Kamilla Kristoffersen
VEILEDER PROF OLAV DALGARD, V/INFEKSJONSMEDISINSK AVDELING, AHUS
Prevalence of
chronic hepatitis among users of
interdisciplinary treatment centres
for substance abuse in Norway
PROSJEKTOPPGAVE, MEDISINSTUDIET
Abstract
In Norway the prevalence of HCV has been monitored by the Norwegian notification system for infectious diseases (MSIS) since 1990, but the lack of notifications by laboratories, uncertainty about the proportion of cases being viremic and no information about antiviral treatment limits the usefulness of the system. In light of this, there is a need for updated surveillance data about hepatitis C, especially among people who inject drugs. We therefore aimed at assessing the HCV inpatients among users of interdisciplinary
treatment centres for substance abuse in Norway, so called TSB institutions, as well as exploring the feasibility of using these institutions for regular surveillance of HCV in the future. In our study we found that the prevalence of HCV antibodies was 52%, and chronic HCV infection was 41%. In our sample 41% were women (higher than the general PWID population), and the fraction of women who were antibody positive as well as RNA postitive was lower than for men (68% of women vs 89% of men). We also proved that TSB institutions have potential as a future platform for HCV prevalence
monitoring, as well as treatment. The implications of the data collected in this specific study is limited due to small sample size, but we have confirmed the feasibility of collecting data on HCV prevalence in these institutions.
Background
Hepatitis C is a small, enveloped, single-stranded RNA virus of the family Flaviviridae. The virus is predominantly blood-borne, and infects primarily through unsafe injection practices and medical procedures such as renal dialysis and blood transfusions. Mother to child transmission occurs in 4-8%
of births to women infected with HCV, and sexual transmission occurs
infrequently – though men who have sex with men (MSM) are at an increased risk. (1)
Global prevalence
Globally an estimated 71 million people are infected with HCV, with a prevalence of 2-3% (2). Unlike most communicable diseases (including
malaria, HIV, tuberculosis), the absolute burden of viral hepatitis is increasing worldwide and is high in both low and high income countries. Viral hepatitis was the 7th leading cause for death in 2013, with hepatitis B and hepatitis C contributing equally. There was an increase in numbers of deaths caused by viral hepatitis from 1990 (0,89 million) to 2013 (1,45 million), where liver related deaths are caused by acute infection, cirrhosis and liver cancer (3).
HCV and PWID
In the western part of Europe the incidence of HCV seems to have declined since the 1990s(4). In high income countries, the prevalence of HCV in the general population is low (<2%), where 50-80% of the disease burden of hepatitis c is found among people who inject drugs (PWID). In this population the prevalence of hepatitis C ranges from 20%-80%, with midpoint estimates making out 67% antibody positive, and 50% RNA positive(5). It is estimated that of 16 million people in 148 countries that actively inject drugs, about 10 million are infected with HCV(1).
The incidence among PWID ranges from 2-66% per year, with the highest incidence observed during the initial years of injecting drugs. It is important to note that in the literature the definition of the PWID population generally
complicated by the high risk of relapse among the former PWID population.
(5)
Natural course of HCV infection
The acute HCV infection – first six months following exposure – is
symptomatic only in 15-30% of cases. These symptoms are non-specific in nature, such as lethargy, myalgia and sometimes jaundice. 70-85% are asymptomatic, which is cause for many patients to be unaware of their HCV status. During this acute period, viral detection is possible 2-14 days after exposure, whereas antibodies are only detectable 20-150 days after
exposure. (4)
After the acute infection, an estimate of 25% of patients will spontaneously clear the virus, and there will not be detectable levels of HCV RNA in their blood. The majority, estimated at 75%, will be chronic carriers, and HCV RNA will persist in their blood. (4) What determines whether a patient will clear the infection is not known, but factors such as young age at exposure, female gender and IL28B genotype increases chances of clearing the infection (6) Patients infected with chronic HCV are at risk of developing complications such as cirrhosis and hepatocellular carcinoma (HCC). The disease usually progresses slowly, with cirrhosis rarely seen with the first 15 years after exposure and often first seen after 40 years (7). Certain host factors are associated with rapid progression of liver fibrosis, such as age >40 years at infection, HBV co infection, diabetes, obesity, and harmful alcohol intake. (4) An estimate of 16% of patients develop cirrhosis 20 years after infection, but observation have reported highly variable proportions ranging from 4- 24%. 1-3% will develop HCC 30 years after infection, with an increased risk in patients with confirmed cirrhosis (2-4% annual rate). Factors associated with HCC include age >55 years, high alcohol consumption, and male sex. Hepatic elastography is predictive of HCC development, where liver stiffness >25 kPa have 1,8-2,7 times the risk of developing HCC. HCV mortality is related to drug overdose, liver disease (HCC, decompensated cirrhosis) and co infection with HIV.
HCV and the health care system
The treatment of HCV has been rapidly developing with the introduction of direct-acting antiviral (DAA) therapy in 2011. Previously treatment consisted of interferon and ribavirin which has been associated with low clearance of the virus as well as frequent and adverse side effects, which caused low treatment uptake. In Norway only 15% of people with chronic hepatitis C on opiate substitution treatment initiated interferon-based treatment between 2004 and 2013 (8). After the introduction of the new regimen the success of treatment for HCV (measured as sustained virological response, SVR, defines as ≤HCV RNA 15 IU/ml in the blood after treatment, at 12 weeks) has increased from 30-60% with standard interferon treatment, to more than 90% with interferon free combination treatment with two DAAs, (1)
increased tolerability and shortened treatment duration. (9) Despite this - the numbers of eligible patients receiving treatment with DAA has remained low.
(10)
The lack of dissemination of treatment is caused by lack of knowledge about HCV, patients who are unaware of their HCV status, and medical barriers such as access to treatment and high cost of medication. The high burden on the budget of the health care system has until recently limited the access to DAA regimens in many countries, including Norway, to patients with fibrosis stage F2-4. Due to the recent drop in DAA pricing, the feasibility of such a
widespread treatment program is increased. (9)
Due to the high fraction of disease burden attributable to intravenous drug use (IDU), it is important that any intervention aiming at reducing prevalence and incidence of HCV targets PWID specifically. OST has been shown to be associated with a 50% reduction in the risk of new HCV acquisition, and this effect is enhanced to 74% by the concomitant use of clean drug injecting equipment (11). Recent modelling studies are also supporting the effect of treatment of PWID as a measure that will reduce HCV prevalence and
transmission – “treatment as prevention” (5) . Any strategy to prevent infection and disease development must therefore include OST and NSP, as well dissemination of treatment at a population level.
PWID were until recently often not considered for HCV treatment, due to concerns of poor adherence, high risk of reinfection, and adverse events.
These perceptions have been challenged through a series of treatment studies among PWID, and international guidelines have recently been
changed, recommending treatment for all PWID who are HCV infected (5).
In 2013 INHSU (International Network for Hepatitis in Substance Users) published a set of guidelines regarding management and treatment of PWID, that were updated in 2015 due to the rapid changes in HCV therapy. These guidelines recommend routinely testing of HCV antibodies and RNA in
uninfected PWID every 12 months, as well as following a high risk injecting episode. Treatment is recommended for PWID with a chronic infection.
Further investigation into the safety and efficacy of DAA regimens is required in PWID, and the decision to institute DAA therapy in PWID should take into account social circumstances, adherence as well as medical and social comorbidities. (12)
Prevalence in Norway
In Norway, acute HCV infections have been notifiable to MSIS (meldeplikt for smittsomme sykdommer) since 1992, and from 2008 all infections are notifiable based on detection of antibodies or RNA. The prevalence of anti HCV among adults in Oslo was 0,7% in 2000 with 0,5% having an active infection (HCV RNA positive)(13). As in the rest of Europe, the prevalence of HCV in Norway is closely related to PWID, and in 85% of cases reported to MSIS, IDU was the suspected route of transmission. (14)
Mathematical modelling suggests an increase in the number of newly HCV infected PWID during the 1990s, mostly due to an increase in numbers of PWID. This trend changed after 2002, when the total numbers of active PWID stabilised and decreased at around 9000 active PWIDs. The estimated
incidence of HCV among recent drug users has been stable at around 7-8%
years throughout the period. As well as proportion with chronic HCV, (estimated at 48,8% in 2000, and 42,7% in 2013.)(14)
Disability life years lost (DALYs) estimate the overall disease burden of HCV in the PWID population. This has increased since 1973, and peaked in 2006 with 80,36 DALYs per 100,000 inhabitants. Since then it has deceased, and in 2015 the DALYs was estimated at 67,71 per 100,000.(14)
Challenges in HCV monitoring.
There are many challenges in the surveillance of HCV prevalence. The
asymptomatic nature of the infection causes many patients to be unaware of their status, and will therefore not seek health care. The difficulties in
distinguishing between acute and chronic infections, and identifying those who will go on to develop a chronic infection is cause for inaccuracy in estimations. PWID as a group is also less likely to seek health care than the remaining population, which adds to these difficulties. (14)
WHO has declared it a goal to eliminate hepatitis B and C by 2030. By combining treatment with prevention strategies the incidence and mortality could be reduced sufficiently to eliminate HBV and HCV as public health
threats. In Norway the prevention strategies are largely in place, with existing NSPs in 75% of Norwegian municipalities in place, but there is still a need for implementation of plans to disseminate treatment.
Interdisciplinary treatment centres for substance abuse in Norway
As the PWID population is a hard to reach population, successful HCV monitoring and treatment has proven difficult in a hospital setting. On the basis of this, there are currently plans under development to set up an
ambulant treatment team for inpatients at interdisciplinary treatment centres for substance abuse in Norway, or so called TSB (tverrfaglig spesialisert
behandling), hoping to reach a broader population of PWID. TSB institutions (interdisciplinary treatment centres) in Norway play a significant role in the treatment of substance dependence. Most of these centres have medical staff present, as well as facilities to take any blood tests needed, making them ideal for performing HCV screening and treatment.
A report published in 2014 analysed the patients admitted to TSB institutions on the 20th of November 2012. There were 1627 patients
admitted, of which there was data accessible for 1526. 72% of the patients were men, and 60% were younger than 40 years of age. The most common substances abused were alcohol (35%), opiates (20%) and amphetamine (17%). 64% of patients were admitted for more than 12 weeks.(15) Based on prevalence data from NSPs in Oslo and Bergen it is reasonable to assume that 30-45% of patients treated for opiate or amphetamine
dependence have chronic hepatitis C. Furthermore, among those with alcohol dependency a prevalence of 5% can be assumed (13). This suggests that the prevalence of chronic HCV in TSB institutions is 18-23% (274-344 patients).
Given that all patients staying for more than 12 weeks could be administered HCV treatment during their stay, and assuming the median stay is 6 months, 320-448 patients admitted each year could receive treatment while in TSB institutions.
As these are all estimates, and there is no existing data on this specific
population, further data is needed. There is also a question if TSB institutions can be used to perform HCV screening at regular intervals, for continued surveillance of the HCV prevalence as well as evaluating the effect of implementation of treatment.
HCV surveillance in Norway
As stated the incidence and prevalence of HCV in Norway has been monitored by MSIS since 1990. Unfortunately, the MSIS register until 2014 drew no distinction between previous or current HCV infection, which is cause for uncertainty of the actual HCV burden in Norway (14). The database of MSIS is also vulnerable to lack of routines in reporting, and investigations have revealed that a significant proportion of HCV infections are not reported (8) Attempts have been made to measure the prevalence in Norway through surveys of low threshold initiatives in Oslo and Bergen (NSP). In Oslo the surveys have been performed at the NSP from 2002 in cooperation with The Norwegian Institute of Public Health (NIPH). The prevalence of chronic hepatitis C was calculated to be 40-49% in the yearly assessments between 2002 and 2012, with an average of 45%. The prevalence has been relatively stable, with no clear trend. Hepatitis C antibodies were present in 65-80% of
participants, with an average of 74%. A similar survey was performed in Bergen in 2015, finding a slightly higher prevalence of chronic hepatitis C, at 53%.
It is important to note that the prevalence numbers from the study
performed in Oslo include both people that participate for the first time in the study, as well as repeat participants, meaning that the different groups are not statistically independent. The recruiting also took place in different locations (SIS (supervised injection sites) and other) from 2009, and it is suspected that participants from SIS to a larger extent are HCV positive.
The knowledge about prevalence of HCV in PWID in Norway has been based on these surveys, but as these surveys are costly to perform and resource demanding, and patients have been lost to follow-up. There is also a risk that the surveys might be biased, as participants at the NSP might exhibit
decreased high-risk behaviour compared to the average person who injects drugs.
Another survey was performed in 2016, attempting to measure the HCV prevalence amongst patients in OST. This report estimates a national prevalence of antibodies of 52%. This is lower than expected, but these numbers are estimates from self-reporting and are therefore very uncertain.
Conclusion
The true prevalence of HCV among PWID in Norway is still uncertain, despite the efforts that have been made. There is an apparent need for further
investigations, not only for the sake of disease surveillance, but also as a step in the management of hepatitis C. Previous surveys have been costly to
perform, with a probable bias of the population investigated. A future survey should be easy to perform, and focused on the target population.
In the outline for a Norwegian strategy for combatting viral hepatitis in Norway (16) it was suggested to provide HCV treatment to patients in TSB institutions. To realise this plan, further data on the HCV status in this population must be collected. As these institutions are already established with the needed medical resources, this could be an opportunity to perform
comparison with already existing data from low threshold initiatives, to describe a baseline prevalence of PWID, as well as differences in risk
behaviour in specific groups of PWID (i.e. amphetamine users vs heroin users) and differences between regions in Norway. Prevalence monitoring will be particularly important to evaluate the effects of treatment, and the impact on the prevalence.
Objectives of the study
The main goal of this study is to estimate the prevalence of hepatitis C in PWID admitted to TSB institutions.
The secondary aim is to assess the feasibility of conducting prevalence studies in TSB institutions, and identify adjustments needed to perform similar surveys at a regular interval in the future. Furthermore, through the study we will try to better understand biases in recruiting, participation and cooperation with the different institutions.
We therefore performed a cross-sectional study in South East Norway, among PWID admitted to TSB institutions to answer these objectives defined.
Materials and Methods
Study design and population
Cross-sectional study amongst inpatients at randomly selected TSB
institutions in South-East Norway. It was set as a requirement that of the inpatients at the different institutions, an estimate of 30% or more had previously injected drugs. All patients admitted to the selected institutions, who had ever injected drugs, were asked to participate in the study, and data was collected on two different predefined dates. The data collected included HCV status, including antibodies and RNA, sex and age.
Sampling Procedure
The goal was to recruit 200 eligible participants to the study, and to reach this goal we aimed at reaching out to institutions with an estimated 250 inpatients. The 40 TSB institutions located in South-East Norway were randomized using a sample program in Excel, and the institutions were
contacted according to the randomized number given. We then recruited 10 institutions with an estimated number of 250 possible participants.
The sampling frame was defined as all inpatients at the 40 institutions in South-East Norway, our sample was the inpatients at the selected
institutions, and participants were the ones who consented to the study. As 3 institutions withdrew from the study due to time and resource limitations, our final sample constituted 7 institutions with 143 inpatients. Of the 143 inpatients, 103 had injected drugs, and of these 66 consented to participate.
Data Collection
The institutions were contacted by telephone by randomized order, and the leader of the institution was informed of the implications of consenting to the study. From participants we collected the following data: HCV status
(antibodies and RNA), sex and age.
If anti HCV and HCV RNA status had been collected after the 1 st of
December, and the written results of the testing was available, this data was registered. When no such testing had been performed the institutions were requested to sample blood and order a anti-HCV test and HCV RNA test at the local lab. The responsibility of informing patients of the results, referring patients with positive HCV RNA results, as well as collecting the data and
Sampling frame: 40 TSB
institutions
Estimated: 719 inpatients
Participants: 7 TSB institutions 143 inpatients 103 PWID
66 consented
Sample: 10 TSB institutions
Estimated: 171 inpatients Randomly
selected 3 institutions
Retracted consent
sending this to the NHIP was left to the medical staff at the institution. The staff then recruited the eligible participants at the individual institutions.
Results
There were a total of 66 participants, from 7 different institutions participating in the study. 58% were men (38 out of 66). There was an average of 9,43 participants from each institution, ranging from 3-20.
The age distribution of the participants is visualized in figure 4. The average age was 37.98, and the median was 36 years (range 21-57). Divided by sex,
T a b le 1 Fig u re 1
Fig u re 2
Figure 3
Out of 66 participants, 34 were positive for HCV antibodies (prevalence of 52%), and 27 were HCV RNA positive (prevalence of 41%). 79% of all HCV antibody positive were also HCV RNA positive.
Divided by sex; 47% of men were positive for HCV antibodies and 42% were HCV RNA positive. 57% of women were HCV antibody positive, and 39%
were HCV RNA positive.
3 of the 10 recruited institutions withdrew from the study. Out of the 143 inaptients at the remaining institutions, 103 had previously injected drugs.
Out of these 103 eligible participants, 66 consented to the study.
Discussion
Interpretation of data and possible bias
We found that monitoring HCV prevalence among PWID in Norwegian TSB institution is feasible and that the prevalence of HCV antibodies in this sample was 52%, and of HCV RNA in serum 41%.
A prevalence of chronic HCV infection of 40% is well in line with previous studies performed in NSPs in Oslo and Bergen, but as the sample size was small and the confidence interval is wide the true prevalence in TSB
institutions in Norway is therefore still uncertain The NSP in Oslo found a prevalence of HCV RNA in serum of 40-49% (avg 45%) were RNA positive.
However, the prevalence of HCV antibodies was only 52% in our study compared to 65-80% (avg 74%) at the NSP in Oslo.
Among 66 participants, 28 were women (42%) which is a higher proportion of women than is usually seen in populations of PWID (estimated 1/3) (17).
Furthermore, we found that women had a higher prevalence of antibodies (57% vs 47% of men), but similar prevalence of HCV RNA (39% vs 42% of men). Consequently, the fraction of women in our study who were antibody positive as well as RNA positive, was significantly lower than for men (68% of women vs 89% of men) - suggesting, in line with previous studies women more often experience a self limiting hep C infection than men (18).
Feasibility and implementation
A secondary objective of the study was to assess the feasibility of surveying the HCV epidemic among PWID in TSB institutions and to identify challenges for the implementation of repeated HCV surveillance of HCV in TSB
institutions. During the study 3 out of 10 TSB institutions retracted consent to participate due to time restraints and internal resource constraints.
Furthermore, although we aimed at recruiting institutions with mainly PWID as opposed to alcohol dependent patients, only 103 of 143 clients had
previously injected drugs, and out of these 103 eligible candidates only 66 consented to participate, giving a recruitment rate of 64%. This is
acceptable, but a higher recruitment rate would have reduced the risk of selection bias. To increase the participation rate in the future, it is an option to offer financial compensation or to avoid requiring informed patient consent by collecting only data on HCV status, and not age and sex. We also believe that by keeping closer contact with selected nurses at the TSB institutions would increase the commitment to the study and thereby improve the participation rate.
To avoid institutions withdrawing from the study, further information on time consumption and expectations of the staff at the institutions should be given at the time of recruitment. Initially in the recruitment, it was not taken into account that participants would have to sign a consent form. As this was added as a requirement by REK (regional ethical committee), the expected workload and time consumption increased for the individual institutions.
Another problem encountered was that emails sent out from FHI (Norwegian
institute of Public Health) were not received by the certain institutions, as the sender was anonymous. This caused a delay in the collecting of the data, giving rise to the two separate prevalence dates, as well as two institutions withdrawing from the study. This can easily be avoided by changing the email server sending out the necessary forms and securing the email
communication at the time of recruitment.
By performing the study at selected institutions repeated times, it is possible to increase the efficiency of the data collection. That way, the needed
resources and routines would be in place from year to year. It could be useful to delegate the task to a specific contact person at each institution. That way, this person can be held accountable for the data collecting, as well as the follow-up of patients who are diagnosed with a chronic hepatitis infection.
To reduce bias that can be expected in recruiting, participation and cooperation, the population investigated has been selected through a
randomized process. As to the composition of the sample population of our study, certain groups of PWID will not be well represented at TSB institutions - typically the hard to reach population of PWID not involved with the health care system. It is also probable that opiate dependent PWID less frequently use TSB institutions than those who use amphetamines (15, 17). Therefore, the sample presented in this study cannot be presumed to be fully
representative of the IDU population of Norway. To what extent this study can be applied in a national epidemiological surveillance of HCV prevalence must be evaluated in the light of results from future similar studies.
WHO has declared elimination of hepatitis B and C by 2030 as a goal, identifying prevention and treatment the main tools. In addition to HBV
vaccines, blood safety and safe injection practices, WHO names the target at diagnosing 90% of HBV and HCV positive, and treating 80% of eligible
patients by 2030 - concluding that population-based approaches to test and treat have proven cost efficient. In line with this, the Norwegian government has released a national strategy plan to combat viral hepatitis, citing
increased test activity for patients exhibiting increase risk behaviour e.g. the IDU population of Norway as well as treatment for patients with severe
confirmation of goals being reached and to identify subpopulations not linked to HCV care.
Based on our experience and with a few adjustments to our methods we believe TSB institutions should be regularly surveyed for HCV prevalence.
During the study we came in contact with several leaders of different institutions, as well as medical staff. All institutions participating were
positive towards the study and were also positive to participate in repeated annual surveys. By including more data in the questionnaire, it is possible to collect data on risk factors like needle sharing and injection debut. This will obviously require informed consent probably at the cost of lowering the participation rate.
The current plans to set up an ambulant treatment team for inpatients at TSB institutions could possibly be connected to such an annual survey. As previously discussed, facilities are largely in place, and by training local staff, as well as recruiting mobile nurses, the treatment can take place in whole at the individual institutions. During planning we based our calculations on HCV prevalence on a report published in 2014 analysing patients admitted to TSB institutions nationwide(15). In the report it was stated that 64% of patients were admitted for more than 12 weeks, making them eligible to receive treatment while admitted, and we assumed that the median stay was 6 months.
In our study we found prevalence 41% of patients that had previously
injected drugs, were chronically infected with HCV (RNA positive). Out of the 143 inpatients, admitted to the 7 participating the institutions, 103 had previously injected drugs. If the same prevalence is true for the participating as well as the non-participating patients, this would mean that out of the 103 patients, 42 would be RNA positive. This would give a total prevalence of 29,4% (42 out of 143) chronically HCV infected inpatients at the
participating institutions, resulting in 574 eligible patients (given 1526
inpatients in all TSB institutions if Norway, where 64% stay a minimum of 12 weeks, and median stay is 6 months). It is important to keep in mind that our study it was set as a requirement that of the inpatients at the individual
institutions from the study, and it is highly likely that these institutions would have a lower prevalence of chronic carriers of HCV.
In conclusion, I found that 4/10 PWID admitted to TSB institutions in Norway had chronic hepatitis C infection. With certain adjustments I recommend that the HCV prevalence in TSB institutions should be monitored annually. This would be a cost efficient and reliable method for HCV surveillance among PWID in Norway.
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