Methdadone use in relation to hepatitis C virus testing in British Columbia.
Buxton, Jane A. ; Kuo, Margot E. ; Ramji, Sabrina 等
Hepatitis C virus (HCV) infection is highly prevalent among persons
who inject drugs (IDU) as well as patients receiving methadone
maintenance treatment (MMT). Seroprevalence rates for antibody to HCV
(anti-HCV) range from 27-96% among IDU populations and 67-96% in
patients in MMT programs. (1) In British Columbia (BC), HCV
seroprevalence among subjects of a longitudinal cohort study, in an
inner city neighbourhood characterized by poverty, mental illness and
drug use, was estimated at 10% in 1992 and 90% by 2004, based on
laboratory data linkage. (2,3) Drug injection duration is clearly
important, with up to half of new injectors acquiring HCV infection
within the first 4 years and greater than 90% after a decade or more of
injecting. (1,4,5)
MMT has been shown to be effective in the treatment of opiate
substance dependence such as addiction to heroin and morphine. Studies
have found that among opiate-dependent patients, sustained MMT reduces
morbidity and mortality, diminishes involvement in crime (6,7) and helps
drug users to gain control of their lives. (8)
MMT programs have been shown to reduce the transmission of HIV more
effectively than HCV. (9,10) High HCV prevalence among IDU, coupled with
the efficient parenteral transmission of HCV, play a role in ongoing HCV
seroconversions, even in MMT recipients who only occasionally inject.
(11) Among individuals who injected opiates in Amsterdam during the
period 1995-2005, HCV infection was shown to decrease with full
participation in harm reduction programs combining syringe distribution
programs and MMT. (12)
From previous studies, the HCV status of those initiating MMT is
unclear. Therefore we examined methadone use in a large cohort of
individuals undergoing serologic testing for HCV infection.
Specifically, we describe HCV testers with laboratory-confirmed
serostatus at the time of entry into the BC Methadone Program.
METHODS
In BC, methadone is dispensed by community pharmacies in accordance
with the methadone maintenance program policies of the BC PharmaCare
program, most often by directly observed therapy. Dispensations are
tracked in the PharmaNet data system using methadone drug identification
numbers (DINs). (13) The DINs for methadone prescribed for maintenance
related to opioid addiction and for the management of chronic pain
differ. PharmaNet excludes medications provided in emergency departments
or to hospitalized patients.
HCV testing in BC is centralized at the Provincial Public Reference
Laboratory at the BC Centre for Disease Control (BCCDC). The laboratory
has performed approximately 95% of anti-HCV tests since testing became
available in 1992, enabling the longitudinal study of HCV testers.
Individuals who underwent anti-HCV testing between April 1, 1992 and
July 16, 2004--when laboratory data were extracted to be linked to
administrative data as part of a larger linkage study--were linked to
PharmaNet records of MMT dispensations. MMT dispensations from September
1, 1995, when PharmaNet was initiated, to December 31, 2006, were
available at the time of the linkage. The linkage used a multi-step,
anonymized process outlined by the BCCDC, BC Ministry of Health, and
College of Pharmacists of BC. (14,15)
The full anti-HCV testing history was considered in assigning each
subject's serologic testing status. Four categories were defined:
1) single negative testers (one non-reactive anti-HCV test), 2) multiple
negative testers (serial non-reactive anti-HCV tests), 3) first-time
positive testers (baseline reactive anti-HCV test), and 4)
seroconverters (non-reactive anti-HCV test followed by a reactive test).
HCV-RNA testing by polymerase chain reaction was available for just a
subset of subjects, therefore anti-HCV testing results only were used to
assign HCV serostatus. Subjects whose only anti-HCV test result was
equivocal were excluded and equivocal test results within a series of
tests were considered anti-HCV negative. Only the first positive
anti-HCV test was considered. For those subjects with only one test on
record--single negative and first-time positive testers--we calculated
the age at time of testing. For those subjects with multiple negative
tests, age at first and last negative test was calculated; for those who
seroconverted, age at first negative and HCV diagnosis was calculated.
We described the age and sex distribution of all anti-HCV testers
and the subgroup who had been dispensed methadone across the four
categories of serologic testing status. The proportion of males to
females in each category was compared between all HCV testers and the
study group of MMT clients by z-testing (95% confidence level, 2
tailed). Median age was compared between all testers and the study group
using the Mann-Whitney test.
Testers' HCV serostatus at the time of MMT initiation was
defined as follows: 1) A negative anti-HCV test following the first
methadone dispensation date confirmed that the individual was HCV
seronegative at MMT initiation; 2) A positive anti-HCV test preceding
the first dispensation confirmed seropositivity at MMT initiation (a
positive test result within 30 days of MMT initiation also confirmed
seropositivity, taking into account the seroconversion window period);
3) A negative test preceding MMT initiation or a positive test >30
days after MMT initiation were considered as unknown status at MMT
initiation.
RESULTS
There were 404,941 individuals in the provincial laboratory dataset
who had anti-HCV testing and were linked with PharmaNet records. Table 1
gives age and sex distribution and methadone dispensation by serologic
testing group. The majority 283,722 (70%) were single negative testers;
22% were multiple negative testers; 7% were first-time positive testers;
and <1% seroconverted from negative to positive. Overall, more
females had anti-HCV testing, but males made up a higher proportion of
the first-time positive and seroconverter groups. Methadone use was low
(2.5%) among all HCV testers, 1% in negative testers and 21% in anti-HCV
positive testers.
In total, 10,314 individuals underwent anti-HCV testing and
received MMT; individuals who received MMT but who did not have an
anti-HCV test are not included. Table 2 provides the age, sex and timing
of MMT initiation in relation to anti-HCV testing. MMT subjects were
significantly younger than all testers (median age 33 versus 38 years,
respectively). In addition, there were proportionally more male MMT
subjects across every serostatus group. The relative proportion of men
and women was statistically different between all testers and the study
group (z=33.881). Among seroconverters, the median age at first negative
test was 26 years and 29 years at the first positive test, indicating an
interval of approximately 3 years between first negative and positive
tests. Overall, MMT initiation was within +/- 1 year of the first
anti-HCV test for about half of the MMT recipients.
Of 10,314 MMT subjects, anti-HCV serostatus was confirmed at MMT
initiation on 7,234 (70.1%); of these 2,596 (35.9%) were negative and
4,638 (64.1%) were positive (Table 3). The median age among those
confirmed negative at MMT initiation was 30 years (IQR 25-37) compared
with 35 years (IQR 28-41) among those who were confirmed positive. Of
the 3,080 subjects among whom anti-HCV serostatus at MMT initiation was
unknown, 1,806 (58.6%) were found to be HCV positive >30 days after
MMT initiation with a median age of 40 years (IQR 32-46) at the time of
diagnosis.
Among seroconverters, 288 (25.6%) were anti-HCV negative at MMT
initiation. Finally, of the 6,732 subjects who tested HCV positive
during the study period, 4,638 (68.9%) were positive at MMT program
entry.
DISCUSSION
We found 64% of individuals whose HCV status was known at MMT
initiation were HCV positive. This suggests that the timing of MMT is,
for many, too late to prevent HCV infection. However, at least 25% of
subjects were anti-HCV negative at MMT initiation, indicating there is
an opportunity to prevent HCV infection for some.
Full participation in harm reduction programs, including syringe
distribution and MMT, is necessary to reduce HCV infection risk.10,12 In
our study, 288 individuals underwent HCV seroconversion after initiating
MMT; this warrants further exploration of MMT dosage and adherence, as
well as access to other harm reduction initiatives.
MMT only addresses opiate addiction and is not appropriate for many
anti-HCV testers. Some single negative testers are at low risk of HCV
infection and are tested for screening purposes (e.g., insurance or
tissue donation). In addition, some single negative and first-time
positive testers are tested due to past risk factors, such as prior IDU
or receipt of blood products. However, multiple testers are more likely
to have ongoing risk factors.
While multiple MMT attempts are common, we used the date of first
MMT dispensation to mark the individual's initial contact with the
program. Adequate daily dosing of methadone is crucial to initial
retention and return to treatment. (16,17) Using BC PharmaNet data on
MMT dispensations from 1996-2007, Nosyk et al. found that persons with
multiple methadone treatment attempts were maintained for successively
longer periods; and higher methadone doses were associated with longer
treatment episodes. (18)
The differing timeframes of the two datasets may affect the
descriptive findings. MMT has been available in Canada for almost 50
years. (16,19) However, the BC program began to expand in 1995. Nosyk
identified 2,827 persons as having received at least one dose of MMT in
BC in 1996; this number rose to 8,841 individuals in 2004 (personal
communication, January 4, 2010). Although information about patients on
MMT prior to 1995 is limited, there were likely fewer than 2000.
Therefore, the PharmaNet inception data of 1995 provide reasonable
capture of MMT history for our study cohort. HCV testing data for the
study cohort end in 2004, thus, there may be some misclassification of
negative testers as continued follow-up may have revealed another
negative test or new infection.
Engaging IDU in harm reduction is complex; barriers include limited
access to MMT and/or sterile syringes. At-risk and street youth, and new
IDU, have a lower HCV prevalence and therefore harm reduction
initiatives have the potential to prevent HCV infection. However, it may
be challenging to engage youth in addiction, harm reduction, or other
social services (20) and lack of awareness of HCV risk makes them
especially susceptible to acquiring HCV infection soon after injection
initiation. (21)
HCV testing and diagnosis represents a point of access to IDU and
may coincide with a period in which individuals both are receptive to
substance use behaviour change and increase engagement with addiction
services and syringe distribution programs. We found methadone was
initiated within a year of the first HCV test in about half of cases. In
2002, Kwiatkowski et al. reported an awareness of HCV positive status
was associated with safer injection practices among older, but not
younger IDU. (22) McCusker et al. similarly found that the knowledge of
HCV infection led to a positive behavioural change. (23)
Accessibility of MMT and other services for HCV positive
individuals is important to prevent subsequent HIV infection. (24) In
another BC data linkage study, over half of cases co-infected with
HCV-HIV were found to have been diagnosed with HCV first with a median
3.5 years before HIV diagnosis. (25)
Sex and age differences occur in testing behaviours and underlying
risk. In our study, more females than males were tested for anti-HCV
overall, with males making up a higher proportion of the seropositive
groups . An evaluation of testing patterns in Alberta also found females
were more likely to undergo anti-HCV testing and identified that repeat
testers were younger. (26) Although females make up 57% of multiple
negative testers in our study, less than 40% of multiple negative
testers who receive MMT are female. Further exploration of testing and
drug use patterns are needed to determine why females are less likely to
initiate MMT.
A major strength of this study is its inclusion of subjects from
the entire province tested for HCV and receiving MMT. In BC, evaluations
of harm reduction initiatives often focus on Vancouver where services
may be more available and/or on large cohort studies of individuals in
specific regions, limiting generalizability to less urban areas and the
province as a whole. (27,28)
Prospective linkages of centralized laboratory and health services
data have the potential to provide a population lens for describing the
health trajectories of at-risk populations and evaluating the
effectiveness of harm reduction and other prevention services to stem
ongoing transmission of HCV.
Our unique cohort of provincial anti-HCV testers linked with
pharmaceutical data enabled us to evaluate HCV serostatus in relation to
MMT initiation for a large, high-risk population. Our findings suggest
there are missed prevention opportunities and support the need for
integrated care models for at-risk groups, to ensure that appropriate
HCV testing, education, MMT and other harm reduction and addiction
services are widely available.
Received: March 10, 2010 Accepted: June 28, 2010
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Jane A. Buxton, MBBS, MHSc, [1] Margot E. Kuo, MPH, [1] Sabrina
Ramji, MHSc, [2] Amanda Yu, MSc, [1] Mel Krajden, MD [1]
Author Affiliations
[1.] BC Centre for Disease Control, Vancouver, BC
[2.] Faculty of Medicine, Dalla Lana School of Public Health,
University of Toronto, Toronto, ON
Correspondence: Dr. Jane Buxton, Physician Epidemiologist, BC
Centre for Disease Control, 655 West 12th Avenue, Vancouver, BC V5Z 4R4,
E-mail: Jane.Buxton@bccdc.ca
Conflict of Interest: None to declare.
Table 1. Age, Sex, and Methadone Use Among Anti-HCV Testers,
1992-2004
All Testers Single Negative
N=404,941 283,722 (70.1%)
Age Median 38 * 39 *
IQR 23 * 25 *
Sex Male 185,744 (45.9%) 126,718 (44.7%)
Female 219,194 (54.1%) 157,003 (55.3%)
Methadone Yes 10,314 (2.5%) 1273 (0.5%)
No 394,627 (97.5%) 282,449 (99.5%)
Multiple Negative First-time Positive
88,301 (21.8%) 30,045 (7.4%)
Age Median 35 * 38 ([dagger]) 42 *
IQR 20 * 20 ([dagger]) 13 *
Sex Male 38,084 (43.1%) 19,359 (64.4%)
Female 50,216 (56.9%) 10,685 (35.6%)
Methadone Yes 2309 (2.6%) 5606 (18.7%)
No 85,992 (97.4%) 24,439 (81.3%)
Seroconverter
2873 (0.7%)
Age Median 29 * 32 ([dagger])
IQR 14 * 14 ([dagger])
Sex Male 1583 (55.1%)
Female 1290 (44.9%)
Methadone Yes 1126 (39.2%)
No 1747 (60.8%)
* Age at time of first (or only) anti-HCV test on record.
([dagger]) For those subjects with multiple tests on record,
multiple negative testers and seroconverters, we also
provided the age at last test on record.
Table 2. Age, Sex, and Timing of Methadone Use Among Anti-HCV
Testers Prescribed MMT, 1992-2004
All MMT Single Negative
Subjects Testers
n=10,314 1273 (12.3%)
Age Median 33 * 30 *
IQR 15 * 14 *
Sex Male 6469 (62.7%) 880 (69.1%)
Female 3845 (37.3%) 393 (30.9%)
1st MMT [+ or -]1 Yes 5322 (51.6%) 892 (70.1%)
year of 1st HCV test No 4992 (48.4%) 381 (29.9%)
Multiple Negative First-time
Testers Positive Testers
2309 (22.4%) 5606 (54.4%)
Age Median 26 * 29 ([dagger]) 37 *
IQR 12 * 13 ([dagger]) 12 *
Sex Male 1448 (62.7%) 3570 (63.7%)
Female 861 (37.3%) 2036 (36.3%)
1st MMT [+ or -]1 Yes 1211 (52.4%) 2891 (51.6%)
year of 1st HCV test No 1098 (47.6%) 2715 (48.4%)
Seroconverter
Testers
1126 (10.9%)
Age Median 26 * 29 ([dagger])
IQR 11 * 11 ([dagger])
Sex Male 571 (50.7%)
Female 555 (49.2%)
1st MMT [+ or -]1 Yes 328 (29.1%)
year of 1st HCV test No 798 (70.9%)
* Age at time of first (or only) anti-HCV test on record.
([dagger]) For those subjects with multiple tests on record,
multiple negative testers and seroconverters, we also
provided the age at last test on record.
Table 3. HCV Serostatus at MMT Initiation
All MMT Single Multiple
Subjects Negative Negative
n=10,314 1273 2309
Anti-HCV Negative at MMT 2596 571 1737
Initiation *
#, (column %) (25.2%) (44.9%) (75.2%)
Anti-HCV Positive at MMT 4638 -- --
Initiation ([dagger])
#, (column %) (45.0%)
Unknown status at MMT 3080 702 572
Initiation ([double dagger])
#, (column %) (29.9%) -55.10% (24.8%)
First-time Sero-
Positive converter
5606 1126
Anti-HCV Negative at MMT -- 288
Initiation * (25.6%)
#, (column %)
Anti-HCV Positive at MMT 4040 598
Initiation ([dagger])
#, (column %) (72.1%) (53.1%)
Unknown status at MMT 1566 240
Initiation ([double dagger])
#, (column %) (27.9%) (21.3%)
* A negative anti-HCV test following the first MMT dispensation
confirmed seronegativity at MMT Initiation.
([dagger]) A positive anti-HCV test preceding the first
dispensation confirmed seropositivity at MMT initiation and
a positive test within 30 days after MMT initiation also
confirmed seropositivity at MMT initiation based on HCV
seroconversion window period.
([double dagger]) A negative test preceding MMT initiation or a
positive test >30 days after MMT initiation were non-confirmatory.
