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Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Hangang Sacred Heart Hospital, Seoul, Republic of Korea
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang-si, Gyeonggi-do, Republic of Korea
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, Republic of Korea
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon, Republic of Korea
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, Republic of Korea
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, Republic of Korea
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, Republic of Korea
Corresponding author. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, 7, Keunjaebong-gil, Hwaseong-si, Gyeonggi-do, 18450, Republic of Korea.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong-si, Republic of Korea
Treatment of latent tuberculosis infection in patients aged 65–78 years is relatively well tolerated.
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The completion rate of the 3-month isoniazid plus rifampin regimen in elderly patients was 88.4%.
•
The primary cause of cessation of treatment was loss to follow-up rather than adverse effects of anti-tuberculosis drugs.
Abstract
Introduction
There are insufficient data on the treatment of latent tuberculosis infection (LTBI) in elderly patients. We investigated the completion rate of treatment in elderly LTBI patients.
Methods
A retrospective multicentre study was conducted at five university hospitals in South Korea. We reviewed the electronic medical records of patients aged 65 years and older who were diagnosed with LTBI via positive interferon-gamma release assay results between January 2016 and December 2018. Treatment completion was defined as ingestion of more than 80% of all prescribed medications without loss to follow-up.
Results
During the study period, 127 LTBI patients aged 65 years and older visited outpatient department. Among them, 77 patients aged 65–78 years (median age, 69 years [interquartile range, 66–71 years]) who received LTBI treatment were analysed. Common reasons for IGRA testing in elderly patients were health-care worker (n = 33, 42.9%) and household contact with infectious TB patients (n = 18, 23.4%).
The overall completion rate of LTBI treatment was 83.1% (n = 64), and the completion rate of 3-month isoniazid plus rifampin regimen was 88.4%. Adverse effects were reported in 23 patients (29.9%), and an increase in aminotransferase level was the most common adverse effect (n = 11, 14.3%). Three patients (3.9%) with the adverse effect discontinued treatment and 10 (13.0%) patients were lost to follow-up.
Conclusions
LTBI treatment in patients aged 65–78 years was relatively well tolerated. In LTBI treatment in elderly patients, the majority of discontinuation of treatment was due to loss to follow-up rather than adverse effects of anti-TB medications.
The disease burden caused by tuberculosis (TB) is decreasing globally. However, high rates of TB are increasingly evident in the elderly population, particularly in the Western Pacific Region and South East Asia [
]. In South Korea, decreasing patterns of new TB notifications were observed in almost all age groups. However, 45.5% of new TB cases involved elderly patients aged 65 years or older in 2018 [
]. Worldwide, the number of people aged 60 years or older is expected to increase by more than double, from 841 million people in 2013 to more than 2 billion in 2050 [
]. Therefore, there is a possibility that the number of elderly TB patients will increase continuously. In the UK, the percentage of TB aged 65 years or older increased from 13% in 1991 to 16% in 2001, and is expected to rise to 23% by 2031 [
]. In TB, cell-mediated immunity plays a key role in controlling infection. As age advances, the related decline in immunity increases the chance of reactivation of latent disease [
]. In addition, other factors, including age-associated comorbid conditions such as malnutrition and diabetes mellitus contribute to the increased risk of TB in the elderly population [
]. Treatment for LTBI is recommended in priority groups, such as household contacts of patients with pulmonary TB or patients initiating anti-TNF treatment or preparing for organ transplantation. However, current guidelines do not offer definite recommendations for LTBI treatment in patients aged 65 years or older [
]. Moreover, elderly LTBI patients, particularly elderly healthcare workers, have been infected in a remote past and may not be at risk of TB reactivation, due to the fact that the risk of reactivation decreases with time after the infection [
]. Fountain et al. reported that isoniazid hepatotoxicity during LTBI treatment ranged from 0.44% in those younger than 35 years to 2.08% for those older than 49 years [
]. Another study of the treatment of LTBI in patients aged 50 years and older showed the rate of hepatotoxicity leading to permanent discontinuation of treatment was 1.9% [
We hypothesized that LTBI treatment with isoniazid or rifampin-based regimens could be tolerable in elderly patients. Therefore, we investigated the completion rate of LTBI treatment and associated factors in patients aged 65 years and older in South Korea.
2. Methods
2.1 Study design and patients
This retrospective multicentre study was conducted at Hallym University Medical Centre, which includes 3100 patient beds in five university hospitals across South Korea. We reviewed the electronic medical records of patients aged 65 years and older who were diagnosed with LTBI between January 2016 and December 2018. Patients were excluded if they did not start LTBI treatment, were diagnosed with active TB at the time of enrolment or were transferred to another hospital.
The study was approved by the Institutional Review Board of Hallym Medical Centre (approval no. 2019-02-008-001). The requirement for informed consent was waived due to the retrospective nature of the analyses.
2.2 Data collection and definitions
According to Korean national strategic plan for tuberculosis control, TB contact investigation on household contacts of TB cases was performed and LTBI has screened mandatorily for healthcare workers, postnatal care workers, nursery workers, workers in children welfare facilities, and teachers at kindergartens and primary, secondary, and high schools since 2017 [
]. People diagnosed with LTBI are recommended to visit outpatient clinics or public health centres. Treatment was started in patients who agreed with LTBI treatment after counselling. We analysed the LTBI patients who visited outpatient department at our five hospitals. Data on the following factors were retrieved via electronic medical records: patient age and sex, diagnosis of outpatient visit, the results of interferon-gamma release assay (IGRA), reasons for IGRA testing, medical history of tuberculosis treatment, comorbidities (diabetes mellitus, hypertension, myocardial infarction, congestive heart failure, cerebrovascular accident, asthma, chronic obstructive pulmonary disease, chronic bronchitis, chronic kidney disease, malignancy, dementia), treatment regimens, duration and dose of treatment regimens, reasons for change or discontinuation of treatment, and adverse effects (gastrointestinal symptoms, skin rash, pruritus, peripheral neuropathy, hepatotoxicity, etc.).
LTBI is defined as a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifested active TB [
]. We diagnosed LTBI on the basis of positive IGRA results in patients without any symptoms of TB and without any chest radiographic abnormalities. For the LTBI diagnosis, a QuantiFERON-TB Gold In-Tube® (QFT-GIT; Qiagen, Hilden, Germany) test was performed, and a chest X-ray was taken at the same time. A positive IGRA result was defined as an interferon-gamma response to the TB antigen minus that of the Nil tube of ≥0.35 IU/ml [
Treatment completion was defined as ingestion of more than 80% of all prescribed medications without loss to follow-up: within 12 months for 9H, within 6 months for 4R and 4 months for 3HR [
]. Ingested doses were estimated by the prescribed medications. Hepatotoxicity was graded as follows by the National Cancer Institute's Common Terminology Criteria for Adverse Effects Version 5.0 [
]: Grade 1: alanine transaminase (ALT) 1–3 times; Grade 2: ALT 3–5 times; Grade 3: ALT 3–10 times with symptoms or 5–10 times without symptoms; and Grade 4: ALT >10 times.
2.3 Treatment of LTBI
Korean guideline for tuberculosis (Supplementary Table 1) recommends treatment of LTBI at risk for progression to active TB classified into two groups (non-contacts to an infectious TB patients and contacts to an infectious TB patient). Health-care workers with LTBI should be treated in the situations of Tuerculin skin test or IGRA conversion or in contact with patients with TB within 2 years. In high-risk groups such as HIV infected patients, LTBI treatment is recommended for those under 65 years of age with hepatotoxicity risk factors. However, there is no age limit if the patients do not have hepatotoxicity risk factors. In the household contacts of TB or healthcare workers, if there are no risk factors for hepatotoxicity, LTBI medications can be prescribed under 65 years of age. If there are risk factors for hepatotoxicity, LTBI medications can be prescribed under 35 years of age [
]. On the other hand, Korean national strategic plan for tuberculosis control recommends LTBI treatment to prevent TB outbreaks without reference of age. Hence, the LTBI treatment recommendations and regimens were determined by the physician's discretion based on risks and benefits of treatments. The guideline recommends isoniazid monotherapy for 9 months (9H; 5 mg/kg, up to 300 mg/d) for treatment of LTBI [
]. Rifampin daily for 4 months (4R; 10 mg/kg, up to 600 mg/d) and rifampin plus isoniazid daily for 3 months (3HR) are also offered as alternative treatments.
Table 1Baseline characteristics of elderly LTBI patients.
Variable
Total (n = 77)
Age (yr), median (IQR)
69 (66–71)
Age range (yr), n (%)
65-69
44 (57.1)
70-74
27 (35.1)
≥75
6 (7.8)
Male sex, n (%)
23 (29.9)
Reasons for IGRA testing, n (%)
Health-care workers
33 (42.9)
Household contacts with patients with infectious TB
18 (23.4)
Workers in kindergartens, childcare centres, and welfare facilities
Data are expressed as the median (IQR) or as number (%) as appropriate. IGRA = interferon gamma release assay; TB = tuberculosis; TNF = tumour necrosis factor; 9H = isoniazid monotherapy for 9 months; 4R = rifampicin daily 4 months; 3HR = rifampin plus isoniazid daily for 3 months.
During LTBI treatment, patients were followed up for the first 2 weeks and then every 4 weeks until the end of the treatment. Laboratory tests (complete blood count, aspartate transaminase (AST), ALT, and total bilirubin) were performed at every visit. Korean guideline for tuberculosis recommends that anti-TB medications should be stopped if aminotransferase levels exceeded 3 times of upper normal range with symptoms of hepatitis or exceeded 5 times of upper normal range without symptoms [
In South Korea, through public–private mix collaboration, the TB-specialist nurses were dispatched to health care facilities. They are responsible for patient education and monitoring of adverse effects during treatment. When the patients are lost to regular follow-up, they encourage them to visit the hospital through telephone consultation or home visits [
]. The government provides diagnostic and treatment services at no cost as well as care until a patient is completely cured.
2.4 Statistical analysis
Continuous variables are expressed as the median (interquartile range), and categorical variables are expressed as numbers (percentages). Data on continuous variables were compared using an independent Student's t-test or the Mann-Whitney U test. Data on categorical variables were compared using the Chi-square test or Fisher's exact test. Multivariable logistic regression analysis using the backward elimination method was performed to identify the factors associated with completion of LTBI treatment. Independent variables were selected on the basis of their statistical significance in univariate analyses and on the basis of being clinically applicable. Calibrations of the models were evaluated with the Hosmer–Lemeshow goodness-of-fit test. A p-value of <0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) Version 24.0 (IBM Corporation, Armonk, NY).
3. Results
During the study period, a total of 1517 IGRA-positive people visited outpatient department at five hospitals. Among 130 aged 65 years and older, three were diagnosed with active TB. The remaining 127 LTBI patients, 46 did not start LTBI treatment after counselling. Four patients were excluded: two patients received wrong medications, and the other two transferred to another hospital, hence data were not available. A total of 77 patients who received LTBI treatment were analysed (Fig. 1).
Fig. 1Flow chart of the patients. IGRA = interferon-gamma assay; LTBI = latent tuberculosis infection; TB = tuberculosis; 9H = isoniazid monotherapy for 9 months; 4R = rifampin daily for 4 months; 3HR = rifampin plus isoniazid daily for 3 months.
Baseline characteristics of the study population are demonstrated in Table 1. The median age of the cohort was 69 years (range, 65–78 years; interquartile range, 66–71 years), and 23 patients (29.9%) were male. Reasons for IGRA testing in elderly LTBI patients were as follows: 33 patients (42.9%) health-care workers; 18 patients (23.4%) household contacts with infectious TB patients; 10 patients (13.0%) workers in kindergartens, childcare centres, and welfare facilities; eight patients (10.4%) patients considering anti-TNF treatment; and eight patients (10.4%) miscellaneous reasons. The most common comorbidities were diabetes mellitus (n = 14, 18.2%) and hypertension (n = 14, 18.2%). Eleven patients (14.3%) had two or more comorbidities.
Three regimens were used: 9H in 12 patients (15.6%); 4R in 22 patients (28.6%); and 3HR in 43 patients (55.8%). The overall completion rate of LTBI treatment by initial regimen was 83.1% (n = 64), and the completion rate of each regimen was as follows: 75% (9 of 12 cases) in the 9H group; 77.3% (17 of 22 cases) in the 4R group; and 88.4% (38 of 43 cases) in the 3HR group (Fig. 2). LTBI regimes were changed in four patients (5.2%). One patient treated with the 9H regimen changed to the 3HR regimen by patient choice. The other three patients changed regimens due to adverse effects, including leukopenia, rifampin drug interaction with anti-hypertension medication, and gastrointestinal symptoms. After adjustment of regimen change, the completion rate of LTBI treatment was as follows: 78.6% (11 of 14 cases) in the 9H group; 76.2% (16 of 21 cases) in the 4R group; and 88.1% (37 of 42 cases) in the 3HR group.
Fig. 2Completion rates of elderly LTBI treatment according to regimens. LTBI = latent tuberculosis infection; 9H = isoniazid monotherapy for 9 months; 4R = rifampin daily for 4 months; 3HR = rifampin plus isoniazid daily for 3 months.
Adverse effects occurred in 23 patients (29.9%), and an increase in aminotransferase level was the most common adverse effect (n = 11, 14.3%; Table 2). In the patients with elevated aminotransferase levels, the median AST and ALT levels were 55 IU/L (range, 47.5–95 IU/L) and 53 IU/L (range, 46.5–106 IU/L), respectively. There was no significant difference in hepatotoxicity according to the age group: 18.2% (eight of 44 cases) in 65–69 age group; 7.4% (two of 27 cases) in 70–74 age group; and 16.7% (one of six) in ≥75 age group (p = 0.446). Gastrointestinal symptoms (n = 5, 6.5%) and skin rash (n = 4, 5.2%) were the next most common adverse effects. Grade 3 hepatotoxicity occurred in one patient in 4R and one patient in 3HR, and the patient treated with the 3HR regimen completed treatment because the increased ALT was identified at the end of treatment. Hence, hepatotoxicity leading to discontinuation of treatment occurred in one patient. There were three patients who discontinued treatment due to any adverse effects and no one retried LTBI treatment.
Table 2Completion rates and adverse effects of LTBI treatment in elderly patients.
Variable
9H (n = 12)
4R (n = 22)
3HR (n = 43)
Total (n = 77)
Completion of LTBI treatment, n (%)
9 (75)
17 (77.3)
38 (88.4)
64 (83.1)
Completed without regimen change
8 (66.7)
16 (72.7)
36 (86.0)
60 (77.9)
Completed after regimen change
1 (8.3)
1 (4.5)
2 (4.7)
4 (5.2)
Leukopenia
0 (0.0)
1 (4.5)
0 (0.0)
1 (1.3)
Patient choice
1 (8.3)
0 (0.0)
0 (0.0)
1 (1.3)
Rifampin drug interaction
0 (0.0)
0 (0.0)
1 (2.3)
1 (1.3)
Gastrointestinal symptoms
0 (0.0)
0 (0.0)
1 (2.3)
1 (1.3)
Completion rate by age group, n (%)
65-69
2/3 (66.7)
10/13 (76.9)
27/28 (96.4)
39/44 (88.6)
70-74
5/7 (71.4)
6/7 (85.7)
10/13 (76.9)
21/27 (77.8)
≥75
2/2 (100)
1/2 (50)
1/2 (50)
4/6 (66.7)
Reasons for incompletion of LTBI treatment, n (%)
3 (25)
5 (22.7)
5 (11.6)
13 (16.9)
Lost to follow-up
3 (25)
3 (13.6)
4 (9.3)
10 (13.0)
Adverse event
0 (0.0)
2 (9.1)
1 (2.3)
3 (3.9)
Gastrointestinal symptoms
0 (0.0)
1 (4.5)
0 (0.0)
1 (1.3)
Rash
0 (0.0)
0 (0.0)
1 (2.3)
1 (1.3)
Hepatotoxicity
0 (0.0)
1 (4.5)
0 (0.0)
1 (1.3)
Adverse effect, n (%)
3 (25)
7 (31.8)
13 (30.2)
23 (29.9)
Gastrointestinal symptoms
0 (0.0)
1 (4.5)
4 (9.3)
5 (6.5)
Rash
0 (0.0)
2 (9.1)
2 (4.7)
4 (5.2)
Pruritus
1 (8.3)
1 (4.5)
1 (2.3)
3 (3.9)
Peripheral neuropathy
0 (0.0)
0 (0.0)
1 (2.3)
1 (1.3)
Increase in aminotransferase level
2 (16.7)
3 (13.6)
6 (14.0)
11 (14.3)
Rifampin drug interaction
0 (0.0)
0 (0.0)
1 (2.3)
1 (1.3)
Leukopenia
0 (0.0)
1 (4.5)
1 (2.3)
2 (2.6)
2 or more adverse events, n (%)
0 (0.0)
1 (4.5)
2 (4.7)
3 (3.9)
Grade of hepatotoxicity, n (%)
Hepatotoxicity (grade 1)
2 (16.7)
2 (9.1)
5 (11.6)
9 (11.7)
Hepatotoxicity (grade 3)
0 (0.0)
1 (4.5)
1 (2.3)
2 (2.6)
Data are expressed as numbers (%). Grading of hepatotoxicity: Grade 1: ALT 1–3 times; Grade 2: ALT 3–5 times; Grade 3: ALT 3–10 times with symptom or 5–10 times without symptom; and Grade 4: ALT >10 times. LTBI = latent tuberculosis infection; 9H = isoniazid monotherapy for 9 months; 4R = rifampicin daily for 4 months; 3HR = rifampicin plus isoniazid daily for 3 months.
There were 13 (16.9%) patients who did not complete treatment, and 10 (13.0%) patients were lost to follow-up. There were three (25%) patients in the 9H group who did not complete the LTBI treatment and were lost to follow-up. The 4R and 3HR groups also had three (13.6%) and four (9.3%) patients lost to follow-up, respectively. In addition, three patients (3.9%) discontinued treatment due to adverse effects (n = 2, 9.1% in the 4R group; n = 1, 2.3% in the 3HR group).
Factors associated with completion of LTBI treatment are shown in Table 3. In univariate analyses, the following factors were significantly associated with completion of LTBI treatment: age (OR 0.836 [95% CI 0.720–0.971], p = 0.019), presence of comorbidity (OR 0.284 [95% CI 0.083–0.978], p = 0.046), and diabetes mellitus (OR 0.262 [95% CI 0.070–0.981], p = 0.047). Compared with 9H, 3HR regimen (OR 2.533 [95% CI 0.509–12.613], p = 0.256) did not show significantly increased odds of completion of LTBI treatment. Multivariable regression analysis was performed using age, sex, presence of comorbidity, 2 or more comorbidities, hypertension, diabetes mellitus, regimens, presence of adverse effects, gastrointestinal symptoms, rash or pruritus, and hepatotoxicity. In multivariable analyses, only old age (OR 0.830 [95% CI 0.712–0.968], p = 0.017) was independently associated with incompletion of LTBI treatment.
Table 3Factors associated with completion of LTBI treatment in elderly patients.
Clinical variables entered into the model were age, sex, presence of comorbidity, 2 or more comorbidities, hypertension, diabetes mellitus, regimens, presence of side effect, gastrointestinal symptoms, rash or pruritus, and hepatotoxicity. LTBI = latent tuberculosis infection; OR = odds ratio; CI = confidence interval; 9H = isoniazid monotherapy for 9 months; 4R = rifampicin daily for 4 months; 3HR = rifampicin plus isoniazid daily for 3 months.
OR (95% CI)
Age (yr)
0.836 (0.720–0.971)
0.019
0.830 (0.712–0.968)
0.017
Male sex
1.515 (0.376–6.109)
0.559
Presence of comorbidity
0.284 (0.083–0.978)
0.046
2 or more comorbidities
0.276 (0.067–1.138)
0.075
0.249 (0.055–1.119)
0.070
Hypertension
0.417 (0.107–1.619)
0.206
Diabetes mellitus
0.262 (0.070–0.981)
0.047
Regimen
9H
Reference
4R
1.133 (0.219–5.864)
0.881
3HR
2.533 (0.509–12.613)
0.256
Presence of adverse event
0.950 (0.260–3.465)
0.938
Gastrointestinal symptoms
0.800 (0.082–7.800)
0.848
Rash or pruritus
1.241 (0.137–11.275)
0.848
Hepatotoxicity
0.900 (0.171–4.749)
0.901
a Clinical variables entered into the model were age, sex, presence of comorbidity, 2 or more comorbidities, hypertension, diabetes mellitus, regimens, presence of side effect, gastrointestinal symptoms, rash or pruritus, and hepatotoxicity. LTBI = latent tuberculosis infection; OR = odds ratio; CI = confidence interval; 9H = isoniazid monotherapy for 9 months; 4R = rifampicin daily for 4 months; 3HR = rifampicin plus isoniazid daily for 3 months.
In this multicentre study, we investigated the completion rate of treatment in LTBI patients aged 65–78 years diagnosed with the IGRA test. The overall completion rate of LTBI treatment in elderly patients was 83.1%, with an 88.4% completion rate in the 3HR group. Although the completion rate decreased with age, the main cause of discontinuation of treatment was loss to follow-up rather than adverse effects of anti-TB medications. In addition, Grade 3 hepatotoxicity occurred in 2.6% of elderly LTBI patients.
We found that the completion rate of our elderly cohort is comparable to that of previous studies of LTBI treatment, with a range from 62.2% to 90.6% [
A retrospective evaluation of completion rates, total cost, and adverse effects for treatment of latent tuberculosis infection in a public health clinic in central Massachusetts.
Baseline abnormal liver function tests are more important than age in the development of isoniazid-induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection.
]. These findings suggest that LTBI treatment could be well tolerated by patients aged 65 years and older. In addition, our results demonstrated that patients in the 3HR group had an 88% completion rate of LTBI treatment. Although a 6- or 9-month isoniazid-based regimen is recommended by current guidelines [
A retrospective evaluation of completion rates, total cost, and adverse effects for treatment of latent tuberculosis infection in a public health clinic in central Massachusetts.
Baseline abnormal liver function tests are more important than age in the development of isoniazid-induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection.
]. A meta-analysis showed that 3 or 4 months of rifampin monotherapy, 3 months of isoniazid plus rifapentine, and 3 or 4 months of isoniazid plus rifampin regimen were associated with higher rates of completion than 12 months of placebo [
Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses.
]. This finding implied that completion rates are inversely related to treatment length. The World Health Organization guidelines for LTBI also emphasized that shorter regimens are expected to help patients adhere to and complete treatment [
]. Although our results did not reach statistical significance due to the small number of patients, the completion rate of the 3HR regimen was higher than that of the 9H regimen [
]. Therefore, our results support a higher likelihood of completion with a shorter regimen in patients aged 65 years and older.
In the present study, we identified that the main reason leading to discontinuation of LTBI treatment in elderly patients was a loss to follow-up, which is comparable with previously reported data of 8%–17% [
A retrospective evaluation of completion rates, total cost, and adverse effects for treatment of latent tuberculosis infection in a public health clinic in central Massachusetts.
Treatment of latent Mycobacterium tuberculosis infection with 12 once weekly directly-observed doses of isoniazid and rifapentine among persons experiencing homelessness.
]. In that study, directly observed treatment for the 3HP regimen was recommended, and the overall completion rate was as high as 91%. Another study of directly observed treatment with 3HP among persons experiencing homelessness, loss to follow-up was 14.0% and completion rate was 76.6%. Persons aged 65 years and older were more likely to discontinue treatment than persons aged 31–44 years [
Treatment of latent Mycobacterium tuberculosis infection with 12 once weekly directly-observed doses of isoniazid and rifapentine among persons experiencing homelessness.
]. Therefore, in elderly patients, LTBI treatment should be more carefully monitored to reduce loss to follow-up which may improve the completion of LTBI treatment.
Elderly people are more likely to undergo adverse drug reactions during anti-tuberculous treatment; in particular, hepatotoxicity is a major concern [
]. The results of our study showed the rate of mild aminotransferase elevation was 12%; however, the rate of grade 3 hepatotoxicity associated with discontinuation of treatment was 2.6% in patients aged 65 years and older. Hosford et al. reported that patients aged 60 years and older had increased odds of hepatotoxicity of 4.14 (95% CI 2.21–7.74) compared to those 60 years and younger [
]. However, the meta-analysis involved limitations such as variable definitions of hepatotoxicity between the included studies. Therefore, future studies including a large study population of elderly LTBI patients are required to evaluate hepatotoxicity leading to permanent discontinuation of treatment.
The present study has several limitations. First, due to the retrospective nature of the study design, no data concerning factors such as reasons for not receiving LTBI treatment, selection of treatment regimen, or discontinuation of treatment (physician's decision or patient's refusal) were available. In addition, we cannot determine why the physicians chose treatment in LTBI patients aged 65 years and older, unlike recommendation of guideline. Potentially toxic LTBI treatment in elderly people with several comorbidities should be initiated carefully. Moreover, Sester et al. claimed that health-care workers which accounts for 43% of our study population may no longer be a risk group in low-incidence countries [
]. There is a discrepancy in indications for IGRA test between Korean guideline for tuberculosis and Korean national strategic plan for tuberculosis control. In our cohort, LTBI patients over 65 years old were mostly workers in various facilities, which performance status might be not too bad. Moreover, Korean guideline for tuberculosis specified that the recommendations for age limitation are temporary proposals due to the lack of evidence for elderly LTBI treatment. Physicians may have determined that the risk of adverse effects would not outweigh the benefits of treatment. Although, the results of our study did not demonstrate the efficacy of LTBI treatment in the elderly people, may present that the potential risk of LTBI treatment is tolerated and hepatotoxicity was not increased by ageing. Second, the small study population may have been underpowered to compare each regimen, and the independent risk factors for adverse effects could not be assessed. Third, the efficacy of LTBI treatment in the prevention of TB reactivation was not investigated because of the short follow-up duration. Fourth, there is a possibility that the patients will not take the medications as prescribed. We cannot excluded the possibility because taking medications were not observed directly or the pill counts were not enforced. As a consequence, adverse reactions may be fewer. Fifth, because IGRA-positive population choose hospitals or public health centres, there may be a selection bias by elderly people with better profiles for tolerating and completing therapy. Despite these limitations, our findings improve the understanding of LTBI treatment in elderly patients. More frequent symptom and biochemical monitoring and more careful monitoring and review of the medical record may be required to improve adherence to LTBI treatment in elderly patients [
LTBI treatment in patients aged 65–78 years was relatively well tolerated. Although the completion rate was decreased by ageing, the main reason for discontinuation of treatment was loss to follow-up rather than adverse effects of anti-TB medications. Therefore, in LTBI treatment in elderly patients, more careful monitoring to reduce loss to follow-up may improve the completion of LTBI treatment.
Declaration of interests
The authors declare that they have no conflict of interest.
Funding
None.
Acknowledgements
None.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
WHO Guidelines Approved by the Guidelines Review Committee. Latent Tuberculosis Infection: Updated and Consolidated Guidelines for Programmatic Management. Geneva: World Health Organization.
A retrospective evaluation of completion rates, total cost, and adverse effects for treatment of latent tuberculosis infection in a public health clinic in central Massachusetts.
Baseline abnormal liver function tests are more important than age in the development of isoniazid-induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection.
Efficacy and completion rates of rifapentine and isoniazid (3HP) compared to other treatment regimens for latent tuberculosis infection: a systematic review with network meta-analyses.
Treatment of latent Mycobacterium tuberculosis infection with 12 once weekly directly-observed doses of isoniazid and rifapentine among persons experiencing homelessness.
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