Håvard Midgard , Jørgen G. Bramness, Svetlana Skurtveit, John W. Haukeland, Olav Dalgard Published: November 15, 2016 http://dx.doi.org/10.1371/journal.pone.0166451
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Abstract
Background and Aims
There is limited data on hepatitis C (HCV) treatment uptake among people who inject drugs including individuals receiving opioid substitution treatment (OST). We aimed to calculate cumulative HCV treatment uptake, estimate annual treatment rates, and identify factors associated with HCV treatment among individuals who have received OST in Norway.
Methods
This observational study was based on linked data from The Norwegian Prescription Database and The Norwegian Surveillance System for Communicable Diseases between 2004 and 2013. Both registries have national coverage. From a total of 9919 individuals who had been dispensed OST (methadone, buprenorphine or buprenorphine-naloxone), we included 3755 individuals who had been notified with HCV infection. In this population, dispensions of HCV treatment (pegylated interferon and ribavirin), benzodiazepines, selective serotonin reuptake inhibitors and antipsychotics were studied.
This observational study was based on linked data from The Norwegian Prescription Database and The Norwegian Surveillance System for Communicable Diseases between 2004 and 2013. Both registries have national coverage. From a total of 9919 individuals who had been dispensed OST (methadone, buprenorphine or buprenorphine-naloxone), we included 3755 individuals who had been notified with HCV infection. In this population, dispensions of HCV treatment (pegylated interferon and ribavirin), benzodiazepines, selective serotonin reuptake inhibitors and antipsychotics were studied.
Results
Among 3755 OST patients notified with HCV infection, 539 (14%) had received HCV treatment during the study period. Annual HCV treatment rates during OST ranged between 1.3% (95% confidence interval [CI] 0.7–2.2) in 2005 and 2.6% (95% CI 1.9–3.5) in 2008 with no significant changes over time. HCV treatment uptake was not associated with age or gender, but associated with duration of active OST (adjusted odds ratio [aOR] 1.11 per year; 95% CI 1.07–1.15), high (> 80%) OST continuity (aOR 1.62; 95% CI 1.17–2.25), and heavy benzodiazepine use (aOR 0.65; 95% CI 0.49–0.87).
Among 3755 OST patients notified with HCV infection, 539 (14%) had received HCV treatment during the study period. Annual HCV treatment rates during OST ranged between 1.3% (95% confidence interval [CI] 0.7–2.2) in 2005 and 2.6% (95% CI 1.9–3.5) in 2008 with no significant changes over time. HCV treatment uptake was not associated with age or gender, but associated with duration of active OST (adjusted odds ratio [aOR] 1.11 per year; 95% CI 1.07–1.15), high (> 80%) OST continuity (aOR 1.62; 95% CI 1.17–2.25), and heavy benzodiazepine use (aOR 0.65; 95% CI 0.49–0.87).
Conclusions
Cumulative HCV treatment uptake among OST patients notified with HCV infection in Norway between 2004 and 2013 was 14%. Annual treatment rates during OST remained unchanged below 3% per year. High continuity of OST over time and absence of heavy benzodiazepine use predicted HCV treatment uptake. Increased awareness for HCV among OST patients is needed as tolerable and efficient directly acting antiviral treatment is being introduced.
Cumulative HCV treatment uptake among OST patients notified with HCV infection in Norway between 2004 and 2013 was 14%. Annual treatment rates during OST remained unchanged below 3% per year. High continuity of OST over time and absence of heavy benzodiazepine use predicted HCV treatment uptake. Increased awareness for HCV among OST patients is needed as tolerable and efficient directly acting antiviral treatment is being introduced.
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This population-based observational study evaluated HCV treatment uptake in Norway between 2004 and 2013 among individuals who had received OST and were notified with HCV infection. Cumulative HCV treatment uptake was 14% and annual treatment rates during OST ranged between 1.3% and 2.6% with no significant changes over time. HCV treatment was associated with duration of active OST, high OST continuity and absence of heavy benzodiazepine use, but was not associated with age or gender. This study provides unique baseline data on HCV treatment uptake among OST patients over a ten-year period prior to the availability of DAA treatment.
The results from this study are consistent with findings from a Norwegian cohort of PWID who previously had been admitted for residential drug dependency treatment, in which 19% of individuals with chronic HCV infection had received HCV treatment during a 16 years observation period [45]. The majority of treated individuals in the present study had received HCV treatment during OST. Still, annual treatment uptake during OST was only marginally higher than treatment rates reported in community-based cohorts of PWID not engaged in OST [12–15]. Although the Norwegian OST program was expanding during the study period, this did not translate into increasing HCV treatment uptake. This could be explained by a reluctance to offer OST patients IFN-based treatment, but might also suggest a low awareness of HCV infection in OST programs in general. Prescription of OST to more vulnerable individuals during the final part of the study period could also have played a role. Stable low treatment rates in this population might therefore reflect ongoing drug use as a barrier to HCV care on both patient- and provider-levels [19]. However, there has been a trend in Norway to increasingly provide HCV treatment for active PWID [43].
Cumulative HCV treatment uptake was similar in all age groups and there was no association between age and HCV treatment. Among diseased HCV RNA positive individuals in a large Norwegian cohort of PWID, advanced liver fibrosis or cirrhosis on autopsy was seen in 35% of those who died 25 years or more after exposure to the virus [46]. In the same cohort, liver disease was the cause of death in 30% of deceased individuals above 50 years of age [4]. Given the high burden of HCV-related liver disease reported from this and other ageing cohorts of PWID with untreated HCV infection [47], it is a concern that treatment uptake was only 15% among individuals above 50 years at the end of the observation.
Certain characteristics of OST were associated with HCV treatment. The odds of receiving HCV treatment increased by 11% for every year spent in active OST. OST continuity by itself was also important; in fact, individuals in active OST more than 80% of the time had 64% increased odds of receiving HCV treatment compared to those with low OST continuity. These are novel findings that raise the hypothesis that retention in OST could promote health-seeking behaviour and facilitate HCV treatment.
This study also found associations between specific drug dispensions and HCV treatment. Heavy, but not moderate benzodiazepine use was associated with decreased odds of receiving HCV treatment, a finding that might reflect a psychosocial vulnerability that characterizes a group of OST patients. Benzodiazepine use is common among Norwegian OST patients and is shown to be associated with negative outcomes including poor social functioning and reduced retention in OST programs [48]. Psychiatric disease is a well-known barrier for IFN-based HCV treatment [18], but no association between dispensions of antipsychotics and HCV treatment was found in this study. SSRI use, however, was more common in patients treated for HCV, but this difference could be attributed to SSRI use initiated during or after HCV treatment. This finding might imply that the increased SSRI use was a consequence of psychiatric side effects of IFN-based treatment [49].
The main strength of this study is its population-based approach, providing a large sample of individuals with opiate dependency who had received OST during a ten-year period. A liberal inclusion of individuals with only sporadic or short-term exposure to OST has ensured a study population more representative of Norwegian PWID. This study is the first to document HCV treatment uptake in this essential target group for HCV treatment, providing important baseline data prior to the availability of DAA treatment.
An inherent limitation of this study is the lack of clinical data available from the registries. This may have impeded detection of factors associated with HCV treatment, although novel pharmaco-epidemiological associations have been identified. Another limitation is that OST administered to institutionalized patients was not registered in NorPD prior to 2008. HCV treatment, however, has almost exclusively been initiated in the outpatient setting and has therefore been captured by the registry throughout the study period. Consequently, annual HCV treatment rates during OST may have been underestimated prior to 2008, since some individuals probably have been misclassified as being treated prior to OST. This might explain the lower trend in treatment rates observed in this period. This bias may also have undervalued OST duration and OST continuity in some individuals, but cumulative HCV treatment uptake has not been affected.
The quality of the MSIS data brings important limitations to this study. Firstly, the registry does not adequately discriminate chronic HCV infections from acute HCV infections with spontaneous clearance. Thus, by including all notified individuals regardless of the method of detection, treatment uptake may have been underestimated. Secondly, the low notification rate is a recognized problem that probably reflects vulnerable notification routines and lacking notifications of chronic infection prior to 2008, as well as low testing activity in OST programs. Also, this study may have missed some individuals notified prior to the study period. Nevertheless, this study has shown that only 38% of OST patients were notified with HCV infection and that only 57% of patients treated for HCV were notified. Although notifications rates among treated individuals improved, it is still a concern that one in four individuals treated for HCV remained un-notified towards the end of the study period.
Restricting the study population to individuals notified with HCV infection has limited the sample size and excluded more than 40% of all patients actually treated for HCV. Although most characteristics were similar between notified and un-notified individuals, un-notified patients were on average three years older than notified individuals. This suggests that the linkage to MSIS may have introduced an age-related selection bias, excluding a group of older HCV infected individuals. Treatment uptake in older age groups may therefore have been underestimated. However, this bias has probably not altered the main finding of the study. Cumulative HCV treatment uptake among all OST patients was 9.5%, and assuming 60% HCV RNA prevalence in the ageing OST population [26, 37], this finding would correspond to 16% treatment uptake among all individuals with presumed chronic HCV infection.
The current availability of tolerable, short-duration and highly efficient DAA regimens has led to significant therapeutic optimism with possibilities for broadened treatment uptake and subsequent HCV elimination among PWID [23, 50–52]. Although derived from IFN-based treatment, the findings from this study are highly relevant, providing baseline data on HCV treatment uptake prior to the introduction of DAAs. Collectively, the findings from this study underscore the need for increased awareness for HCV infection in a growing population of PWID including OST patients now being eligible for HCV treatment. The results should inform health political decisions and support improved HCV testing activity and linkage to HCV care among individuals receiving OST. Although treatment uptake is expected to increase, challenges concerning drug pricing and delivery of care will probably remain. Future studies should therefore monitor treatment rates in this population.
In conclusion, this study has shown that HCV treatment uptake among patients who have received OST in Norway was low and stable during the final ten years of the IFN-based treatment era. Although long-term stability in OST might facilitate HCV treatment, the findings from this study highlight the need for improved awareness for HCV infection in this increasingly important target group for HCV treatment.
This population-based observational study evaluated HCV treatment uptake in Norway between 2004 and 2013 among individuals who had received OST and were notified with HCV infection. Cumulative HCV treatment uptake was 14% and annual treatment rates during OST ranged between 1.3% and 2.6% with no significant changes over time. HCV treatment was associated with duration of active OST, high OST continuity and absence of heavy benzodiazepine use, but was not associated with age or gender. This study provides unique baseline data on HCV treatment uptake among OST patients over a ten-year period prior to the availability of DAA treatment.
The results from this study are consistent with findings from a Norwegian cohort of PWID who previously had been admitted for residential drug dependency treatment, in which 19% of individuals with chronic HCV infection had received HCV treatment during a 16 years observation period [45]. The majority of treated individuals in the present study had received HCV treatment during OST. Still, annual treatment uptake during OST was only marginally higher than treatment rates reported in community-based cohorts of PWID not engaged in OST [12–15]. Although the Norwegian OST program was expanding during the study period, this did not translate into increasing HCV treatment uptake. This could be explained by a reluctance to offer OST patients IFN-based treatment, but might also suggest a low awareness of HCV infection in OST programs in general. Prescription of OST to more vulnerable individuals during the final part of the study period could also have played a role. Stable low treatment rates in this population might therefore reflect ongoing drug use as a barrier to HCV care on both patient- and provider-levels [19]. However, there has been a trend in Norway to increasingly provide HCV treatment for active PWID [43].
Cumulative HCV treatment uptake was similar in all age groups and there was no association between age and HCV treatment. Among diseased HCV RNA positive individuals in a large Norwegian cohort of PWID, advanced liver fibrosis or cirrhosis on autopsy was seen in 35% of those who died 25 years or more after exposure to the virus [46]. In the same cohort, liver disease was the cause of death in 30% of deceased individuals above 50 years of age [4]. Given the high burden of HCV-related liver disease reported from this and other ageing cohorts of PWID with untreated HCV infection [47], it is a concern that treatment uptake was only 15% among individuals above 50 years at the end of the observation.
Certain characteristics of OST were associated with HCV treatment. The odds of receiving HCV treatment increased by 11% for every year spent in active OST. OST continuity by itself was also important; in fact, individuals in active OST more than 80% of the time had 64% increased odds of receiving HCV treatment compared to those with low OST continuity. These are novel findings that raise the hypothesis that retention in OST could promote health-seeking behaviour and facilitate HCV treatment.
This study also found associations between specific drug dispensions and HCV treatment. Heavy, but not moderate benzodiazepine use was associated with decreased odds of receiving HCV treatment, a finding that might reflect a psychosocial vulnerability that characterizes a group of OST patients. Benzodiazepine use is common among Norwegian OST patients and is shown to be associated with negative outcomes including poor social functioning and reduced retention in OST programs [48]. Psychiatric disease is a well-known barrier for IFN-based HCV treatment [18], but no association between dispensions of antipsychotics and HCV treatment was found in this study. SSRI use, however, was more common in patients treated for HCV, but this difference could be attributed to SSRI use initiated during or after HCV treatment. This finding might imply that the increased SSRI use was a consequence of psychiatric side effects of IFN-based treatment [49].
The main strength of this study is its population-based approach, providing a large sample of individuals with opiate dependency who had received OST during a ten-year period. A liberal inclusion of individuals with only sporadic or short-term exposure to OST has ensured a study population more representative of Norwegian PWID. This study is the first to document HCV treatment uptake in this essential target group for HCV treatment, providing important baseline data prior to the availability of DAA treatment.
An inherent limitation of this study is the lack of clinical data available from the registries. This may have impeded detection of factors associated with HCV treatment, although novel pharmaco-epidemiological associations have been identified. Another limitation is that OST administered to institutionalized patients was not registered in NorPD prior to 2008. HCV treatment, however, has almost exclusively been initiated in the outpatient setting and has therefore been captured by the registry throughout the study period. Consequently, annual HCV treatment rates during OST may have been underestimated prior to 2008, since some individuals probably have been misclassified as being treated prior to OST. This might explain the lower trend in treatment rates observed in this period. This bias may also have undervalued OST duration and OST continuity in some individuals, but cumulative HCV treatment uptake has not been affected.
The quality of the MSIS data brings important limitations to this study. Firstly, the registry does not adequately discriminate chronic HCV infections from acute HCV infections with spontaneous clearance. Thus, by including all notified individuals regardless of the method of detection, treatment uptake may have been underestimated. Secondly, the low notification rate is a recognized problem that probably reflects vulnerable notification routines and lacking notifications of chronic infection prior to 2008, as well as low testing activity in OST programs. Also, this study may have missed some individuals notified prior to the study period. Nevertheless, this study has shown that only 38% of OST patients were notified with HCV infection and that only 57% of patients treated for HCV were notified. Although notifications rates among treated individuals improved, it is still a concern that one in four individuals treated for HCV remained un-notified towards the end of the study period.
Restricting the study population to individuals notified with HCV infection has limited the sample size and excluded more than 40% of all patients actually treated for HCV. Although most characteristics were similar between notified and un-notified individuals, un-notified patients were on average three years older than notified individuals. This suggests that the linkage to MSIS may have introduced an age-related selection bias, excluding a group of older HCV infected individuals. Treatment uptake in older age groups may therefore have been underestimated. However, this bias has probably not altered the main finding of the study. Cumulative HCV treatment uptake among all OST patients was 9.5%, and assuming 60% HCV RNA prevalence in the ageing OST population [26, 37], this finding would correspond to 16% treatment uptake among all individuals with presumed chronic HCV infection.
The current availability of tolerable, short-duration and highly efficient DAA regimens has led to significant therapeutic optimism with possibilities for broadened treatment uptake and subsequent HCV elimination among PWID [23, 50–52]. Although derived from IFN-based treatment, the findings from this study are highly relevant, providing baseline data on HCV treatment uptake prior to the introduction of DAAs. Collectively, the findings from this study underscore the need for increased awareness for HCV infection in a growing population of PWID including OST patients now being eligible for HCV treatment. The results should inform health political decisions and support improved HCV testing activity and linkage to HCV care among individuals receiving OST. Although treatment uptake is expected to increase, challenges concerning drug pricing and delivery of care will probably remain. Future studies should therefore monitor treatment rates in this population.
In conclusion, this study has shown that HCV treatment uptake among patients who have received OST in Norway was low and stable during the final ten years of the IFN-based treatment era. Although long-term stability in OST might facilitate HCV treatment, the findings from this study highlight the need for improved awareness for HCV infection in this increasingly important target group for HCV treatment.
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