Hepatitis C elimination in Sweden: Progress, challenges and opportunities for growth in the time of COVID-19.

BACKGROUND & AIMS: In 2014, the burden of hepatitis C virus (HCV) in Sweden was evaluated, to establish a baseline and inform public health interventions. Considering the changing landscape of HCV treatment, prevention, and care, and in light of the COVID-19 pandemic, this analysis seeks to evaluate Sweden's progress towards the World Health Organization (WHO) elimination targets and identify remaining barriers. METHODS: The data used for modelling HCV transmission and disease burden in Sweden were obtained through literature review, unpublished sources and expert input. A dynamic Markov model was employed to forecast population sizes and incidence of HCV through 2030. Two scenarios ('2019 Base' and 'WHO Targets') were developed to evaluate Sweden's progress towards HCV elimination. RESULTS: At the beginning of 2019, there were 29 700 (95% uncertainty interval: 19 300-33 700) viremic infections in Sweden. Under the base scenario, Sweden would achieve and exceed the WHO targets for diagnosis, treatment and liver-related death. However, new infections would decrease by less than 10%, relative to 2015. Achieving all WHO targets by 2030 would require (i) expanding harm reduction programmes to reach more than 90% of people who inject drugs (PWID) and (ii) treating 90% of HCV + PWID engaged in harm reduction programmes and ≥7% of PWID not involved in harm reduction programmes, annually by 2025. CONCLUSIONS: It is of utmost importance that Sweden, and all countries, find sustainability in HCV programmes by broadening the setting and base of providers to provide stability and continuity of care during turbulent times.

Absence of interferon-λ 4 enhances spontaneous clearance of acute hepatitis C virus genotypes 1-3 infection.

OBJECTIVES: Absence of a functional interferon-λ 4 (IFN-λ4) gene (IFNL4) predicts spontaneous resolution of acute hepatitis C virus (HCV) infections in regions with a predominance of genotype 1, whereas variants of the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) entailing reduced activity associate with increased sustained virologic response rates following some therapeutic regimens. This study aimed at investigating the impact of IFNL4 on acute HCV genotype 2 or 3 infections, and whether ITPase activity influenced outcome. MATERIALS AND METHODS: Two hundred and seven people who injected drugs (PWID) with documented anti-HCV seroconversion, and 57 PWID with reinfection with HCV were analyzed regarding IFNL4 (rs368234815 and rs12979860) and ITPA (rs1127354 and rs7270101), and longitudinally followed regarding HCV RNA. RESULTS: The spontaneous clearance of HCV infection in anti-HCV seronegative PWID was enhanced when IFN-λ4 was absent (44% vs. 20% for IFNL4 TT/TTrs1368234815 and ΔGrs1368234815 respectively, p < .001; OR 3.2) across genotypes 1-3. The proportion lacking IFN-λ4 was further increased following resolution of repeated re-exposure to HCV (74% among re-infected participants who had cleared at least two documented HCV infections). ITPA genetic variants did not independently impact on the outcome, but among males lacking IFN-λ4, reduced ITPase activity markedly augmented the likelihood of resolution (65% vs. 29% for <100% and 100% ITPase activity, p = .006). CONCLUSIONS: Absence of IFN-λ4 entails an enhanced likelihood of spontaneous resolution both following primary acute infection and repeated re-exposure to HCV across genotypes 1-3. Among men lacking IFN-λ4, reduced ITPase activity improved outcome.

High risk of non-alcoholic liver disease mortality in patients with chronic hepatitis C with illicit substance use disorder.

Aims: Hepatitis C virus (HCV) is a slowly progressive disease, often transmitted among people who inject drugs (PWID). Mortality in PWID is high, with an overrepresentation of drug-related causes. This study investigated the risk of death in patients with chronic hepatitis C virus (HCV) infection with or without illicit substance use disorder (ISUD).Methods: Patients with HCV were identified using the Swedish National Patient Registry according to the International Classification of Diseases-10 (ICD-10) code B18.2, with ≤5 matched comparators from the general population. Patients with ≥2 physician visits with ICD-10 codes F11, F12, F14, F15, F16, or F19 were considered to have ISUD. The underlying cause of death was analyzed for alcoholic liver disease, non-alcoholic liver disease, liver cancer, drug-related and external causes, non-liver cancers, or other causes. Mortality risks were assessed using the standardized mortality ratio (SMR) with 95% CIs and Cox regression analyses for cause-specific hazard ratios.Results: In total, 38,186 patients with HCV were included, with 31% meeting the ISUD definition. Non-alcoholic liver disease SMRs in patients with and without ISUD were 123.2 (95% CI, 103.7-145.2) and 69.4 (95% CI, 63.8-75.3), respectively. The significant independent factors associated with non-alcoholic liver disease mortality were older age, being unmarried, male sex, and having ISUD.Conclusions: The relative risks for non-alcoholic liver disease mortality were elevated for patients with ISUD. Having ISUD was a significant independent factor for non-alcoholic liver disease. Thus, patients with HCV with ISUD should be given HCV treatment to reduce the risk for liver disease.

Protocol for a multi-site study of the effects of overdose prevention education with naloxone distribution program in Skåne County, Sweden.

BACKGROUND: Continuously high rates of overdose deaths in Sweden led to the decision by the Skåne County to initiate the first regional take-home naloxone program in Sweden. The project aims to study the effect of overdose prevention education and naloxone distribution on overdose mortality in Skåne County. Secondary outcome measures include non-fatal overdoses and overdose-related harm in the general population, as well as cohort-specific effects in study participants regarding overdoses, mortality and retention in naloxone program. METHODS: Implementation of a multi-site train-the-trainer cascade model was launched in June 2018. Twenty four facilities, including opioid substitution treatment units, needle exchange programs and in-patient addiction units were included for the first line of start-up, aspiring to reach a majority of individuals at-risk within the first 6 months. Serving as self-sufficient naloxone hubs, these units provide training, naloxone distribution and study recruitment. During 3 years, questionnaires are obtained from initial training, follow up, every sixth month, and upon refill. Estimated sample size is 2000 subjects. Naloxone distribution rates are reported, by each unit, every 6 months. Medical diagnoses, toxicological raw data and data on mortality and cause of death will be collected from national and regional registers, both for included naloxone recipients and for the general population. Data on vital status and treatment needs will be collected from registers of emergency and prehospital care. DISCUSSION: Despite a growing body of literature on naloxone distribution, studies on population effect on mortality are scarce. Most previous studies and reports have been uncontrolled, thus not being able to link naloxone distribution to survival, in relation to a comparison period. As Swedish registers present the opportunity to monitor individuals and entire populations over time, conditions for conducting systematic follow-ups in the Swedish population are good, serving the opportunity to study the impact of large scale overdose prevention education and naloxone distribution and thus fill the knowledge gap. TRIAL REGISTRATION: Naloxone Treatment in Skåne County - Effect on Drug-related Mortality and Overdose-related Complications, NCT03570099, registered on 26 June 2018.

High Perineal and Overall Frequency of Staphylococcus aureus in People Who Inject Drugs, Compared to Non-Injectors.

To investigate the prevalence, distribution, and colonization burden of Staphylococcus aureus (S. aureus) and MRSA in different body sites among people who inject drugs (PWID) and compare it to a control group consisting of non-injectors. In this cross-sectional survey, 49 active PWID from the needle exchange program (NEP) in Malmö, Sweden, and 60 non-injecting controls from an emergency psychiatric inpatient ward at Malmö Addiction Centre were tested for S. aureus (including MRSA) by culture, PCR, and MALDI-TOF. Samples were taken from anterior nares, throat, perineum, and skin lesions if present. Sixty-seven percent of the PWID were colonized with S. aureus, compared to 50% of the controls (P = 0.08). Perineal carriage was significantly more frequent among PWID than in the control group [37 vs 17%, OR 2.96 (95% CI 1.13-7.75), P = 0.03], also after adjusting for sex and age in multivariate analysis [OR 4.01 (95% CI 1.34-12.03)]. Only one individual in the whole cohort (NEP participant) tested positive for MRSA. PWID may be more frequently colonized with S. aureus in the perineum than non-injection drug users, and there was a trend indicating more frequent overall S. aureus colonization in PWID, as well as higher perineal colonization burden. No indication of a high MRSA prevalence among PWID in Sweden was noted. However, further MRSA prevalence studies among PWID are needed. Knowledge about S. aureus colonization is important for the prevention of S. aureus infections with high morbidity in PWID.

Correlates of Skin and Soft Tissue Infections in Injection Drug Users in a Syringe-Exchange Program in Malmö, Sweden.

BACKGROUND: Injection drug users (IDUs) are at increased risk of various medical conditions, including bacterial skin and soft tissue infections (SSTIs). SSTIs, which are painful and can lead to life-threatening complications, are common but scarcely studied. OBJECTIVES: To investigate life time, past 12 month and past 30-day prevalence for SSTI related to injection drug use, in IDUs at Malmö syringe exchange program (Malmö SEP). To investigate factors associated with having ever had an SSTI. METHODS: IDUs were recruited from Malmö SEP (N = 80). They participated in a survey with questions about demographics, drug use, and experience of SSTIs. Factors independently associated with self-reported SSTI ever were assessed using logistic regression analysis. RESULTS: The lifetime reported prevalence of SSTI was 58%, past 12 months 30%, and past 30 days 14%. Factors independently associated with SSTI ever were age (adjusted odds ratio [AOR] = 1.09; 95% confidence interval [CI] = 1.01-1.18), female sex (AOR = 6.75; 95% CI = 1.40-32.47), having ever injected prescribed drugs (AOR = 52.15; 95% CI = 5.17-525.67), and having ever injected in the neck (AOR = 8.08; 95% CI = 1.16-56.08). CONCLUSIONS/IMPORTANCE: SSTI is common among IDUs in Malmö. Women and those injecting in the neck or injecting prescribed drugs (crushed tablets/liquids), are more likely to have had an SSTI.

Staphylococcus aureus carriage and prevalence of skin and soft tissue infections among people who inject drugs: a longitudinal study.

People who inject drugs are frequently colonized with Staphylococcus aureus and have an increased risk for skin and soft tissue infections. This longitudinal study aims to describe S. aureus carriage in this group and the risk for infections during a 1-year follow-up. We included 61 participants from the Malmö Needle Exchange Program. Mapping of S. aureus carriage was conducted by screening cultures every third month and S. aureus growth was semi-quantified. Data regarding infections and living conditions were collected from structured interviews. Statistics included univariate analysis with the Fischer's exact test, univariate logistic regression and multivariate logistic regression. S. aureus carriage was detected in 46-63% of participants, and 75% reported one or more infections during the study period. Self-reported infections were associated with carriage in perineum (OR 5.08 [95% CI 1.45-17.73]), in skin lesions (OR 1.48 [95% CI 1.21-1.81]), and unstable housing situation (OR 12.83 [95% CI 1.56-105.81]). Thus, people who inject drugs are frequent carriers of S. aureus and report a surprisingly high prevalence of skin and soft tissue infections. Homeless people and those with skin carriage seem to be at highest risk. Effective clinical interventions are needed, aiming at preventing infections in this vulnerable group.

Distribution of intranasal naloxone to potential opioid overdose bystanders in Sweden: effects on overdose mortality in a full region-wide study.

OBJECTIVES: Distribution of take-home naloxone is suggested to reduce opioid-related fatalities, but few studies have examined the effects on overdose deaths in the general population of an entire community. This study aimed to assess the effects on overdose deaths of a large-scale take-home naloxone programme starting in June 2018, using an observational design with a historic control period. DESIGN: From the national causes of death register, deaths diagnosed as X42 or Y12 (International Classification of Diseases, 10th revision, ICD-10) were registered as overdoses. Numbers of overdoses were calculated per 100 000 inhabitants in the general population, and controlled for data including only individuals with a prior substance use disorder in national patient registers, to focus on effects within the primary target population of the programme. The full intervention period (2019-2021) was compared with a historic control period (2013-2017). SETTING: Skåne county, Sweden. PARTICIPANTS: General population. INTERVENTIONS: Large-scale take-home naloxone distribution to individuals at risk of overdose. PRIMARY AND SECONDARY OUTCOME MEASURES: Decrease in overdose deaths per 100 000 inhabitants, in total and within the population with substance use disorder diagnosis. RESULTS: Annual average number of overdose deaths decreased significantly from 3.9 to 2.8 per 100 000 inhabitants from the control period to the intervention period (a significant decrease in men, from 6.7 to 4.3, but not in women, from 1.2 to 1.3). Significant changes remained when examining only prior substance use disorder patients, and decreases in overdose deaths could not be attributed to a change in treatment needs for opioid use disorders in healthcare and social services. CONCLUSIONS: The present study, involving 3 years of take-home naloxone distribution, demonstrated a decreased overdose mortality in the population, however, only in men. The findings call for further implementation of naloxone programmes, and for further studies of potential effects and barriers in women. TRIAL REGISTRATION NUMBER: NCT03570099.

The risk of cancer among persons with a history of injecting drug use in Sweden - a cohort study based on participants in a needle exchange program.

BACKGROUND: Injecting drug use (IDU) may lead to exposure to a range of carcinogenic agents. We investigated the risk and distribution of cancers among individuals with a history of IDU in Sweden. MATERIAL AND METHODS: The cancer incidence in a cohort of longitudinally followed participants in a needle exchange program (NEP), recruited between 1987 and 2007, was compared to that in the Swedish general population, matching for age group and gender. Baseline demographic and drug use data were collected and longitudinal testing of serological markers for HIV, hepatitis B and C virus was performed during NEP participation. Standardized incidence ratios (SIR) for types of cancer found in the study cohort were calculated, using data from the Swedish National Cancer Registry for reference. RESULTS: The mean follow-up time for the 3255 participants was 11.8 years, constituting 38 419 person years at risk. The mean age at end of follow-up was 42.7 years, and 75% of participants were men. Seventy-eight cases of cancer were observed (SIR 1.1 [95% CI = 0.9-1.4]). The SIR was significantly increased for five cancer types among men; primary liver, laryngeal, lung, oropharyngeal and non-melanoma skin cancer (respective SIR 12.8 [95% CI = 4.2-30.0], 9.2 [95% CI = 1.9-26.8], 3.2 [95% CI = 1.5-6.1], 7.3 [95% CI = 1.5-21.2], and 3.5 [95% CI = 1.1-8.2]), and for cancers of endocrine organs among women (5.3 [95% CI = 1.7-12.4]). CONCLUSION: Although the standardized overall cancer incidence in this relatively young IDU cohort was similar to that in the general population, the risk of specific types of cancer was significantly increased, suggesting that IDU confers elevated risks for certain malignancies. These findings prompt further studies to investigate causative factors and suggest the need for surveillance among persons with a history of IDU.

Characteristics of and Experience Among People Who Use Take-Home Naloxone in Skåne County, Sweden.

Background: Opioid overdose related injury or death can be prevented by bystander naloxone administration. For naloxone to be present when and where overdoses occur, opioid prevention education and naloxone distribution (OPEND) must be established on a broad level. This is the 30-month follow-up of the first multi-site naloxone project in Sweden, implemented at 31 sites in the County of Skåne 2018. Aim: To address participant characteristics and factors associated with returning for naloxone refill and with having used naloxone for overdose reversal. An additional aim was to describe self-reported reasons for naloxone refill and overdose experiences. Methods: Data were collected during June 2018-December 2020 through questionnaires at baseline and upon naloxone refill of the initial and subsequent naloxone kit. Descriptive statistics was used to address participant characteristics, those returning for naloxone refill and reporting overdose reversal. Chi-2 test was used for variable comparison between groups. Factors associated with overdose reversals were examined by logistic regression analysis. Reasons for naloxone refill, overdose situation and management were presented descriptively. Results: Among 1,079 study participants, 22% (n = 235) returned for naloxone refill, of which 60% (n = 140) reported a total of 229 overdose reversals. Reversals were more likely to be reported by participants trained at needle exchange programs (NEPs) [adjusted odds ratio (AOR) = 5.18, 95% Confidence interval (CI) = 3.38-7.95)], with previous experience of own (AOR = 1.63, 95% CI = 1.03-2.58) or witnessed (AOR = 2.12, 95% CI = 1.05-4.29) overdose, or who had used sedatives during the last 30 days before initial training (AOR = 1.56, 95% CI = 1.04-2.33). A majority of overdoses reportedly occurred in private settings (62%), where the victim was a friend (35%) or acquaintance (31%) of the rescuer. Conclusion: Participants with own risk factors associated with overdose (e.g., injection use, concomitant use of benzodiazepines and previous experience of own overdose) were more likely to report administering naloxone for overdose reversal. Overdose management knowledge was high. The findings indicate that implementation of multi-site OPEND reaches individuals at particularly high risk of own overdose in settings with limited previous harm reduction strategies and favors a further scaling up of naloxone programs in similar settings.

Hepatitis C treatment at a Swedish needle exchange program, a successful model of care - the ACTIONNE study.

BACKGROUND: To engage people who inject drugs (PWID) in HCV care, innovative models of care are urgently needed. A needle exchange program (NEP) could serve as an ideal platform for comprehensive HCV management including post treatment follow up. METHODS: 50 actively injecting patients at the Malmö Needle exchange program (MNEP) were consecutively enrolled between April 2018 and May 2019. All patients received a fixed-dose combination of once-daily glecaprevir/pibrentasvir for 8 or 12 weeks. Patients were monitored weekly during treatment and data on adherence and side effects was recorded. The primary endpoint was SVR12. Adherence to treatment was the secondary endpoint. RESULTS: 47/50 (94%) patients completed treatment. 45/50 were HCV negative at 12 weeks post treatment giving an SVR12 rate per ITT of 90% and an SVR12 rate per protocol of 96%. One patient showed reinfection 12 weeks post treatment and one patient was lost to follow up and did not produce an SVR12 result. The mean adherence per week, according to pill count, was 98%. CONCLUSION: Our study shows that the NEP can be a useful tool for engaging actively injecting PWID in HCV management and that SVR rates, comparable to those in non-PWID settings, can be achieved.

Mortality and causes of death among people who inject amphetamine: A long-term follow-up cohort study from a needle exchange program in Sweden.

BACKGROUND: Abuse of amphetamines is a worldwide problem with around 34 million users, and amphetamine is commonly used by people who inject drugs (PWID). Despite this, there is relatively little research on mortality and cause of death among people who use amphetamines primarily. The present study aimed to examine mortality and causes of death among people who inject amphetamine, and compare these results to the general population. METHODS: This retrospective cohort study was based on data from The Malmö Needle Exchange Program in Sweden (MNEP) and on data from The Swedish National Cause of Death Register. Participants in the MNEP, between 1987 and 2011, with registered national identity number and amphetamine as their primary drug of injection use, were included in the study. Standardized mortality ratios (SMR) was calculated for overall mortality and categories of causes of death. RESULTS: 2019 individuals were included (mean follow-up-time 13.7 years [range 0.02-24.2 years], a total of 27,698 person-years). Of the 448 deceased, 428 had a registered cause of death. The most common causes of death were external causes (n = 162, 38%), followed by diseases of the circulatory system (n = 67, 16%). SMR were significantly elevated (8.3, 95% CI [7.5-9.1]) for the entire study population, and for every category of causes of death respectively. CONCLUSIONS: People injecting amphetamine as a primary drug were found to have significantly elevated mortality compared with the general population, with high rates of both external and somatic causes of death.

Death from liver disease in a cohort of injecting opioid users in a Swedish city in relation to registration for opioid substitution therapy.

INTRODUCTION AND AIMS: Injecting opioid users are at elevated risk of death. Although liver disease (especially hepatitis C) is common, its impact on mortality is low in active injectors. Because opioid substitution therapy (OST) reduces the risk of death from directly drug related causes, we hypothesised that the proportion of liver-related deaths would increase in subjects receiving OST. We investigated liver-related mortality in a cohort of injecting opioid users attending a needle exchange program (NEP) in a Swedish city in relation to OST exposure. DESIGN AND METHODS: Participants enrolled in the NEP between 1987 and 2011 with available national identity numbers, and registered use of opioids, were included. Linkage based on national identity numbers was performed with national registers for death, emigration and prescription of OST. Participants were categorised as non-OST recipients until the registered date of first OST prescription, and hence as OST recipients. Hazard ratios were calculated by Cox regression for overall and liver-related mortality in relation to OST, with OST as a time-dependent variable. RESULTS: Among 4494 NEP participants, 1488 opioid users were identified; 711/1488 had been prescribed OST. During a follow-up period of 15 546 person-years 368 deaths occurred. Sixteen deaths were caused by liver disease; 10 of these occurred in OST recipients. The risk of liver-related death was significantly increased in OST receiving participants (hazard ratio 3.08, 95% confidence interval [1.09, 8.68], P = 0.03). CONCLUSIONS: Liver related mortality among opioid users was significantly elevated in OST recipients, showing the long-term importance of chronic liver disease in this population. [Jerkeman A, Håkansson A, Rylance R, Wagner P, Alanko Blomé M, Björkman P. Death from liver disease in a cohort of injecting opioid users in a Swedish city in relation to registration for opioid substitution therapy. Drug Alcohol Rev 2017;36:424-431].

Hepatitis C viremia patterns in incident hepatitis C infection and one year later in 150 prospectively tested persons who inject drugs.

OBJECTIVES: To assess HCV viremia levels just before, during and one year after anti-HCV seroconversion in people who inject drugs (PWID). METHODS: PWID enrolling into a needle exchange program in Malmö, Sweden, 1997-2005 constituted the source population. Sera were obtained at enrolment and at approximately 3-4 monthly intervals afterwards, and were initially tested for anti-HIV, HBsAg/anti-HBc and anti-HCV and thereafter for markers previously negative. Seroconversion to anti-HCV had occurred during the study period in 186 out of 332 seronegative subjects. In these anti-HCV seroconverters, quantitative HCV RNA PCR was retrospectively performed on frozen sera to determine viremia levels in the last anti-HCV negative, the first anti-HCV positive and in one year follow-up samples. RESULTS: Among 150 subjects seroconverting to anti-HCV with samples available from all three defined time-points, eight different patterns of viremia were observed. Spontaneous clearance at one year was noted in 48 cases (32%) and was associated with female gender (p = 0.03, CI 0.17-1.00). In 13 cases HCV-RNA was not detected in any study sample. Among 61 subjects with pre-seroconversion viremia, viral load was significantly higher in the pre-seroconversion samples compared to subsequent samples. For the whole group, viral load declined to undetectable levels at seroconversion in 28% of cases (but with recurrent viremia in 15%). CONCLUSIONS: Different patterns of HCV RNA kinetics were observed among PWID with documented seroconversion to anti-HCV. The frequently observed absence of detectable HCV RNA in the first anti-HCV positive sample (irrespective of subsequent viremia) demonstrates the importance of repeated sampling and RNA testing for determination of the outcome of acute infection.