Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV).

BACKGROUND: The standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID. METHODS AND FINDINGS: INTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals. Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment. CONCLUSIONS: Integrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov.no NCT03155906.

Integrated treatment of hepatitis C virus infection among people who inject drugs: study protocol for a randomised controlled trial (INTRO-HCV).

BACKGROUND: A large proportion of people who inject drugs (PWID) living with hepatitis C virus (HCV) infection have not been treated. It is unknown whether inclusion of HCV diagnostics and treatment into integrated substance use disorder treatment and care clinics will improve uptake and outcome of HCV treatment in PWID. The aim is to assess the efficacy of integrating HCV treatment to PWID and this paper will present the protocol for an ongoing trial. METHODS: INTRO-HCV is a multicentre, randomised controlled clinical trial that will compare the efficacy of integrated treatment of HCV in PWID with the current standard treatment. Integrated treatment includes testing for HCV, assessing liver fibrosis with transient elastography, counselling, treatment delivery, follow-up and evaluation provided by integrated substance use disorder treatment and care clinics. Most of these clinics for PWID provide opioid agonist therapy while some clinics provide low-threshold care without opioid agonist therapy. Standard care involves referral to further diagnostics, treatment and treatment follow-up given in a hospital outpatient clinic with equivalent medications. The differences between the delivery platforms in the two trial arms involve use of a drop-in approach rather than specific appointment times, no need for additional travelling, less blood samples taken during treatment, and treatment given from already known clinicians. The trial will recruit approximately 200 HCV infected individuals in Bergen and Stavanger, Norway. The primary outcomes are time to treatment initiation and sustained virologic response, defined as undetectable HCV RNA 12 weeks after end of treatment. Secondary outcomes are cost-effectiveness, treatment adherence, changes in quality of life, fatigue and psychological well-being, changes in drug use, infection related risk behaviour, and risk of reinfection. The target group is PWID with HCV diagnosed receiving treatment and care within clinics for PWID. DISCUSSION: This study will inform on the effects of an integrated treatment program for HCV in clinics for PWID compared to standard care aiming to increase access to treatment and improving treatment adherence. If the integrated treatment model is found to be safe and efficacious, it can be considered for further scale-up. TRIAL REGISTRATION: ClinicalTrials.gov.no. NCT03155906.

Association of Constellations of Parental Risk With Children's Subsequent Anxiety and Depression: Findings From a HUNT Survey and Health Registry Study.

Importance: The research focus on children of parents with alcohol use disorder has eclipsed the potentially wider-reaching detrimental effects of subclinical parental drinking, both alone and in combination with other parental risk factors. Objective: To identify constellations of early parental risk characterized by variations in drinking, mental health, and education in both parents and examine their prospective associations with children's contact with the health care system for anxiety and/or depression (ie, diagnoses or treatment). Design, Setting, and Participants: This prospective study was based on linked survey and health registries data. The sample included 8773 children from 6696 two-parent families in Norway who participated in the Nord-Trøndelag Health Study (HUNT) survey in 1995 to 1997 or 2006 to 2008, when the children were aged 13 to 19 years. Data were analyzed from January to September 2018. Exposures: Five constellations of early parental risks, characterized by variations in drinking frequencies and amounts, mental health, and education for both parents, as identified through latent profile analysis. Main Outcomes and Measures: Children's diagnoses or treatment of anxiety and/or depression from 2008 to 2016 were recorded in 3 health registries. The primary outcome was the total number of registries where participants presented (ranging from 0 to 3). Results: Of the 8773 included children, 4404 (50.2%) were boys, and the mean (SD) age at the time of participation in the Nord-Trøndelag Health Study was 16.1 (1.8) years. Prevalence of anxiety and/or depression, as evidenced in at least 1 registry record, was 24.3% (2132 of 8773). Early parental risk profiles risks marked by (1) the lowest parental education (adjusted relative risk, 1.13; 95% CI, 1.01-1.25) and (2) elevated drinking in both parents and elevated mental health symptoms in fathers (adjusted relative risk, 1.52; 95% CI, 1.03-2.22) were associated with a significant increase in risk of anxiety and/or depression in children from those families compared with children from no-risk families. Conclusions and Relevance: Studies seeking to understand prospective associations of parental drinking with children's mental health need to consider additional risk factors in combination with one another as well as parental behaviors and characteristics below clinically defined levels. When accumulated at a family level, even seemingly innocuous characteristics contributed to meaningful increases in risk of anxiety and/or depression among children, potentially translating into poorer mental health outcomes for many young people.

A complete national cohort study of prescriptions of analgesics and benzodiazepines to cancer survivors in Norway 10 years after diagnosis.

Chronic pain due to surgery, radiotherapy, or chemotherapy is prevalent in long-term cancer survivors. Chronic pain due to successful cancer treatment should be treated as chronic nonmalignant pain, primarily with nonpharmacological strategies. Based on complete national data from the Cancer Registry of Norway and the Norwegian prescription database, the aim of this study was to compare the use of nonopioid analgesics, opioids, and benzodiazepines 10 years after cancer diagnosis in long-term cancer survivors and the age- and sex-adjusted general population. The 1-year periodic prevalence of use was higher in long-term cancer survivors in all the studied drug classes: opioids (143.5 vs 129.6/1000), paracetamol (88.3 vs 80.7/1000), nonsteroidal anti-inflammatory drugs (229.1 vs 221.7), gabapentinoids (13.4 vs 10.0/1000), benzodiazepines (88.3 vs 77.9/1000), and benzodiazepine-like hypnotics (118.1 vs 97.4/1000). The prevalence of persistent and high-dose opioid use (>365 defined daily doses [DDDs] and >730 DDDs, respectively, during 365 days, and prescriptions all quarters of the year) was also higher in the cancer survivors than in the general population (6.5 vs 4.8/1000 for persistent use and 2.7 vs 1.3/1000 for high-dose use). Less than 10% of persistent and high-dose users received only long-acting opioid formulations. Furthermore, most long-term cancer survivors with persistent or high-dose opioid use were also high-dose users (>100 DDDs/year) of either benzodiazepines or benzodiazepine-like hypnotics. It is an issue of concern that most of those using opioids did not adhere to guidelines regarding opioid formulation and comedication with other drugs with addictive properties.

Coffee and wine consumption is associated with reduced mortality from alcoholic liver disease: follow-up of 219,279 Norwegian men and women aged 30-67 years.

PURPOSE: To study the association between coffee and alcoholic beverage consumption and alcoholic liver disease mortality. METHODS: In total, 219,279 men and women aged 30-67 years attended cardiovascular screening in Norway from 1994 to 2003. Linkage to the Cause of Death Registry identified 93 deaths from alcoholic liver disease. Coffee consumption was categorized into four levels: 0, 1-4, 5-8, and greater than or equal to 9 cups/d and alcohol consumption as 0, greater than 0 to less than 1.0, 1.0 to less than 2.0, and greater than or equal to 2.0 units/d, for beer, wine, liquor, and total alcohol consumption. RESULTS: The hazard ratios per one category of consumption were 2.06 (95% confidence interval 1.62-2.61), 0.68 (0.46-1.00), and 2.54 (1.92-3.36) for beer, wine, and liquor, respectively. Stratification at 5 cups/d (the mean) revealed a stronger association between alcohol consumption and alcoholic liver disease at less than 5 versus 5 or more cups/d. With less than 5 cups/d, 0 alcohol units/d as reference, the hazard ratio reached to 25.5 (9.2-70.5) for greater than or equal to 2 units/d, whereas with greater than or equal to 5 cups/d, it reached 5.8 (1.9-17.9) for greater than or equal to 2 units/d. A test for interaction was significant (P = .01). CONCLUSIONS: Coffee and wine consumption were inversely associated with alcoholic liver disease death. Total alcohol consumption was adversely associated with alcoholic liver disease mortality and the strength of the association varied with the level of coffee consumption.

Prenatal Exposure to Folic Acid and Antidepressants and Language Development: A Population-Based Cohort Study.

OBJECTIVE: The aim of the study was to determine the effect of simultaneous use of folic acid supplements and selective serotonin reuptake inhibitors (SSRIs) by pregnant women on language development in their offspring at the age of 3 years. DESIGN: We conducted a cohort study of 45,266 women with 51,747 singleton pregnancies in the population-based Norwegian Mother and Child Cohort study (1999-2008). The association between the use of SSRIs with and without concomitant folic acid and language competence in the offspring was investigated using multinomial logistic regression. Self-reported use of folic acid supplements and SSRIs was prospectively collected in 4-week intervals during pregnancy and validated with prescription data and plasma concentrations, respectively. The children's language competence was measured by a validated language grammar rating scale and classified into 3 categories. RESULTS: Women reported the use of folic acid in 44,417 (85.8%) and SSRI in 372 (0.7%) of the pregnancies, 260 used the 2 simultaneously. Compared with women who used folic acid and no SSRIs, the adjusted relative risk ratio of lower language competence rose with the increased duration of simultaneous use of folic acid and SSRIs. After simultaneous use at 4 to 8 four-week intervals, the relative risk ratio reached 4.5 (95% confidence interval, 2.5-8.0) and 5.7 (2.5-13.0) for the intermediate and most delayed category, respectively, using the best language competence category as the reference. The use of SSRIs without folic acid was not significantly associated with an increased risk. CONCLUSIONS: We detected a significant association between long-term use of SSRIs during pregnancy and delayed language competence in the offspring only when folic acid supplementation was used concomitantly. This surprising result warrants further studies.

Benzodiazepine prescription for patients in treatment for drug use disorders: a nationwide cohort study in Denmark, 2000-2010.

BACKGROUND: Benzodiazepines are frequently prescribed to patients with drug use disorders. However, it has previously been difficult to distinguish whether this frequent prescribing was due to underlying psychiatric disorders or inappropriate prescribing. In a nationwide cohort study, we investigated the prescribing of benzodiazepines to patients with drug use disorders in connection with treatment admission. METHODS: Benzodiazepine prescriptions to patients (N = 33203) aged 18 to 67 years admitting for outpatient treatment for drug use disorders in Denmark, 2000 to 2010, were studied by using linked data from nationwide health registries. Factors associated with increasing amounts of benzodiazepine use within the first year after admission were assessed by multinomial logistic regression. Proportions of very long-term benzodiazepine prescription were calculated. RESULTS: During the first year after admission to treatment, 26.2 % of patients were prescribed benzodiazepines. Of these, 35.5 % were prescribed benzodiazepines at dose levels that might indicate inappropriate use (>365 Defined Daily Dose per year), and 34.6 % were prescribed more than one type of benzodiazepines. Diazepam was the most commonly prescribed type. Among patients with opioid use, 43.2 % were prescribed benzodiazepines which were three times higher than for patients with cannabis (12.2 %) or central stimulating drugs (13.8 %) as their primary drug use. Admitting to treatment for a drug use disorder did not increase the specialized psychiatric treatment coverage of this patient group, disregarding use of prescribed benzodiazepines. 29.5 % were new users of prescribed benzodiazepines, and of these, 27.5 % continued into very long-term use (≥4 years after admission) during the study period. CONCLUSIONS: Benzodiazepines were commonly prescribed to patients admitting to treatment for drug use disorders, and included prescription of multiple and non-optimal types, high doses, and very long-term prescriptions. These findings point towards inappropriate prescribing of benzodiazepines in many cases more than treatment for psychiatric disorders.

Coffee intake and mortality from liver cirrhosis.

PURPOSE: The aim of the study was to evaluate the association between coffee consumption and mortality from liver cirrhosis. METHODS: We conducted a mortality follow-up of 51,306 adults who underwent screening for cardiovascular disease from 1977 to 1983. During the subsequent 17 years, the total number of deaths from all causes in the studied cohort was 4207. Fifty-three had the diagnosis of cirrhosis mentioned on the death certificate; of these, 36 had alcoholic cirrhosis. RESULTS: The relative risk of liver cirrhosis mentioned on the death certificate associated with an increase of two cups of coffee, adjusted for sex, age, alcohol use and other major cardiovascular risk factors was 0.6 (95% confidence interval, 0.5-0.8). For alcoholic cirrhosis the results were identical. When studying cirrhosis as the underlying cause of death, the inverse relationship becomes somewhat stronger. CONCLUSIONS: The present study confirms the existence of an inverse association between coffee consumption and liver cirrhosis.

Erratum to "Sex differences in gamma-glutamyltransferase in people aged 40-42 years in two Norwegian counties".

Gamma-glutamyltransferase (GGT) is widely used as a marker of alcohol intake, although it is documented that other factors are also associated with serum levels of GGT. The total population of men and women aged 40-42 years in two Norwegian counties was invited to participate in a health survey program. GGT was measured in 8116 men and 8689 women--67 % of the eligible population. In sex-specific multiple regression analyses, GGT showed a positive association with body mass index (BMI), cholesterol, ln triglycerides, systolic blood pressure, and number of drinks per 2 weeks for both men and women. Glucose and 'years of smoking' were significant in women only. Cups of boiled coffee per day and physical activity in spare time were inversely associated with GGT level for both men and women. A significant positive interaction between alcohol intake and BMI was observed for men but not for women. The use of GGT as a marker of alcohol consumption in middle-aged persons should take into account sex, BMI and drinking of boiled coffee.

Sex differences in gamma-glutamyltransferase in people aged 40-42 years in two Norwegian counties.

Gamma-glutamyltransferase (GGT) is widely used as a marker of alcohol intake, although it is documented that other factors are also associated with serum levels of GGT. The total population of men and women aged 40-42 years in two Norwegian counties was invited to participate in a health survey program. GGT was measured in 8116 men and 8689 women--67 % of the eligible population. In sex-specific multiple regression analyses, GGT showed a positive association with body mass index (BMI), cholesterol, ln triglycerides, systolic blood pressure, and number of drinks per 2 weeks for both men and women. Glucose and 'years of smoking' were significant in women only. Cups of boiled coffee per day and physical activity in spare time were inversely associated with GGT level for both men and women. A significant positive interaction between alcohol intake and BMI was observed for men but not for women. The use of GGT as a marker of alcohol consumption in middle-aged persons should take into account sex, BMI and drinking of boiled coffee.