http://orcid.org/0000-0001-6643-3245
Abstract
Background and aims: Sharing of unsterile injection equipment among people who inject drugs (PWID) is the major transmission-route for hepatitis C (HCV). HCV is highly prevalent in PWID in the Stockholm needle exchange programme (NEP). The frequency of advanced liver fibrosis among the participants is, however, unknown.
Methods: From December 2016 to April 2018, all participants with chronic hepatitis C infection (CHC) were offered liver fibrosis evaluation at the Stockholm NEP, including liver stiffness measurement (LSM), a medical history and expanded blood tests to evaluate APRI and FIB-4 scores.
Results: A total of 2037 individuals were enrolled of whom 964 (47.3%) had CHC. LSM was performed in 203 (21.1%) of eligible participants of whom 85% had mild fibrosis (LSM ≤9.4 kPa) and 15% advanced fibrosis (LSM ≥9.5 kPa). APRI >1 and FIB-4 > 3.25 only identified 30% of participants with advanced fibrosis. However, all 31(100%) participants with advanced fibrosis were detected when APRI >1 was combined with an age of ≥40 years and an injection drug use (IDU) duration of ≥15 years.
Conclusions: We found that the diagnostic work-up for advanced fibrosis can be simplified with this combination of easily available factors. This allows identification of PWID in need of immediate HCV treatment to prevent further disease progression. Furthermore, LSM can be avoided among PWID with mild fibrosis, identified by age <40 years combined with IDU duration of <15 years and APRI score <1. This strategy enhances the HCV care cascade where LSM is not easily available, and will thus facilitate HCV treatment initiation.
Introduction
An estimated 71 million people worldwide have chronic hepatitis C (CHC) [Citation1]. Among people who inject drugs (PWID) the prevalence of CHC is high, and the major route for hepatitis C virus (HCV) transmission is the sharing of unsterile injection equipment [Citation2,Citation3]. Among the 15.5 million people with recent injection drug use (IDU) worldwide, 6.1 million (39.2%) are estimated to be HCV infected. The global burden of disease related to previous exposure to HIV, hepatitis B (HBV), and HCV via IDU accounts for more than 10 million disability-adjusted life years (DALYs). Furthermore, it is estimated that 7 million DALYs are caused by the long-term adverse events caused by HCV [Citation4].
HCV treatment with direct-acting antivirals (DAAs) achieve cure rates ≥95% [Citation5]. In 2016, the World Health Organisation (WHO) set targets for HCV elimination by 2030, including 90% reduction of new CHC cases, 80% treated CHC cases and a 65% reduction of CHC related deaths [Citation6]. With the increased availability of DAA treatment in Europe and in the world, the feasibility of HCV elimination as proposed by the WHO will increase [Citation7].
Previous studies in Stockholm have found a 60% prevalence of chronic HCV infection in PWID [Citation8]. HCV knowledge, however, is insufficient among PWID participants and the HCV incidence rate is high in Stockholm [Citation8,Citation9]. The actual prevalence of advanced HCV liver disease/cirrhosis at the Stockholm NEP, and factors associated with advanced disease among the participants is largely unknown. Since 1 January 2018, unrestricted access to HCV treatment is available in Sweden. Presently it is thus feasible to treat all HCV infected individuals. To reach previously untreated populations, such as PWID, for testing, diagnosis and treatment, an enhanced HCV care cascade is needed.
The aims of this study were to find easy to use parameters to pinpoint advanced fibrosis/cirrhosis, and to evaluate the liver fibrosis stages in PWID attending the Stockholm NEP by using liver stiffness measurement (LSM), APRI (aspartate aminotransferase to platelet ratio index), and FIB-4 (Fibrosis-4) score. Furthermore, we investigated possible correlations for mild and advanced fibrosis as defined by LSM (cut-off 9.5 kPa) using participant demographics (i.e., age, duration of IDU, history of alcohol use, diabetes mellitus and body mass index).
Methods
As described in earlier publications [Citation8,Citation9], the Stockholm NEP is a low threshold unit that offers needle and syringe exchange with mandatory tests for hepatitis A, HBV, HCV and HIV at inclusion in the programme. Treatment for infectious diseases is provided, including HCV treatment according to Swedish HCV treatment guidelines [Citation10,Citation11]. Up until 2018, 2910 participants have been enrolled in the programme and 1799 individual participants engaged in the programme during 2017 with over 25,000 visits. Among these NEP participants, 43% were primarily using amphetamine and 43% heroin. The overall mean age was 38 years, and 25% were females. The prevalence of HIV and HBV infection was 5.7% and 1.6%, respectively. The prevalence of HCV infection was 59% [Citation12].
Between 8 December 2016 and 24 April 2018, all participants with CHC infection, defined as positive HCV RNA tests >6 months, were offered an evaluation of liver fibrosis at the Stockholm NEP. All participants evaluated with LSM were included in the study. The evaluation of liver fibrosis also included a medical history (debut of IDU, main drug used past 12 months, diabetes mellitus (DM) yes/no/treated/non-treated) and an LSM assessment. Furthermore, the current use of alcohol was evaluated with AUDIT-C and B-PEth. Body Mass Index (BMI) was calculated and blood testing for AST, ALT, platelets, albumin, INR, HCV genotype, HBV and HIV was performed.
During the study period, participants at the Stockholm NEP were informed and recruited through personal information from the staff and digitally through an information screen in the waiting room. All non-included individuals with CHC acted as a control group regarding baseline characteristics.
Liver stiffness measurement
Liver stiffness measurement (LSM) was performed with transient elastography, a non-invasive assessment of liver fibrosis [Citation13,Citation14]. The result is obtained in kilo Pascal (kPa) and the value was correlated to the stage of liver fibrosis (Metavir F0–F4). Liver stiffness cut-offs in accordance with Swedish HCV treatment guidelines were <7 kPa for Metavir F0–F1, 7–9.4 kPa for Metavir F2, 9.5–12.4 kPa for Metavir F3 and ≥12.5 kPa for Metavir F4 indicating cirrhosis [Citation10,Citation15]. Individuals were further classified as having mild or advanced fibrosis. Mild fibrosis corresponded to LSM levels 9.4 or less and advanced to ≥9.5 kPa. The liver elasticity (LSM) was measured using FibroScan 402® with an M probe. Experienced members of the staff performed the LSM assessment. All participants were fasting for at least 2 h prior to assessment. A valid assessment was defined as ≥10 successful readings with a success rate of >60% and an interquartile range of <30%.
APRI and FIB-4 score
The APRI score (aspartate aminotransferase to platelet ratio index) was used to identify advanced fibrosis/cirrhosis (F3-F4). An APRI score greater than 1.0 has a sensitivity of 77% and specificity of 75% for predicting F3–F4 and an APRI score greater than 2.0 has a sensitivity of 48% and specificity of 94% for predicting F3–F4 [Citation16].
The FIB-4 (Fibrosis-4) score was used to identify severe fibrosis/cirrhosis. A FIB-4 score <1.45 has a negative predictive value of 90% for advanced fibrosis and a FIB-4 > 3.25 a 97% specificity and a 65% positive predictive value to identify advanced fibrosis [Citation17].
ALT and AST upper limit of normal was 1.1 and 0.76 μkat/L for men, and 0.76 and 0.61 μkat/L, respectively for women. ALT and AST in μkat/L were normalised to U/L for the FIB-4 score, where upper limit of normal was 35 U/L for ALT and 40 U/L for AST.
Audit-C
The AUDIT-C questionnaire is a short version of AUDIT (alcohol use disorder identification test) that consists of three questions about alcohol consumption patterns during the last year. The answers are summed up to a total score that varies between 0 and 12. As a cut-off score for risk use, 4 points were used for women and 5 points for men [Citation18].
B-PEth
A phosphatidylethanol test (B-PEth) is a specific alcohol marker in blood with high sensitivity [Citation19,Citation20]. The phospholipid PEth is formed only in the presence of alcohol and is dose-dependent and correlates to alcohol intake the past month. A result of <0.05 μmol/l represents no or low/sporadic alcohol consumption, 0.05–0.30 μmol/l a moderate alcohol consumption, and >0.30 μmol/l a severe/continuous consumption [Citation21].
BMI
Body Mass Index (BMI) is defined as a person’s weight in kilograms divided by the square of the person’s height in metres (kg/m2). A BMI of <18.5 was defined as underweight, 18.5–24.9 as normal weight, 25–29.9 as pre-obesity and ≥30 as obesity [Citation22].
Statistics
All data, including laboratory data, were registered in InfCare NSP (needle syringe programme), a database used as a quality register and a clinical decision tool for collecting and analysing data for participants in the Stockholm NEP. Data from InfCare NSP were exported to and analysed in the statistical programmes, JMP®, Version 13, SAS Institute Inc., Cary, NC.
Demographic data are presented as proportions, mean or median levels with ranges. The Chi-square test or Fisher exact two-tailed test was used to test categorical variables and the Wilcoxon rank sum test for continuous values. A p value of <.05 was considered statistically significant.
Ethics
The study was performed in accordance with the Helsinki declaration and was approved by the Regional Ethical Review Board in Stockholm (Dnr: 2013/495-31/3, 2015/1374-32 and 2018/904-32).
Results
A total of 2037 individuals were enrolled in the Stockholm NEP during the study period. Among them, 1159/2037 (56.9%) were HCV-RNA positive. The definition of CHC (positive HCV RNA tests >6 months) was met in 964/2037 (47.3%) individuals. LSM was performed in 203/964 (21.1%) of eligible participants included ().
Figure 1. Flowchart of included participants.
Demographics of the included participants and controls are depicted in . The overall mean age of the participants was 44 years. In total 153 were men and 50/203 (24.6%) women. Females were significantly younger than men, mean age 40.4 vs. 45.2 years (p < .05). The mean duration of IDU was 21.8 years and the median 21 years (range 1–51). Females had a significantly shorter duration of IDU than men, 15.9 vs. 23.7 years (p < .001). Amphetamine was the main drug used in 58.1% of the participants. Compared to PWID admitted to the Stockholm NEP who were not included in the study, included participants were to a higher proportion aged ≥40 years (65.0 vs. 55.1%, p < .05), and were more frequently using amphetamine as the main drug (58.1 vs. 43.7%, p < .001).
Table 1. Baseline demographics of included chronic hepatitis C (CHC) participants (n = 203) compared with non-included CHC participants (n = 761) at the Stockholm NEP during the study period.
The distribution of HCV genotypes (only tested in included participants, n = 203) was 3a, 1a, 2b and 1b in 47.7%, 39.2%, 11.1% and 2.0%, respectively
Liver elasticity
A total of 203 participants were evaluated with liver elasticity. The mean value was 7.2 kPa with a range of 3–58 kPa (data not shown). Among evaluated participants, 70.9% had a value of <7 kPa (corresponding to Metavir fibrosis stage F0–F1), and 13.8%, 9.4% and 5.9% a value of 7–9.4, 9.5–12.4 and ≥12.5 kPa (Metavir F2, F3 and F4) respectively.
Concomitant diseases and previous HCV treatment
Diabetes mellitus (DM) was seen in 6/203 (3.0%) and 117/203 (58.2%) had a normal BMI and 14/203 (7%) were obese. As depicted in , there was no statistically significant association between DM or BMI ≥30 (or BMI ≥25) and fibrosis stage (mild versus advanced). A total of 14/203 (6.9%) reported the experience of previous HCV treatment.
Table 2. Association between baseline demographics and fibrosis stages classified as mild (F0–F2, LSM ≤9.4 kPa) versus advanced (F3–F4, LSM ≥9.5 kPa), (n = 203).
History of alcohol use
Overall 69/203 (34.0%) reported having a risk consumption of alcohol during the last year (AUDIT-C). A PEth level >0.05 representing risk consumption was noted in 71/203 (35.0%). There was a 79.1% overlap among those who reported having a risk consumption with those with a PEth level of >0.05. A history of treatment for alcohol use disorder was reported in 24/203 (11.8%) of participants.
There was no significant correlation between alcohol consumption (self-reported risk consumption, PEth >0.05, PEth >0.3, or previous treatment for alcohol use disorder) and fibrosis stage (mild versus advanced).
APRI and FIB-4 score
A total of 23/190 (12.1%) participants had an APRI score >1, and 7/190 (3.7%) an APRI score >2. The APRI score was significantly correlated to fibrosis stage and differed in participants with mild versus advanced fibrosis (p < .0001) and in participants with or without cirrhosis (LSM ≥12.5 versus LSM ≤12.4) (p < .001) ().
Figure 2. (a) The APRI score according to fibrosis stage F0–F2 mild fibrosis (LSM ≤9.4 kPa) and F3–F4 advanced fibrosis (LSM ≥9.5 kPa). A significant difference in APRI score was seen in participants with mild versus advanced fibrosis, p < .0001. (b)The APRI score according to fibrosis stage F0–F3 (no cirrhosis, LSM ≤12.4 kPa) and F4 (cirrhosis, LSM ≥12.5 kPa). A significant difference in APRI score was seen in participants with and without cirrhosis, p < .001.
As shown in , 9/23 (39.1%) of participants with APRI >1 had advanced fibrosis (by LSM). On the other hand, the APRI score >1 identified only 9/30 (30.0%) of all participants with advanced fibrosis (by LSM). For participants with APRI >2, the corresponding figures were 4/7 (57.1%) and 4/30 (13.3%) (data not shown).
There was an overall significant difference between FIB-4 cut-off (1.45 < and >3.25) and mild versus advanced fibrosis (p < .001).
Fibrosis stages according to age and IDU duration
A total of 132/203 (65.0%) participants were aged ≥40 years, and 137/203 (67.5%) had an IDU duration ≥15 years. In total, 114/203 (56.2%) were both aged ≥40 years and had an IDU duration ≥15 years. As depicted in , participants aged ≥40 years or with an IDU duration ≥15 were significantly more likely to have advanced fibrosis (p < .001 and p < .01). With these respective cut-offs, 28/31 (90.3%) participants with advanced fibroses were identified. Fibrosis stages according to age and IDU duration is shown in .
Figure 3. Advanced fibrosis (fibrosis stage F3–F4, LSM ≥9.5 kPa) and mild fibrosis (fibrosis stage F0–F2, LSM ≤9.4 kPa) plotted against age and IDU duration with cut-offs by age ≥40 years and IDU duration ≥15 years (dotted lines).
An age of ≥40 years in combination with an IDU duration of ≥15 years identified 26/31 (83.9%) of participants with advanced fibrosis, however, only 26/114 (22.8%) actually had advanced fibrosis with this cut-off. APRI >1 was present in 13/23 (56.5%) of participants with an age of ≥40 years and an IDU duration of ≥15 years. When an APRI score of >1 was combined with age ≥40 years in combination with an IDU duration of ≥15 years, all 31(100%) participants with advanced fibrosis were detected.
The outlier with advanced fibrosis (LSM >9.5 kPa), age 26 years and IDU duration of 8 years who was only identified by APRI >1 was a female who reported a risk consumption of alcohol (AUDIT-C score 12) and had a PEth value of 1.4, AST 1.98 µkat/L (130 U/L), ALT 2.07 µkat/L (95 U/L), normal platelet count, albumin, no data on clinical cirrhosis and a FIB-4 of <1.45.
For cirrhosis (LSM ≥12.5 kPa) a cut-off of at age ≥45 years in combination with IDU duration of ≥20 years identified 11/12 (91.7%) participants with cirrhosis but overall only 11/90 (12.2%) within this cut-off had cirrhosis.
Sensitivity, specificity and predictive values
The sensitivity, specificity and predictive values (positive predictive value (PPV) and negative predictive value (NPV)) for variable cut-off levels for age and duration of IDU to detect advanced fibrosis are presented in .
Table 3. Accuracy testing of possible cut-offs for detecting advanced fibrosis (LSM ≥9.5 kPa).
HIV and hepatitis B
In this cohort, 3/203 (1.5%) were HIV positive and 89/203 (43.8%) were anti-HBc positive indicating a previously cleared HBV infection. 17/203 (8.4%) were HBV naive and 97/203 (47.8%) were anti-HBs positive after vaccination. None had an active HBV infection. Neither HIV infection nor a spontaneously cleared HBV infection was associated with severe fibrosis (data not shown).
Discussion
In our study, we found that 15% of PWID in the Stockholm NEP had advanced fibrosis (LSM ≥ 9.5 kPa) roughly corresponding to Metavir fibrosis stage F3 and F4. Those with advanced fibrosis are in need of immediate treatment for HCV to prevent further disease progression and also need to be included in hepatocellular carcinoma (HCC) screening programmes. Assessment with LSM has been well received in PWID, and is reasonably effective in identifying advanced fibrosis [Citation23,Citation24]. A need for reliable diagnosis of advanced liver fibrosis is at hand since it may predict future liver-related events [Citation25]. A prerequisite for LSM assessment pre-treatment, however, may be a limiting factor if it is mandatory before HCV treatment is offered and will thus have a negative impact on the efficacy of the HCV care cascade [Citation5].
The effort to eliminate HCV and thus fulfil the goals set by WHO, require that new patient groups in particular PWID are targeted. To enhance the HCV care cascade, and thus facilitate treatment initiation, algorithms for simplified pre-treatment fibrosis evaluations are needed. We sought to find alternatives by combining age and duration of IDU with an easily available test such as APRI score and FIB-4 measurement. We also tried to determine if well-known factors for a more advanced fibrosis development such as diabetes, overweight and alcohol was associated with the development of advanced fibrosis in our cohort.
Alcohol, overweight and diabetes
We found no association between the extent of alcohol use and advanced fibrosis when the use of alcohol was evaluated with AUDIT-C and PEth levels in blood, even though this association is well known. On the other hand, our data may have failed to identify the risk use of alcohol over a longer duration of time. Defining long-term risk use of alcohol in our PWID population is a challenge and we might have failed to do this properly. Self-reported data on ever having treatment for alcohol use disorder (as a long-term alcohol use marker) may be response biased. Furthermore, a high percentage of individuals with alcohol use disorders never seek treatment [Citation26,Citation27]. It is well known that any level of alcohol consumption in combination with HCV infection, constitute a health risk [Citation28,Citation29]. This is noted in other studies where the association between significant alcohol intake (>40 g alcohol/day in women and >60 g in men during >5 years) and HCV infection carries an increased risk to develop liver cirrhosis and decompensated liver disease [Citation30].
In our PWID cohort, we found no association between BMI, diabetes and having advanced fibrosis. These factors are known to be associated with the development of fibrosis and are associated with persistent fibrosis after treatment induced sustained viral response [Citation31,Citation32]. Thus, individuals with these risk factors should be generously considered for LSM evaluation and prioritised for treatment. In our study, only 15% of the participants had developed advanced fibrosis (LSM ≥9.5 kPa), and only 3% had diabetes and 7% BMI ≥30, respectively. Consequently, the influence of diabetes and BMI on advanced fibrosis could not be properly evaluated.
Use of APRI score and FIB 4 to detect advanced fibrosis
In Swedish HCV treatment guidelines, pre-evaluation of fibrosis stages with LSM (or liver biopsy) was earlier required before HCV treatment was offered [Citation10,Citation11]. In international guidelines, APRI and FIB-4 are recommended for detecting advanced fibrosis (LSM ≥9.5 kPa) [Citation33]. In Australian HCV guidelines, an APRI <1 may be used to ‘exclude the presence of cirrhosis in settings where other tools, such as LSM, are not accessible’ [Citation34] and in Scotland a FIB-4 < 1.45 is used to exclude cirrhosis [Citation35]. A further pragmatic exclusion criteria used in parts of Scotland is age <35 years in combination with the absence of alcohol use [Citation35].
An APRI score was available in 30 of our participants with advanced fibrosis (LSM ≥9.5 kPa) but only 9/30 (30%) had an APRI score >1 whereas the remaining 21 (70%) had an APRI score <1. Thus, using APRI score >1 to identify the presence of advanced fibrosis (LSM ≥9.5 kPa), and even cirrhosis (LSM ≥12.5 kPa) in our cohort was not appropriate. The poor performance of the APRI score is not totally unexpected. Also when multiplied with INR, the so-called GUCI score, it does not perform very well in particular when differentiating F1–F3 fibrosis scores [Citation36].
We found a significant difference in FIB-4 levels <1.45 and >3.25 in participants with mild (LSM ≤9.4 kPa) versus advanced fibrosis stage (LSM ≥9.5 kPa). The specificity and positive predictive value of FIB-4 > 3.25 to identify advanced fibrosis (LSM ≥9.5 kPa) were in accordance with previous data [Citation17]. However, 8/118 (7%) of our participants with a low FIB-4 level <1.45, all the same, had advanced fibrosis, and 4/13 (31%) with a high FIB-4 level >3.25 did not. Overall only 9/30 (30%) of participants with advanced fibroses had a FIB-4 level >3.25.
To summarise, when using an APRI score >1 or a FIB-4 level >3.25 as cut-offs for finding participants with advanced fibrosis (LSM ≥9.5 kPa), only a limited part of those with advanced fibrosis will be identified.
Use of age and IDU duration to detect advanced fibrosis
We further investigated whether age and/or duration of IDU were associated with the stage of fibrosis. When we used age with cut-off ≥40 years we identified 90% of all cases with advanced fibrosis (LSM ≥9.5 kPa). Also, a cut-off for IDU ≥15 years (as a surrogate marker for the duration of HCV infection) identified 90% of those with advanced fibrosis (LSM ≥9.5 kPa). These cut-offs combined, identified 84% of our participants with advanced fibrosis (LSM ≥9.5 kPa) but when combined with APRI score >1, all 31 cases with advanced fibrosis were detected.
Our data thus suggest that a cut-off by age ≥40 years together with IDU duration ≥15 years, in combination with APRI score >1 is a reasonable and easy to use a combination of factors to detect advanced fibrosis. On the other hand, with the high sensitivity of using only age and duration of IDU, there are possible benefits of excluding fibrosis scores based on blood sampling, especially in PWID due to difficulties in finding a usable vein for blood sampling [Citation37,Citation38].
Strengths and limitations
In this study, we used LSM as a method to detect advanced fibrosis. LSM, with FibroScan examination is, however, subjected to confounding factors such as acute/unspecific liver inflammation, congestive heart failure, liver blood congestion after a meal, and obesity, which are all the factors that can interfere and cause false high LSM levels indicating advanced fibrosis [Citation14]. To minimise these confounders, our participants were investigated in a fasting state. LSM was not systematically repeated but the intention is to repeat LSM levels indicating cirrhosis before referral for ultrasound evaluation.
During the study period, LSM was not available at all times, mainly due to logistical reasons, and hence only 21% were examined. To reduce the possible bias introduced from this selection, we used those not included as a control group and compared them concerning demographics to highlight if any major bias was introduced. We noted that included participants were generally of higher age than the non-included controls, which favours detection of advanced fibrosis. With the open inclusion study approach used we reached a higher proportion of individuals aged ≥40 years, and a higher number of amphetamine users. Possibly older participants were more concerned about their liver health and thus more inclined to participate. For amphetamine users, lacking effective drug substitution treatment (as in opioid substitution treatment (OST) clinics where other health issues are also targeted) assessment of liver health at a NEP may be an effective way to reach this population.
Lastly, we have throughout this study defined the duration of IDU as the difference between current age and self-reported age of injection drug debut. In this estimate, we have not taken into account that there might have been long periods of abstinence from IDU. Furthermore, the debut of IDU is not necessarily concurrent with being HCV exposed, although our previous data have demonstrated early HCV infection [Citation8].
Conclusions
Only 15% of our PWID were found to have advanced liver fibrosis (LSM ≥9.5 kPa) corresponding to a Metavir fibrosis stage F3 and F4. We managed to pinpoint these PWID in a high percentage when age ≥40 years and IDU ≥15 were combined with an APRI score >1. With this combination of easily available data, we found that the diagnostic work-up to detect advanced fibrosis can be simplified, and makes it possible to find participants with advanced fibrosis in need of immediate treatment for HCV to prevent further progression and screening to prevent HCC development. Furthermore, LSM can be avoided among PWID with mild fibrosis, identified by age <40 years combined with IDU duration of <15 years and APRI score <1. This strategy enhances the HCV care cascade where LSM is not easily available, and will thus facilitate HCV treatment initiation. We further suggest that this algorithm should be validated in an independent and larger population before general use can be recommended.
Acknowledgements
The help from the clinical staff at the Stockholm NEP in terms of data collection is highly appreciated. The authors especially thank the nurses, Ann-Marie Lang and Linda Näslund.
Disclosure statement
No potential conflict of interest was reported by the authors.
Additional information
Funding
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