCV retreatment due to reinfection and treatment failure. Retreatment for reinfection increased over time, reflecting increasing numbers of people at risk for reinfection following HCV cure. Increased retreatment for treatment failure corresponded to the availability of pangenotypic and salvage DAA regimens. The findings of this study can be used by public health agencies and policy makers to guide and assess HCV elimination strategies, while the novel methodology for monitoring trends in HCV retreatment has the potential to be used in other settings, and health conditions

Timely Hepatitis C RNA Testing and Treatment in the Era of Direct-Acting Antiviral Therapy among People with Hepatitis C in New South Wales, Australia

This study aimed to identify the factors associated with timely (within four weeks) HCV RNA testing and timely (within six months) DAA initiation following HCV notification in the DAA era. We conducted a cohort study of people with an HCV notification in NSW, Australia. Notifications of positive HCV serology were linked to administrative datasets. Weights were applied to account for spontaneous clearance. Logistic regression analyses were performed. Among 5582 people with an HCV notification during 2016–2017, 3867 (69%) were tested for HCV RNA, including 2770 (50%) who received timely testing. Among an estimated 3925 people with chronic HCV infection, 2372 (60%) initiated DAA therapy, including 1370 (35%) who received timely treatment. Factors associated with timely HCV RNA testing included age (≥30 years), female sex, non-Aboriginal ethnicity, country of birth being Australia, and no history of drug dependence. Factors associated with timely treatment were age (≥30 years), male sex, non-Aboriginal ethnicity, country of birth being Australia, no history of drug dependence, and HCV/HIV co-infection. In the DAA era, 50% of people with an HCV notification did not receive timely HCV RNA testing. Most people with an HCV infection received therapy; however, DAA initiation was delayed among many

MicroRNA-129-1 acts as tumour suppressor and induces cell cycle arrest of GBM cancer cells through targeting IGF2BP3 and MAPK1

Background MicroRNA-129-1 (miR-129-1) seems to behave as a tumour suppressor since its decreased expression is associated with different tumours such as glioblastoma multiforme (GBM). GBM is the most common form of brain tumours originating from glial cells. The impact of miR-129-1 downregulation on GBM pathogenesis has yet to be elucidated. Methods MiR-129-1 was overexpressed in GBM cells, and its effect on proliferation was investigated by cell cycle assay. MiR-129-1 predicted targets (CDK6, IGF1, HDAC2, IGF2BP3 and MAPK1) were also evaluated by western blot and luciferase assay. Results Restoration of miR-129-1 reduced cell proliferation and induced G1 accumulation, significantly. Several functional assays confirmed IGF2BP3, MAPK1 and CDK6 as targets of miR-129-1. Despite the fact that IGF1 expression can be suppressed by miR-129-1, through 30-untranslated region complementary sequence, we could not find any association between IGF1 expression and GBM. MiR-129-1 expression inversely correlates with CDK6, IGF2BP3 and MAPK1 in primary clinical samples. Conclusion This is the first study to propose miR129-1 as a negative regulator of IGF2BP3 and MAPK1 and also a cell cycle arrest inducer in GBM cells. Our data suggests miR-129-1 as a potential tumour suppressor and presents a rationale for the use of miR-129-1 as a novel strategy to improve treatment response in GBM

HCC incidence after hepatitis C cure among patients with advanced fibrosis or cirrhosis: A meta-analysis

Background and aims: HCV cure reduces but does not eliminate the risk of HCC. HCC surveillance is recommended in populations where the incidence exceeds 1.5% per year. In cirrhosis, HCC surveillance should continue after HCV cure, although it is uncertain if this should be indefinite. For patients with advanced fibrosis (F3), guidelines are inconsistent in their recommendations. We evaluated the incidence of HCC after HCV cure among patients with F3 fibrosis or cirrhosis. Approach and results: This systematic review and meta-analysis identified 44 studies (107,548 person-years of follow-up) assessing the incidence of HCC after HCV cure among patients with F3 fibrosis or cirrhosis. The incidence of HCC was 2.1 per 100 person-years (95% CI, 1.9-2.4) among patients with cirrhosis and 0.5 per 100 person-years (95% CI, 0.3-0.7) among patients with F3 fibrosis. In a meta-regression analysis among patients with cirrhosis, older age (adjusted rate ratio [aRR] per 10-year increase in mean/median age, 1.32; 95% CI, 1.00-1.73) and prior decompensation (aRR per 10% increase in the proportion of patients with prior decompensation, 1.06; 95% CI, 1.01-1.12) were associated with an increased incidence of HCC. Longer follow-up after HCV cure was associated with a decreased incidence of HCC (aRR per year increase in mean/median follow-up, 0.87; 95% CI, 0.79-0.96). Conclusions: Among patients with cirrhosis, the incidence of HCC decreases over time after HCV cure and is lowest in patients with younger age and compensated cirrhosis. The substantially lower incidence in F3 fibrosis is below the recommended threshold for cost-effective screening. The results should encourage the development of validated predictive models that better identify at-risk individuals, especially among patients with F3 fibrosis