|Year : 2022 | Volume
| Issue : 1 | Page : 38-46
Predictors of treatment outcomes in drug resistant tuberculosis-observational retrospective study
July Mary Johnson1, Aswini Kumar Mohapatra2, Saleena Ummer Velladath1, Kavitha S Shettigar1
1 Department of Medical Laboratory Technology, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal, Karnataka, India
2 Department of Pulmonary Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
|Date of Submission||08-Dec-2021|
|Date of Decision||29-Dec-2021|
|Date of Acceptance||08-Feb-2022|
|Date of Web Publication||12-Mar-2022|
Kavitha S Shettigar
Department of Medical Laboratory Technology, Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
Background: In this study, we evaluate the predictors of treatment outcomes in drug resistant tuberculosis. Methods: An observational retrospective study was conducted by using the medical records of patients confirmed for TB at Kasturba Medical College from January 2015 to December 2018. Results: Four hundred and sixty-two TB patients were included in this study. Of the total TB-confirmed patients, about 85.1% are diagnosed with pulmonary TB (PTB) (n = 393), 11.7% were extrapulmonary tuberculosis (EPTB) (n = 54), and 3.2% (n = 15) cases had both PTB and EPTB. Among the 462 cases, the frequency of multidrug-resistant TB (MDR-TB) was 25% (n = 117), extensively drug-resistant TB was 1% (n = 3), and non-MDR cases were 74% (n = 342). The frequency of unsuccessful treatment outcome was 92.9% (n = 429) and successful outcome was 7.1% (n = 33). There were 68.2% of new and 31.8% retreatment cases of TB. HIV co-infection was found in 2.3% (n = 14) of TB cases, and among them, 64.3% (n = 9) were found in PTB cases. The major comorbidities found were diabetes (21.2%), weight loss (12.6%), and anemia (12.6%). There was a difference in rate of PTB cases across years decreasing in the year 2017, whereas ETB cases were increasing in the year 2017. The TB treatment success rate was increased from 2015 (4.8%) to 2018 (8.3%). Conclusion: The higher rate of poor treatment outcome emphasizes the need of improvement in TB surveillance, treatment, more stringent follow-up, monitoring, and patient education to ensure complete and successful treatment.
Keywords: Drug resistance, multidrug resistance, pulmonary and extrapulmonary tuberculosis, treatment outcomes, tuberculosis, predictors, comorbidities
|How to cite this article:|
Johnson JM, Mohapatra AK, Velladath SU, Shettigar KS. Predictors of treatment outcomes in drug resistant tuberculosis-observational retrospective study. Int J Mycobacteriol 2022;11:38-46
|How to cite this URL:|
Johnson JM, Mohapatra AK, Velladath SU, Shettigar KS. Predictors of treatment outcomes in drug resistant tuberculosis-observational retrospective study. Int J Mycobacteriol [serial online] 2022 [cited 2022 May 21];11:38-46. Available from: https://www.ijmyco.org/text.asp?2022/11/1/38/339514
| Introduction|| |
The worldwide prevalence of tuberculosis (TB) is about 10 million people in 2019. TB is one among the top ten causes of mortality. In India, newly diagnosed TB cases were increasing from 1.2 million to 2.2 million between 2013 and 2019. Multidrug-resistant TB (MDR-TB) is the major public health crisis and a global concern. TB patients have 5%–10% lifetime risk of falling ill with TB. TB is one of the most common comorbidities found in HIV patients. Among TB patients with antiretroviral treatment, India accounts for 25% of the global TB count. An increased number of new TB cases are reported in South-East Asian region. India is one among the high TB burden countries. The WHO's latest global TB report reports an estimated 5,946,816 cases of PTB cases, 206,030 cases of MDR/rifampicin-resistant (RR) TB cases, and 12,350 cases of extensively drug-resistant (XDR) TB globally in 2019, and India (27%) is one of the top three countries with MDR-TB followed by China (14%) and Russian Federation (8%). MDR-TB and XDR-TB hamper the global efforts to control the TB because the treatment of MDR-TB and XDR-TB requires longer time than drug-susceptible TB and has toxic side effects and treatment outcome is often poor. Currently, only 57% of MDR-TB patients are successfully treated, and in India, treatment success rate (TSR) was below 50% owing to high rates of mortality and loss to follow-up cases.
Few studies are reported on treatment outcomes of DR-TB, but reports on sociodemographic and clinical factors associated to unfavorable treatment outcomes are less in India. An understanding of risk factors associated with TB treatment outcomes is required for the effective treatment management of TB. Hence, the objectives of this study are (1) to describe the sociodemographic and clinical characteristics of drug-resistant (DR) TB during the period from 2015 to 2018 and (2) to describe factors associated with unfavorable treatment outcomes.
| Methods|| |
Study design and study population
This single-centric retrospective study was carried out in patients having TB at Kasturba Hospital, Manipal, in the southern part of India. This study was initiated after the approval of Institutional Ethics Committee, MAHE, Manipal (IEC: 380/2020).
Data sources and variables
All TB patients visiting Kasturba Hospital from 2015 to 2018 were included in this study. Data of all TB patients >18 years having pulmonary TB (PTB) and extrapulmonary TB (EPTB) between 2015 and 2018 were included in the study. A case was considered as PTB if the sputum of the patient tested positive for acid-fast bacillus staining, cartridge-based nucleic acid testing, or culture. A case was considered EPTB if there were clinical, radiological, and pathological features suggestive of tubercular involvement of sites other than the lung. Both inpatient and outpatient records of patients were collected. Data on sociodemographic details, TB treatment history, comorbidities, treatment outcomes, blood parameters, drug intake history, drug resistance, and chest radiography report were collected. The study was approved by the Institutional Ethics Committee (IEC: 380/2020). Patients who were diagnosed with DR-TB but have not started the treatment were excluded from this study.
Diagnosis and drug-resistant tuberculosis treatment
The patients who were identified with DR-TB were included in this study. The diagnosis was made by using Ziehl–Neelsen acid fast staining, GeneXpert, nucleic acid detection method, and the drug sensitivity testing for the first-line medication of TB such as ofloxacin, capreomycin, and kanamycin. One sample is collected prior to treatment for GeneXpert. Lowenstein–Jensen media is used for drug sensitivity test.
Questionnaire for data collection was designed. Data on patients undergoing second-line TB treatment (kanamycin, ofloxacin, cycloserine, ethionamide, and capreomycin) are included in this study. Sociodemographic and clinical data were retrospectively collected from Medical Records Department at Kasturba Hospital, Manipal, and the data included the age of the individual, gender and residence of patients, and their employment details, with comorbidity disease status, HIV co-infection status, TB drug resistance types, smoking, alcoholic intake, or tobacco chewing habit of patients, their smear-positive PTB at baseline (PTB+), smear, culture positivity, drug sensitivity test results, chest X-ray for cavitation, histopathological tests, adverse drug reactions (ADRs), drug dosage, previous TB treatment history, treatment duration, and the clinical outcomes. The ADRs such as hepatitis, nephrotoxicity, dermatitis, gastritis, and ototoxicity were included.
Treatment outcomes and definition
Treatment outcomes are assigned based on patient's progress (adhering to treatment and favorable signs of clinical improvement) and bacterial culture results for TB bacteria. In this study, treatment outcomes are recorded as cured, treatment completed, treatment failure (failure due to side effects, or failure due to other causes), died, lost to follow-up (i.e., default), or not evaluated (others causes). The WHO guidelines are followed to classify and define the treatment outcome. The treatment outcomes are defined as follows:
- Cured can be defined as TB confirmed by culture at the beginning of treatment and culture negative in the last month of treatment and on at least one previous occasion. Their two sputum sample cultures should be negative.
- Patients who completed anti-TB dosage for at least 18 months are included under completed treatment.
- Those patients under treatment regimen if died are included in the death category whatever the cause will be.
- Failed outcome of treatment includes those patients who show smear positivity at the 5th month of treatment or whose negative smear again turns positive.
- Successful outcome of treatment includes those patients having the combination of cured and completed treatment.
- Lost to follow-up was defined as treated patients who did not come back to complete chemotherapy and there was no evidence of cure through the sputum result during the fifth month of therapy.
- Default includes those who did not collect the medicines for more than 2 months or more.
- Relapse was defined as a case who reinitiated TB treatment after being designated a cure at treatment completion.
- XDR-TB can be defined as resistance to rifampicin and isoniazid, and additional resistance to ﬂuoroquinolone and any second-line injectable drugs (amikacin, capreomycin and/or kanamycin).
The poor treatment or clinical outcomes comprise situations such as loss of follow-up, TB relapse, failure to complete the treatment regimen, and death.
In this retrospective study, the data analysis was done using Excel and IBM SPSS Statistics for Windows, version 16 (IBM Corp., Armonk, N.Y.,USA). The mean and the standard deviations are used to express quantitative variables whereas the percentage (%) and frequency (n) for qualitative data. Comparison of frequencies will be done by Chi-squared test and Fisher's exact test. Unsuccessful treatment outcomes of DR-TB predictors are determined by using univariate and multivariate binary logistic regression method (entry method). The final independent factors are predicted using this logistic method. Test has statistical significance if P ≤ 0.05.
The study was conducted after prior approval from Institutional Ethics Committee, MAHE, Manipal (IEC: 380/2020). The need for informed consent was waived because this was an observational retrospective study, and patient data were analyzed anonymously.
| Results|| |
The sociodemographic characteristics of TB patients (n = 462) are shown in [Table 1]. A total of 525 TB patients were registered with a diagnosis of drug resistance TB during 2015–2018. Among them, 63 medical records of TB patients were excluded as they were having chronic obstructive pulmonary disease or cancer. Patients with DR-TB and who have not started the treatments were also excluded from the study. The remaining 462 TB patients with >18 years of age (MDR, 117; XDR, 3; non-MDR, 342) were eligible and results were included in the analysis. Majority of the patients were labors (139, 30.1%) and male (330, 71.4%) and with the age group of 25–64 years.
|Table 1: Sociodemographic and clinical characteristics of 462 tuberculosis patients|
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The PTB accounted for 85.1% of the TB cases; 11.7% of the cases had EPTB and the remaining 3.2% cases had both PTB and EPTB. The frequency of unsuccessful treatment outcome was 92.9% (n = 429) and successful outcome was 7.1% (n = 33). There were 68.2% of new and 31.8% retreatment cases of TB. HIV co-infection was found in 2.3% (n = 14) of TB cases, and among them, 64.3% (n = 9) were found in PTB cases. Among the 462 tuberculosis cases, the frequency of multidrug-resistant TB (MDR-TB) was 25% (n = 117), extensively drug-resistant TB was 1% (n = 3), and non-MDR cases were 74% (n = 342). Two cases of XDR were from PTB and one from EPTB. Among the total MDR cases, 87.2% (n = 102) were PTB, 11.1% (n = 13) were EPTB, and 1.7% (n = 2) of cases had both PTB and EPTB. The frequency of comorbidities in TB cases was 86.6% (n = 400), and most of the comorbidities were found in PTB cases (n = 338). The major comorbidities found were diabetes (21.2%), weight loss (12.6%), and anemia (12.6%) [Table 1] and [Table 2].
|Table 2: Frequency of factors among type of tuberculosis (pulmonary tuberculosis, extrapulmonary tuberculosis, and both)|
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Trends of the tuberculosis types
The 4-year trend of all the TB types from the year 2015–2018 is shown in [Figure 1]. Most of the TB cases were reported in the year 2017 (n = 146, 31.6%) and 2016 (n = 142, 30.7%). The number of PTB cases (n = 393) was higher than extrapulmonary cases (n = 54). The rate of PTB cases varied across years steadily decreasing in 2017, whereas ETB cases were increasing in the year 2017.
|Figure 1: Trend of all forms of TB cases (n = 462) from 2015 to 2018. PTB: Pulmonary tuberculosis, EPTB: Extrapulmonary tuberculosis|
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The mean trend of new cases of TB during 2015–2018 was 68.2% (n = 315) and retreatment cases was 31% (n = 143). The trend of new cases of TB was increasing steadily from 33.3% to 81.1% during the year 2015–2018 and the trend of retreated cases was decreasing from 66.7% to 16.7% [Figure 2].
Trend of treatment outcome
The mean TSR of the 4-year TB treatment was 7.1% (n = 33/462). As shown in [Figure 3], the TSR increased steadily from 4.8% in the year 2015 to 9.2% in the year 2016. In the subsequent year 2017, the treatment trend showed variation decreasing to 4.8% and increasing to 8.3% in the year 2018.
|Figure 3: Trends of tuberculosis treatment outcomes (n = 462) from 2015 to 2018|
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Treatment success rate and associated factors
The TSR and its associated predictors are described in [Table 3]. The frequency of successful treatment outcome was less (7.1%, n = 33) comparing to number of unsuccessful outcome (92.9%, n = 429). Multivariable analysis shows the significant increase in the odds of having unsuccessful outcome among the retreatment cases compared to the newly treated cases (adjusted odds ratio [AOR] = 13.12; 95% confidence interval [CI] = 1.050–164.07). Kidney-related comorbidities in TB patients have high association with unsuccessful outcome (AOR = 0.034; 95% CI = 0.003–0.448). The rate of PTB (n = 365, 92.9%) was higher in unsuccessful treatment outcome comparing to EPTB (n = 51, 94.4%) and cases having both PTB and EPTB (n = 13, 86.7%). Both non-MDR and MDR cases were high in unsuccessful outcomes [Table 3]. There was no statistical significant association between gender, age group, weight, occupation, type of TB, and HIV status.
|Table 3: Factors related to unsuccessful treatment outcome among patients with tuberculosis in the bivariate and multivariate logistic regression analysis (n=462)|
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| Discussion|| |
This study highlights the large burden of drug resistance TB. The role of relationship between TB disease pathogenicity and drug resistance in treatment outcomes are not well understood. The present study aims to identify the relationship between different variables to treatment outcome. While the TSR in this study was less (7.1%) and the large number of patients had unfavorable treatment outcomes owing largely to loss to follow-ups and treatment failure. The TSR in this study is less comparing to the target success rate set by the Global Plan to stop TB http://www.stoptb.org/wg/new_diagnostics/and other studies targeting 70%–77%. The poor treatment outcomes are also reported in other countries, and in India by previous studies. The poor treatment outcome of 74.1% and 40% is reported in India. The TSR in this study is less comparing to other previously reported studies: 53% (40%–70%) in 25 countries, 54% in Shanghai, and 48% in South Korea. Majority of the patients were labors (139, 30.1%) followed by farmer (86, 18.6%). The TB incidence characteristics of occupation varied in other studies. Recent study has reported high incidence TB in farmers, unemployed/laid-off staffs, and retired people. Baseline characteristics such as male gender, middle age, labors, EPTB status, retreated TB cases (P = 0.04) and diabetes as the comorbidity are found more associated with unsuccessful treatment outcomes. The factors associated with unsuccessful treatment outcomes are similar to previous studies. A systematic review of 31 treatment programs in 21 countries reported that male gender was associated with poor treatment outcomes in MDR-TB patients. Similar finding is also reported in India. The PTB rate was also higher in male gender. This may be due to increased rates of smoking and alcohol consumption which lead to poor TB treatment outcome.,,
Majority of the patients were male (71.4%, n = 330) and in the age group of 25–64 years. In a previous study, age <40 years and BMI (>18.5) were positively related to favorable treatment outcome. This could be absence of comorbid conditions, lack of major physiologic changes, better nutrition, and immunity in young patients., Tobacco chewing and alcohol consumption were also reported to be negative predictors of successful treatment outcome which lead to suppression of immune mechanisms by nicotine and altered drug metabolisms. This may lead to altered serum levels of drugs causing ADR, drug interruptions, discontinuation, and poor treatment outcome.
In this study, the poor treatment outcome was higher (92.9%, n=429). The death rate was less than 1% and loss to follow-up case was 3.6%. Among the poor treatment outcomes , 64% of recurrent and 4.1% of relapse cases were seen. The rate of death, loss to follow-up, and treatment failure were found different from other studies.,,,, One reason for this variation could be the difference in the burden of HIV co-infection, and it is found to be a significant factor associated with unsuccessful treatment outcome., However, in our study, HIV-positive TB case was less (2.3%). Similarly, a recent study has reported 2.95% of HIV co-infection. In addition, HIV co-infection was not found significant with unsuccessful treatment outcome.
Even though the unfavorable treatment outcome was more, the frequency of MDR was lesser than non-MDR cases. In the present study, only 3.3% of MDR cases and 8.5% of non-MDR patients showed successful treatment outcome. In this study, frequency of new TB cases was more than the repeat cases among unsuccessful treatment outcome. It is known that previous TB history is one of the associated factors for ill health of DR-TB patients., The association of high proportion of MDR-TB and repeat TB cases may be a factor for increased unsuccessful treatment outcome of this study.
The major comorbidities found were diabetes (21.2%), weight loss (12.6%), and anemia (12.6%) followed by drug-induced complications, hypothyroidism, and kidney-related problems. Among the unfavorable outcome group, all these comorbidities were present in higher frequency (80%–98%). Multiple comorbidities are reported in TB. Among the successful treatment outcome group, the common comorbidities found were kidney-related problems (20%) and hypothyroidism (16.7%). Anemia and diabetes were reported as associated factors of poor treatment outcome in previous studies. A recent study has reported the difference in sputum microbiota diversity in RR and MDR-TB patients with or without diabetes mellitus as comorbid. In addition, sputum microbiome has a major role in pathogenesis and drug resistance in PTB., Anemia is associated with delayed sputum smear conversion among sputum-positive TB patients, advanced disease, inflammatory response, and mortality.,,,, Anemia may be a factor for ill health condition and advanced disease.
Even though the mean TSR of the 4-year TB treatment was less in this study, the TSR steadily increased during 2015–2016. In the subsequent year 2017, the treatment trend showed variation where TSR decreased and again increased in the year 2018. This study emphasizes the need for improvement in TB surveillance, treatment, more stringent follow-up, monitoring, and patient education to ensure complete and successful treatment.
As it is a retrospective study design, follow-up details of all the patients were not available.
| Conclusion|| |
In this study, we describe various factors associated with successful and unsuccessful treatment outcomes. Our study reports many clinically important comorbidities among PTB and EPTB patients. The mean TSR of the TB patients in this study is not satisfactory comparing with the target set by End TB Strategy. The increased unfavorable treatment outcome emphasizes the need of strategies to reach the successful treatment outcome targets.
Ethical clearance was obtained prior to the study. IEC number: 380/2020 (date: June 10, 2020).
The authors thank the Manipal Academy of Higher Education for providing the support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interests.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]