Completion rates of treatment for latent tuberculosis infection in Quebec, Canada from 2006 to 2010.
Rivest, Paul ; Street, Maria-Constanza ; Allard, Robert 等
In 2010, 1,575 tuberculosis (TB) cases (4.6 per 100,000) were
reported to the Canadian Tuberculosis Reporting System. (1) The disease
remains a significant health problem among Aboriginal persons and
immigrants, with incidence rates of 26.3 and 13.3 per 100,000,
respectively. In comparison, the incidence rate for non-Aboriginal
Canadian-born individuals is 1.9 per 100,000. (1) For the same year, 208
TB cases (2.6 per 100,000) were reported in Quebec. Among these cases,
61.5% were reported in Montreal residents.
Screening for and treatment of latent TB infection (LTBI) in
high-risk populations (e.g., close contacts of individuals with active
TB, persons with HIV infection, foreign-born persons referred for
medical surveillance by Citizenship and Immigration Canada, urban
homeless and the under-housed, including staff at homeless shelters)
have been identified as priority activities for reducing the TB
incidence in Canada. (2)
A 300 milligram (mg) daily dose of isoniazid (INH) for nine months
is the current standard LTBI treatment for adults. (3) INH daily for six
months is acceptable when nine months daily treatment is not accepted by
the patient. Rifampin (RMP) 600 mg daily for four months is an
acceptable alternative when INH cannot be used. (3) However, convincing
patients with LTBI to take medication for nine months has always been
challenging: asymptomatic patients often perceive LTBI as a
non-contagious infection that progresses to active TB in only 10% of
cases, and patients may fear developing adverse effects from treatment
lasting nine months. (4)
Many studies have shown variable treatment completion rates in
developed countries, usually far from the Canadian program performance
standard of 80% for LTBI treatment. (3) In a US study examining contact
investigations in 24 states, 4 large cities, and Puerto Rico in 1999, of
13,083 contacts exposed to pulmonary TB cases and found to have LTBI,
5,746 (44.5%) completed treatment to prevent TB. (5) In another study in
five health departments in the US, among 398 contacts of pulmonary TB
cases who initiated LTBI treatment, 203 (51%) were documented to have
completed a six-month treatment. However, these contacts represented
less than one third of all contacts with newly detected LTBI. (6) In a
more recent retrospective cohort study in New York City, from 1997 to
2003, 30,561 contacts were identified during investigation of 5,182
pulmonary TB cases. Of 6,001 infected contacts who initiated LTBI
treatment, 3,642 (60.7%) completed the treatment. (7)
Among 2,484 foreign-born who screened positive for TB at county
health departments for public health services in Tennessee, 1,416 (57%)
completed LTBI treatment.8 With a cultural case management approach
established for finding and treating LTBI among former Soviet Union,
former Yugoslavia, and Somalia refugees, a completion rate of 72% was
obtained from July 1999 through December 2000 in the Seattle & King
County TB Clinic. (9)
[FIGURE 1 OMITTED]
In other settings, a systematic review of studies on adherence to
LTBI treatment has found that completion rates varied from 32% to 61%
within correctional facilities, and from 39% to 70% among injection drug
users. (4) A four-month regimen with RMP seemed to be associated with
better completion rates, ranging from 72% to 91%. (10-12)
The aim of this study was to evaluate the proportion of adult
patients who started LTBI treatment and completed it within 12 months of
first prescription.
METHODS
Data source
We used a database administered by the Regie de l'assurance
maladie du Quebec (RAMQ), * established in 1969 for the purpose of
setting up and managing the public Health Insurance Plan. Most residents
of the province (7.9 million in 2011) are eligible for the plan, which
covers many health-related services, including medical services. Since
1997, prescription drug insurance coverage has been compulsory for all
citizens. It is a mixed system, where those who have access to private
plans must join them (most often available through employment); all
others must register for the public plan, administered by the RAMQ.
However, provision of medication for the treatment of sexually
transmitted diseases and active TB or LTBI is covered for all under the
Health Insurance Plan. This is to ensure that anyone needing these
prescription drugs has access to them at no cost, regardless of
insurance coverage (public or private plan). Therefore, data collected
by the RAMQ likely reflects the use of anti-TB therapy for the whole
population.
Data relative to drug dispensation by pharmacists are collected in
a central database. Any medication covered by the Health Insurance Plan
and dispensed to insured persons is automatically entered into the
database by the pharmacist via an interactive communications network.
Information collected includes patient identifiers, patient
characteristics (sex, age group, and region of residence), medication,
quantity dispensed, length of treatment, and pharmacist identifiers.
We extracted data on all prescriptions for active TB or LTBI
treatment reimbursed through the Health Insurance Plan from January 1,
2006 to December 31, 2010. No personal information was included except a
unique encrypted identifier number for each patient. The data set was
organized as a line list of prescriptions. Any medication dispensed to
an insured patient on a specific date is entered in the data set as one
prescription, even if the original prescription written by the physician
included more than one medication. Lines were aggregated by patient, and
aggregate variables for each individual included treatment regimen
received and the length of treatment.
Cohort construction
The cohort is made up of adult patients who were prescribed LTBI
treatment and obtained medication within a 12 month-period following the
date of first prescription. A prescription is defined as a "first
prescription" when no other prescription for the same medication
has been dispensed in the previous six months. For 2006, the first year
of observation, patients who had received a prescription on June 30,
2006 or before were excluded. The last cases included in the cohort had
to have received a first prescription by December 31, 2009 at the
latest, to enable verification of treatment adherence for the 12 months
after the prescription was issued. Patients who had obtained drugs other
than INH or RMP were excluded. Patients who had received INH and RMP
simultaneously at first prescription were also excluded to avoid
inclusion of active TB cases. Because we wanted to limit our analysis to
adults receiving standard LTBI treatment, patients under 20 years of age
were excluded, as were patients who had prescriptions for INH 100 mg
tablets, INH syrup (50 mg/5 ml) or RMP 150 mg tablets. Also excluded
were patients who had initiated treatment with INH 300 mg tablets and
continued treatment with RMP 300 mg tablets.
Patients were observed for 12 months following the date of the
first prescription. We analyzed medications procured every month as well
as duration of treatment indicated on the prescription for each patient
in the cohort. To calculate the total number of days of treatment, we
added the number of days indicated on each prescription for the 12
months following first prescription.
Data analysis
The data were analyzed using the Stata Data Analysis and
Statistical software version 10.0 (StataCorp LP). We calculated the
proportion of patients who had obtained at least 270 doses or at least
180 doses for daily INH 300 mg treatment, and the proportion of patients
who had obtained at least 120 doses for daily RMP 300 mg treatment.
Proportions are displayed by type of regimen, sex, age group and region
of residence (Greater Montreal [Montreal Island, Laval Island and
Montreal South Shore] vs. all other regions of Quebec). Pearson's
[chi square] significance test was applied to calculate p-values for
cross-tabulated variables. P-values were considered significant if
<0.05. Kaplan-Meier survival analysis was used to estimate the
probability of acquiring INH or RMP each month for 12 months following
the date of the first prescription. Follow-up began at the time the
patient filled out his or her first LTBI prescription and the outcome
event was the filling out of the last LTBI prescription during the study
period (referred to as "cessation"). We used Cox proportional
hazards regressions to further test the association between the
independent variables and INH and RMP adherence. Graph plots and tests
for each covariate (results not shown) indicate no violation of the
proportional hazards assumption. Hazard ratios (HR) larger than 1
indicate a higher rate of cessation in the exposed category and
therefore a shorter average length of treatment. Ethics approval was not
required for this study.
RESULTS
Figure 1 shows the study cohort flowchart, from all the LTBI
treatments prescribed down to the patients meeting all eligibility
criteria. Thus, from July 1, 2006 to December 31, 2009, 2,895 patients
were given a first prescription for 30 days of INH 300 mg tablets (Table
1). Among them, 907 (31.3%) procured at least 270 doses of medication
(nine months), and 1,625 (56.1%) at least 180 doses (six months). Figure
2 shows how the risk of cessation evolved over time in all subjects. The
Cox regression analysis of the survival data shows that, after
controlling for age, region of residence and year of prescription, women
were more likely to stop INH treatment before acquiring 270 doses of the
medication than men (hazards ratio [HR] = 1.08; 95% confidence interval
[CI]: 1.01-1.17). Consequently, the proportion of patients who had
obtained at least 270 doses of medication was higher among men than
among women (34.7 vs. 28.9, p=0.001), and the proportion of patients who
had obtained at least 270 doses of treatment did not vary significantly
by age, place of residence, or year of prescription.
[FIGURE 2 OMITTED]
For the same period, 373 individuals began LTBI treatment with RMP
(Table 2 and Figure 2), 242 (64.9%) of whom obtained at least 120 doses
of treatment (four months). The proportion of patients who had obtained
at least 120 doses of medication did not vary significantly by sex, age,
place of residence, or year of prescription.
DISCUSSION
Our results indicate that only 31.3% of patients who initiated INH
for preventive LTBI treatment obtained at least 270 doses, which
corresponds to nine months of treatment. This figure rises to 56.1% when
we consider patients who procured at least 180 doses. These results are
comparable to those from two recently published studies. In one
retrospective cross-sectional study of 68 clinics in 19 regions in the
United States and Canada, only 57.1% of patients who had been prescribed
nine months of INH treatment had taken it for at least six months. (13)
In a study that used RAMQ data to assess adverse effects associated with
LTBI treatment from 1998 to 2003, 54.1% of patients had completed six
months of INH treatment; in this study, 56.2% of patients had completed
four months of RMP treatment. (14) The corresponding figure in our study
is 64.9%.
Based on Kaplan-Meier curves, 17.4% of patients did not renew their
INH prescription after the first month of treatment. From the second to
the ninth month, an average of 7.3% of patients (range: 5.0-9.5) stopped
treatment each month. The step at one month being higher than the others
suggests that some patients never renew their prescription, possibly
because of adverse reactions or fear of these. Afterwards, the risk of
cessation remains constant until completion. The absence of a large step
after six months means that the majority of patients probably received a
ninemonth prescription of INH.
Our study has several limitations. We cannot be sure that the RAMQ
database captures all patients who were prescribed and obtained a LTBI
treatment. However, it is unlikely that a patient chooses to pay a
monthly deductible and a co-insurance fee when he or she can get his or
her medication totally free of charge. Moreover, there is no reason to
believe that patients getting INH or RMP through private insurance would
have higher or lower completion rates than those we obtained in our
study.
From a database such as the one we used, we cannot determine
whether patients who purchase LTBI medication actually take the number
of doses prescribed. Moreover, our results did not take into account the
number of patients who were prescribed LTBI medication but declined all
treatment. Usually, a significant proportion of patients for whom LTBI
treatment is offered decline. In the New York City study cited
previously, of 7,597 infected contacts, 1,596 (21.0%) never initiated
treatment. (7) In 32 US and Canadian clinics that performed skin testing
and offered treatment, of 720 infected patients, 123 (17.1%) declined
initiation of treatment; employees at a health-care facility were more
likely to refuse treatment, whereas contacts of a case of TB were less
likely to decline. (13) Results indicate that usual completion rates
obtained in the field leave much to be desired and are considerably
lower than the objective of 80% established by the Canadian Tuberculosis
Standards. (3) Effectiveness of LTBI treatment with INH is a function of
adherence and duration of treatment. In persons taking >80% of doses,
daily INH for one year provided 93% protection, and daily INH for six
months provided 69% protection. (3) Incomplete LTBI treatment is
probably better than no treatment at all. In the New York study, not
only LTBI treatment completion in infected contacts was associated with
a lower risk of incident tuberculosis compared with no treatment
(adjusted Hazard Ratio, 0.16) but also initiation without completion
(adjusted Hazard Ratio, 0.24). Despite completion rates around 50%,
offering LTBI treatment to infected contacts or to persons at high risk
for TB exposure or progression to active TB seems to be an effective
intervention and may reduce TB rates over times. (7,8)
Completion rates with four months of RMP treatment are better than
completion rates with six months of INH but are still far from the
recommended targets. This suggests that successful LTBI treatment may
depend on the availability of effective regimens shorter than the six-
or nine-month INH schedule. Recently, treatment based on weekly doses of
INH and rifapentine (RPT) for three months has shown promising results:
82% completion rate, efficacy comparable to nine months of INH
treatment, and similar toxicity profile. (15) These results have
prompted the US Centers for Disease Control to recommend the new INH-RPT
treatment as an equivalent alternative to the nine-month INH regimen for
healthy patients aged >12 years who have LTBI and have factors
predictive of developing active TB. (16) Unfortunately, until RPT is
approved in Canada, this regimen will not be available for LTBI
treatment.
REFERENCES
(1.) Public Health Agency of Canada. Tuberculosis in Canada 2010 -
Pre-release. Ottawa, ON: Ministry of Public Works and Government
Services, 2011. Available at: http://www.publichealth.gc.ca/tuberculosis
(Accessed April 2, 2012).
(2.) Public Health Agency of Canada. Guidance for Tuberculosis
Prevention and Control Programs in Canada. Ottawa: Ministry of Public
Works and Government Services, 2011.
(3.) Public Health Agency of Canada. Canadian Tuberculosis
Standards. Ottawa: Ministry of Public Works and Government Services,
2007. Available at: http://www.phac-aspc.gc.ca/tbpc-latb/pubs/pdf/tbstand07e.pdf (Accessed April 2, 2012).
(4.) Hirsch-Moverman Y, Daftary A, Franks J, Colson PW. Adherence
to treatment for latent tuberculosis infection: Systematic review of
studies in the US and Canada. Int J Tuberc Lung Dis 2008;12(11):1235-54.
(5.) Jereb J, Etkind SC, Joglar OT, Moore M, Taylor Z. Tuberculosis
contact investigations: Outcomes in selected areas of the United States,
1999. Int J Tuberc Lung Dis 2003;7(Suppl 3):S384-S390.
(6.) Reichler MR, Reves R, Bur S, Ford J, Thompson V, Mangura B, et
al. Treatment of latent tuberculosis infection in contacts of new
tuberculosis cases in the United States. South Med J 2002;95:414-20.
(7.) Anger HA, Proops D, Harris TG, Li J, Kreiswirth BN, Shashkina
E, Ahuja SD. Active case finding and prevention of tuberculosis among a
cohort of contacts exposed to infectious tuberculosis cases in New York
City. Clin Infect Dis 2012;54:1287-95.
(8.) Cain KP, Garman KN, Laserson KF, Ferrousier-Davis OP, Miranda
AG, Wells CD, Haley CA. Moving toward tuberculosis elimination:
Implementation of statewide targeted tuberculin testing in Tennessee. Am
J Respir Crit Care Med 2012;186(3):273-79.
(9.) Goldberg SV, Wallace J, Jackson JC, Chaulk CP, Nolan CM.
Cultural case management of latent tuberculosis infection. Int J Tuberc
Lung Dis 2004;8:76-82.
(10.) Menzies D, Dion MJ, Rabinovitch B, Mannix S, Brassard P,
Schwartzman K. Treatment completion and costs of a randomized trial of
Rifampin for 4 months versus Isoniazid for 9 months. Am J Respir Crit
Care Med 2004;170:445-49.
(11.) Lardizabal A, Passannante M, Kojakali F, Hayden C, Reichman
LB. Enhancement of treatment completion for latent tuberculosis
infection with 4 months of Rifampin. Chest 2006;130:1712-17.
(12.) Page KR, Sifakis F, Montes de Oca R, Cronin WA, Doherty MC,
Federline L, et al. Improved adherence and less toxicity with Rifampin
vs Isoniazid for treatment of latent tuberculosis: A retrospective
study. Arch Intern Med 2006;166:1863-70.
(13.) Horsburgh CR Jr, Goldberg S, Bethel J, Chen S, Colson PW,
Hirsch-Moverman Y, et al. Latent TB infection treatment acceptance and
completion in the United States and Canada. Chest 2010;137(2):401-9.
(14.) Smith BM, Schwartzman K, Bartlett G, Menzies D. Adverse
events associated with treatment of latent tuberculosis in the general
population. CMAJ 2011;183(3):E173-E179.
(15.) Sterling TR, Villarino ME, Borisov AS, Shang N, Gordin F,
Bliven-Sizemore E, et al. Three months of Rifapentine and Isoniazid for
latent tuberculosis infection. N Engl J Med 2011;365:2155-66.
(16.) Centers for Disease Control and Prevention. Recommendations
for use of an Isoniazid-Rifapentine regimen with direct observation to
treat latent Mycobacterium tuberculosis infection. MMWR
2011;60(48):1650-53.
* Quebec's health insurance board.
Received: September 19, 2012
Accepted: January 5, 2013
Paul Rivest, md, MSc, [1,2] Maria-Constanza Street, MSc, [1] Robert
Allard, mdcm, MSc, FRCPC [1,3]
Author Affiliations
[1.] Direction de sante publique, Agence de la sante et des
services sociaux, Montreal, QC
[2.] Departement de medecine sociale et preventive, Universite de
Montreal, Montreal, QC
[3.] Department of Epidemiology, Biostatistics and Occupational
Health, McGill University, Montreal, QC
Correspondence: Paul Rivest, Direction de sante publique de
Montreal, 1301 Sherbrooke Street East, Montreal, QC H2L 1M3, Tel:
514-528-2400, ext. 3678, Fax: 514-528-2452, E-mail:
privest@santepub-mtl.qc.ca
Conflict of Interest: None to declare.
Table 1. Completion Rates of LTBI Treatment With INH *
Characteristic LTBI Treatment With
INH 300 mg Daily
Patients [greater than
n (%) or equal to]
([dagger]) 270 Doses n (%)
([double dagger])
Sex
Female 1686 (58.2) 487 (28.9)
Male 1209 (41.8) 420 (34.7)
Age group (years)
20-34 1210 (41.8) 365 (30.2)
35-64 1558 (53.8) 511 (32.8)
[greater than or 127 (4.4) 31 (24.4)
equal to] 65
Residence region
([section])
Greater Montreal 2226 (76.9) 700 (31.5)
Other regions 652 (22.5) 202 (31.0)
Year of prescription
2006 ([parallel]) 460 (15.9) 138 (30.0)
2007 1004 (34.7) 327 (32.6)
2008 838 (28.9) 260 (31.0)
2009 593 (20.5) 182 (30.7)
Total 2895 (100) 907 (31.3)
Characteristic LTBI Treatment With
INH 300 mg Daily
95% CI of [greater than
Row Percent or equal to]
180 Doses n (%)
([double dagger])
Sex
Female (26.7-31.1) 905 (53.7)
Male (32.0-37.4) 720 (59.6)
([paragraph])
Age group (years)
20-34 (27.6-32.8) 672 (55.5)
35-64 (30.5-35.1) 894 (57.4)
[greater than or (16.9-31.9) 59 (46.5)
equal to] 65
Residence region
([section])
Greater Montreal (28.7-34.3) 1271 (57.1)
Other regions (27.4-34.6) 342 (52.5)
Year of prescription
2006 ([parallel]) (25.8-34.2) 257 (62.8)
2007 (29.7-35.5) 579 (61.5)
2008 (27.9-34.1) 476 (68.6)
2009 (27.0-34.4) 313 (52.8)
Total (29.6-33.0) 1625 (56.1)
Characteristic LTBI Treatment
With INH 300
mg Daily
95% CI of
Row Percent
Sex
Female (51.3-56.1)
Male (56.8-62.4) **
Age group (years)
20-34 (52.7-58.3)
35-64 (54.9-59.9)
[greater than or (37.8-55.2)
equal to] 65
Residence region
([section])
Greater Montreal (55.0-59.2)
Other regions (48.7-56.3)
Year of prescription
2006 ([parallel]) (58.4-67.2)
2007 (58.5-64.5)
2008 (65.5-71.7)
2009 (48.8-56.8)
Total (54.3-57.9)
* LTBI: latent tuberculosis infection; INH: isoniazid.
([dagger]) Column percent.
([double dagger]) Row percent.
([section]) Data missing for 17 cases.
([parallel]) July 1st to December 31st.
([paragraph]) p = 0.001.
** p = 0.002.
Table 2. Completion of Treatment for LTBI With RMP *
Characteristic LTBI Treatment With RMP 600 mg Daily
Patients [greater than or 95% CI
n (%) equal to] 120
([dagger]) Doses n (%)
([double dagger])
Sex
Female 182 (48.8) 118 (64.8) (57.9-71.7)
Male 191 (51.2) 124 (64.9) (58.1-71.7)
Age group (years)
20-34 184 (49.3) 116 (63.0) (56.0-70.0)
35-64 171 (45.8) 117 (68.4) (61.4-75.4)
65 18 (4.8) 9 (50.0) (26.9-73.1)
Residence region
([section])
Greater Montreal 334 (89.6) 220 (65.9) (60.8-71.0)
Other regions 35 (9.4) 20 (57.1) (40.7-73.5)
Year of prescription
2006 ([parallel]) 63 (16.9) 44 (30.0) (58.5-81.1)
2007 97 (26.5) 61 (62.9) (51.3-70.7)
2008 99 (26.0) 61 (61.6) (52.0-71.2)
2009 114 (30.6) 76 (66.7) (58.1-75.4)
Total 373 (100) 242 (64.9) (60.1-69.7)
* LTBI: latent tuberculosis infection; RMP: rifampine.
([dagger]) Column percent.
([double dagger]) Row percent.
([section]) Data missing for 4 cases.
([parallel]) July 1st to December 31st.
