|Year : 2019 | Volume
| Issue : 5 | Page : 384-392
Treatment outcome of multidrug-resistant tuberculosis with modified DOTS-plus strategy: A 2 years' experience
Abhijeet Singh1, Rajendra Prasad1, Ram Awadh Singh Kushwaha1, Rahul Srivastava1, Belur Hosmane Giridhar1, Viswesvaran Balasubramanian2, Amita Jain3
1 Department of Pulmonary Medicine, King George Medical College, Lucknow, Uttar Pradesh, India
2 Department of Pulmonary Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
3 Department of Microbiology, King George Medical College, Lucknow, Uttar Pradesh, India
|Date of Web Publication||23-Aug-2019|
Dr. Rajendra Prasad
Department and Pulmonary Medicine, King George Medical College, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Multidrug-resistant tuberculosis (MDR-TB) is a global health problem with notoriously difficult and challenging treatment. This study determined treatment outcome in patients of MDR-TB with modified DOTS-Plus strategy. Methods: Ninety-eight consecutive MDR-TB patients treated with standardized regimen according to modified DOTS-Plus strategy aligned to the existing national DOTS-Plus guidelines with relevant modifications proposed by Chennai consensus were analyzed prospectively. Treatment included monthly follow-up with clinical, radiological, and bacteriological assessment (sputum smear advised monthly till conversion then quarterly; culture for Mycobacterium tuberculosis at 0, 4, 6, 12, 18, and 24 months), ensuring adherence, intense health education, and monitoring of adverse events (AEs). Patients' outcome was considered as cure when at least two of the last three cultures (all three or last two) were negative and as failure when the same were positive. Results: Favorable and unfavorable outcomes in this cohort were reported to be 71/98 (72.4%) and 27/98 (27.6%) (failure – 10 [10.2%], default – 7 [7.1%], and expiry – 10 [10.2%]), respectively. Sputum smear and culture conversion rate were 75/81 (92.5%) and 71/81 (87.7%), respectively. Major AEs were experienced in only 17.4% of patients. Conclusions: MDR-TB can be cured successfully with modified DOTS-Plus strategy and requires much effort from both the patients and health-care workers. It can be an alternative model for treating MDR-TB patients in private sector.
Keywords: Drug resistant, individualized, programmatic management of multidrug-resistant tuberculosis, regimen, standardized, tuberculosis
|How to cite this article:|
Singh A, Prasad R, Kushwaha RA, Srivastava R, Giridhar BH, Balasubramanian V, Jain A. Treatment outcome of multidrug-resistant tuberculosis with modified DOTS-plus strategy: A 2 years' experience. Lung India 2019;36:384-92
|How to cite this URL:|
Singh A, Prasad R, Kushwaha RA, Srivastava R, Giridhar BH, Balasubramanian V, Jain A. Treatment outcome of multidrug-resistant tuberculosis with modified DOTS-plus strategy: A 2 years' experience. Lung India [serial online] 2019 [cited 2020 Jan 21];36:384-92. Available from: http://www.lungindia.com/text.asp?2019/36/5/384/265180
| Introduction|| |
Multidrug-resistant tuberculosis (MDR-TB) has become a major public health problem worldwide and considered to be an obstacle for effective global TB control. The management of patients with MDR-TB in India is being undertaken by the Revised National Tuberculosis Programme (RNTCP) under the Programmatic Management of Multidrug-Resistant Tuberculosis (PMDT), formerly known as DOTS-Plus. It is a comprehensive management strategy for MDR-TB patients by providing a standardized treatment regimen based on common drug sensitivity testing (DST) profile of the prevalent MDR-TB strains. DOTS-Plus has been implemented phase wise in India since 2006, with complete geographical coverage achieved in 2013. Out of 130,000 MDR-TB cases emerging annually in India (22% of global burden), 79,000 were among the notified cases of TB in 2015. Among 79,000 MDR-TB cases, only 36% were diagnosed with suboptimal treatment success rate of 46%. Nearly 64% of cases remained uncovered leading to amplification of resistance in the community. Therefore, these large number of uncovered MDR-TB patients will have to consult private health sector for treatment. Another issue is that the standardized approach provided by DOTS-Plus programs in resource-limited settings has also confronted significant difficulties in the enrollment, diagnosis, and management of MDR-TB patients.,,, Retention and adherence to therapy remains a major challenge in the treatment of MDR-TB patients as treatment course is expensive, is consisting of more toxic second-line drugs (SLDs), and is lengthy with frequent follow-up cultures. An innovative method based on the local availability of resources is required in order to be devised to address these unmet needs. A modified approach was introduced in order to support the existing national DOTS-Plus program by overcoming these challenges that are encountered in the management of MDR-TB cases., Therefore, the present study has been conducted to determine the treatment outcome in patients of MDR-TB with an alternative approach known as modified DOTS-Plus strategy at Lucknow, India.
| Methods|| |
Study design and setting
It was a prospective cohort study performed among 132 consecutive patients of pulmonary TB referred from Lucknow and other districts of Uttar Pradesh (UP), India, between June 2009 and February 2010 to the Department of Pulmonary Medicine having an established DOTS center and the Department of Microbiology, King George Medical University, Lucknow, India, which is a WHO-recommended Intermediate Reference Laboratory certified by the RNTCP of India.
Inclusion and exclusion criteria
All patients provided informed consent before participating in the study. These patients were cases of pulmonary TB with proven culture positive for Mycobacterium tuberculosis and resistant to at least isoniazid (INH) and rifampin (RIF) and having age >18 years. Patients were excluded from the study if they had (1) non-MDR-TB pattern according to drug susceptibility testing (DST) results, (2) taken SLDs >1 month before confirmation of diagnosis, (3) pregnancy, (4) age <18 years, and (5) concurrent major medical or psychiatric illnesses at baseline. These exclusions were according to the RNTCP guidelines prevailing at the time of study.
Pretreatment investigations included sputum smear for acid-fast bacilli (Ziehl–Neelsen staining), culture for M. tuberculosis (conventional method using Löwenstein–Jensen medium) and DST (proportion method), complete hemogram, chest X-ray, renal and liver function tests, and thyroid profile. All patients were routinely tested for human immunodeficiency virus (HIV) infection before the initiation of treatment. The BACTEC method (Becton Dickinson, Sparks, MD, USA) for culture and DST for SLDs were also used whenever possible. DST for SLDs was performed when subsequent cultures after 6 months of treatment remained positive. Care was taken to interpret the culture results cautiously along with clinicoradiological data although our laboratory setup underwent regular surveillance for external quality assurance. The minimum inhibitory concentration of the first-line drugs and SLDs used was as follows: streptomycin 16 μg/ml, INH 0.5 μg/ml, RIF 128 μg/ml, ethambutol 8 μg/ml, pyrazinamide (PZA) 50 μg/ml, kanamycin (KM) 30 μg/ml, and levofloxacin or ofloxacin (OFX) 2 μg/ml.
Management protocol according to the modified DOTS-Plus strategy
A committee consisting of clinicians (6), laboratory technicians (2), domiciliary DOT-providers (3), TB health workers (2), health educator (1), and microbiologists (2) was constituted at Lucknow center. One domiciliary DOT-provider from each DOTS center of 18 districts (Kanpur, Basti, Gorakhpur, Allahabad, Faizabad, and Varanasi divisions) was selected and also included in the committee. Operational guidelines as framed by the modified DOTS-Plus strategy were implemented in this study. Modified DOTS-Plus strategy is essentially DOTS-Plus Protocol of the RNTCP based on the WHO guidelines prevailing at that time with relevant modifications according to the Chennai consensus.,, The protocol of the modified DOTS-Plus strategy is described in [Table 1]. All members of the committee underwent 1 month of training regarding implementation of this strategy. Emphasis was given on training of all domiciliary DOT-providers and TB health workers in order to ensure adherence to treatment as well as to access adverse events (AEs) associated with antitubercular therapy. Sample collection of sputum for smear examination and culture inoculation were done daily on an outpatient department basis (excluding Sundays and other holidays). Prior intimation was given to patients for sputum sample deposition at a specified date in order to avoid inconvenience. Regular supply of consumable and nonconsumable staining and culture material was ensured at our established DOTS center. Regular supply of quality-assured drugs was also ensured in collaboration with the Central Tuberculosis Division Ministry of Health and Family Welfare, Government of India, and Uttar Pradesh State Tuberculosis Association. Care was taken to safeguard standardized quality of health care for patients. A subcommittee comprising two clinicians, one microbiologist, and one laboratory technician was framed and assigned to take care of this issue. This subcommittee continued to follow up patients with the prevailing DOTS-Plus guidelines of the RNTCP, particularly in terms of the frequency of culture monitoring, treatment outcomes, as well as monitoring of any AEs. This supervision was performed in order to detect any discrepancy in management with adopted the modified DOTS-Plus strategy as compared to the standard RNTCP guidelines.
|Table 1: Characteristic features of the modified Directly Observed Treatment Short-Course-Plus strategy|
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Data were single entered on Microsoft Excel 2007 sheet, and the accuracy of the entry was verified against the original paper forms. The data were further checked for any errors and then analyzed using descriptive statistics. Absolute and relative frequency counts and measures of central tendency (mean) were calculated. Measure of dispersion such as standard deviation was also calculated. Chi-square test, Fisher's exact test, Student's t-test, and Mann–Whitney U-test were used for univariate analyses. Cumulative survival was compared by using the Kaplan–Meier method with the log-rank test. P < 0.05 was considered statistically significant. All statistical analyses were performed using Epi Info software version 3.5.3 (Centre for Disease Control and Prevention; Atlanta; Georgia; USA).
The ethical committee of King George Medical University approved the present study.
| Results|| |
Out of 132 patients, a total of 98 patients proved to be cases of MDR-TB by culture were enrolled for treatment. All the patients were categorized under re-treatment cases. Thirty-four patients were excluded from the study (non-MDR susceptibility – 13, >1 month treatment of SLDs before diagnosis – 8, migrated/not traced –3, unwillingness for treatment – 2, major medical/psychiatric illnesses at baseline – 6, and expiry before the initiation of treatment – 2). All patients were HIV seronegative after testing. Of them, 68 (69.4%) were males and 30 (30.6%) were females. The mean age and weight were 29.3 ± 9.3 years and 42.9 ± 9.1 kg, respectively. The clinical and demographic profile of the patients is illustrated in [Table 2]. Fifty-six of 98 (57.2%) patients were from areas in and around Lucknow, whereas 42/98 (42.8%) cases were referred from other districts as the DOTS-Plus program was not implemented in UP. The mean duration of total illness was 4.8 ± 3.6 years. Radiologically, 5 (5.1%) patients had unilateral disease, whereas 93 (94.9%) had bilateral disease. The average duration of anti-TB treatment received by the cohort as a whole prior to referral was 26 ± 12.3 months. The cohort was resistant to a mean of 3.17 ± 1.06 drugs. The intensive phase (IP) was extended to 9 months in 30 (30.6%) patients with proven culture positivity at the 4th month. Mean smear and culture conversion time were 3.4 ± 2.1 months (1–11) and 4.6 ± 2.5 months (4–12), respectively. Sputum smear and culture conversion rates were 75/81 (92.5%) and 71/81 (87.7%), respectively, with only ten (10.2%) patients remained culture positive as shown in [Table 3]. Seven patients were resistant to SLDs during the course of treatment among which four were either resistant to KM or OFX in addition to MDR-TB, while the remaining three met the revised WHO diagnosis of extensively drug-resistant (XDR)-TB. These patients were treated either with individualized or standardized regimens for XDR-TB (CAT V under the RNTCP). The clinical characteristics of patients showing unfavorable outcome after treatment with MDR-TB therapy are described in [online Supplementary Table S1 [Additional file 1]]. A wide range of AEs was observed during the treatment, some requiring discontinuation of the offending drug as shown in [Table 4] and [Table 5]. Seventeen (17.4%) patients had major AE requiring drug substitution or permanent discontinuation of drugs. Seven (7.1%) patients required admission to hospital for the occurrence of AE. None of the patients had to discontinue their complete regimen permanently due to major AE. The offending drugs responsible for these major AE were injectable KM (deafness/renal failure), CS (psychosis), ETO (gastrointestinal tolerance), and PZA (arthralgia/hepatitis). No mortality occurred due to major AE in our cohort. Sixteen of thirty (53.3%) female patients were of childbearing age. None of these female patients included in the study conceived during treatment as they were counseled either to avoid intercourse or to use contraception (barrier methods – 8, intrauterine device – 3). Of the total 98 patients included in this study, 81 (82.7%) completed the treatment, with 71 (74.5%) declared successfully cured and 10 (10.2%) failed, whereas 7 (7.1%) defaulted and 10 (10.2%) died at the completion of treatment. The reason behind default in all cases was migration due to social reasons. The causes for mortality among the ten patients were found to be acute respiratory failure due to extensive disease (4), accidental trauma (2), viral hemorrhagic fever with multiorgan failure (2), acute coronary syndrome (1), and complicated malaria (1). No significant discrepancy was observed in treatment outcome with reduced frequency of monitoring with culture under modified strategy as reported by the subcommittee in [online Supplementary Table S2 [Additional file 2]]. [Figure 1] shows Kaplan–Meier plot of the probability of survival among MDR-TB patients from the time of diagnosis. Overall median survival of 98 MDR-TB patients was 26.5 months (95% confidence interval [CI]: 25.6–27.4), with 27 months (95% CI: 25.9–28.1) and 26 months (95% CI: 25.2–26.8) for males and females, respectively. No significant difference in survival rate was observed based on gender (P = 0.37, log–rank – Mantel–Cox test). The association of clinical and demographic variables with treatment outcome for MDR-TB patients is described in [Table 6]. Patients were more likely to have poor outcomes if they were drug addicts (odds ratio [OR] 0.11; 95% CI: 0.01-0.77; P = 0.03), had a previous history of TB episodes >2 (OR 0.14; 95% CI: 0.11-0.39; P < 0.001), and had resistance to both KM and OFX (OR 0.15; 95% CI: 0.01-0.98; P = 0.05). All patients with successful outcome were observed for 1 year after completion of treatment with no relapse.
|Table 2: Clinical and demographic characteristics of the cohort of 98 patients treated with multidrug-resistant tuberculosis therapy|
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|Table 3: Bacteriological response of 98 patients treated with multidrug-resistant tuberculosis therapy over 2 years|
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|Table 4: Frequency of adverse events among 98 patients receiving multidrug-resistant tuberculosis treatment|
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|Table 5: Frequency of major adverse events and suspected agents among the 98 patients receiving multidrug-resistant tuberculosis treatment|
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|Figure 1: (a) Kaplan–Meier plot of the probability of survival among 98 multidrug-resistant tuberculosis patients from the time of diagnosis. (b) Probability of survival based on gender (P = 0.37, log-rank – Mantel–Cox test)|
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|Table 6: Summary of association of clinical and demographic variables with treatment outcome for multidrug-resistant tuberculosis patients|
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| Discussion|| |
India constitutes a considerable burden of MDR-TB patients. National programs in developed countries with adequate laboratory facilities may monitor treatment outcome frequently with cultures without constraints. However, in a resource-poor country like India, performing frequent cultures is cumbersome, considering the long waiting period for the results, lack of skilled workforce, and poor quality control of laboratories both in the public and private sectors. A study reported major constraints influencing the outcome such as difficulty in arranging daily DOT for 2 years particularly at peripheral centers, ensuring compliance especially on Sunday and other holidays, lack of access to specialized laboratory facilities, and managing major AEs in field conditions. Taking note of this huge discrepancy, the Chennai consensus was framed in order to overcome these limitations. Meanwhile, laboratory services should be strengthened for adequate and timely diagnosis of MDR-TB, and DOTS-Plus should be scaled up as per the target set by the Global Plan to Stop TB 2011–2015.
The present study has reported successful treatment outcome in 71 (72.5%) and unsuccessful treatment outcomes in 27 (27.5%) patients (failure – 10 [10.2%], treatment default – 7 [7.1%], and death – 10 [10.2%]). Several studies including systematic reviews and meta-analyses revealed variable results, with treatment success rate for MDR-TB patients worldwide ranging from 21% to 83% with considerable unsuccessful treatment outcomes ranging from 29% to 39% (failure or relapse: 6% to 7.6%, treatment default: 12% to 15%, and death: 11% to 13%).,,,,, The treatment outcome remains variable even among different regions of India as shown in [online Supplementary Table S3 [Additional file 3]]. This may be attributed to heterogeneity in the demographic profile of cohorts, frequency of associated comorbid illnesses, settings, methodology, regimens, and definition of outcomes. The success rate was high in our cohort with lower default rate indicating that the modified DOTS-Plus strategy might be effective in improving success outcomes as emphasis was given on patient-centric care, timely management of AE related to SLDs, intense health education, counseling, and psychosocial support apart from reducing follow-up cultures.
In our study, the culture conversion rate was 87.7%, which was in accordance with previous studies reporting conversion rates ranging from 74% to 92%,,,,,,,,,,, suggesting that adoption of the modified DOTS-Plus strategy might be a cost-effective strategy, particularly in high MDR-burden resource-limited setting like India. Reduction in culture examinations in the continuation phase can also help in diversion of available resources in further expansion of the existing program to cater to unmet populations.
Certain characteristics were responsible for poor treatment outcome in this study such as drug addiction, previous history of TB episodes >2, and resistance to KM as well as OFX, as reported in other studies.,,,,,,,,, Many studies with diversity in demographic profile, setting, and methodology have reported other characteristics such as alcoholism, diabetes, extensive cavitary lesions, and HIV seropositivity with poor outcome, although not observed in our study due to limited sample size and no HIV seropositivity in our cohort.
Overall, 119 AEs were reported in 46 (46.9%) patients. The most commonly grouped AEs were gastrointestinal followed by ototoxicity and arthralgia as reported similarly in other studies.,,,,, Major AEs were reported in 17.4% of patients, which is lower in comparison to other studies.,,,,, Among major AEs, the most common was deafness induced by KM and psychosis by CS. This lower incidence may be attributed to the adopted methodology for active surveillance and systematic periodic follow-up.
A major issue of concern still remains that 21/132 (15.9%) patients were excluded from our study as 8 (6.1%) were exposed to SLDs >1 month and 13 (9.8%) showed non-MDR resistance patterns. These subset of patients could lead to amplification of drug resistance in households and community if left untreated. There could also be a high probability of either suboptimal treatment outcome with standardized regimen or baseline resistance to SLDs at initiation of treatment responsible for failure detected during the course of treatment. Appropriate individualized regimens based on DST pattern would be preferred for treating these subset of patients. Several studies from urban sector reported remarkable treatment success rate with individualized regimens ranging from 48.4% to 68%.,,,,, A systematic review and meta-analysis reported that individualized regimens had better outcome (successful rate – 67.2%; unsuccessful rate – 30.8%) than standardized regimens (successful rate – 56.9%; unsuccessful rate – 43%) as prescribed under the DOTS-Plus programs. However, treatment with individualized regimens remains challenging in resource-limited settings requiring support of quality-assured laboratory facilities and expertise in interpretation of results with prescription of appropriate regimens.
There is expanding evidence over the last decade regarding the management of MDR-TB patients under national PMDT program. Additional SLD's resistance even at baseline, created by irrational use of drugs especially in private sector, has significantly increased and has become a major issue.,,, Majority of TB patients seek consultation from private sector, but the quality of care remains suboptimal with undernotification of cases, wide variations in knowledge, poor adherence to guidelines, and misuse of SLDs leading to increase in drug resistance.,,, The introduction of genotypic diagnostic tests (GeneXpert, line probe assays) providing rapid diagnosis and individualized regimens fortified with newer drugs (bedaquiline and delamanid) has created revolution in the management of DR-TB patients. The recently released national PMDT guidelines focus on the active surveillance of disease and AE, re-classification of drugs, individualized regimens according to the most recent pattern of DST, patient-centric approach, universal DST, and engagement of private sector.
Current national guidelines primarily rely on culture reports for treatment regimen optimization, i.e., shift from IP to continuation phase (CP) and decision to define the outcome of treatment. Monitoring with follow-up cultures entails time, travel, and work loss costs for the patient and because culture result by the conventional method is not available before a lag period of approximately 6–8 weeks, there is a delay in decision-making by health-care professionals. It is observed that culture conversion which reflects the viability of tubercle bacilli is more sensitive and is considered necessary to monitor progress in MDR-TB patients. There was no significant difference between smear conversion rate and culture conversion rate at 4 months (69.2% vs. 67.1%; 95% CI:-11.3 − 15.4; P = 0.76), 6 months (88.9% vs. 83.3%; 95% CI:-4.7 − 15.9; P = 0.28), and 12 months (93.1% vs. 89.7%; 95% CI:-5.4 − 12.4; P = 0.43). The trend of diagnostic accuracy of smear examination with reference to culture as gold standard during the course of treatment is described in [online Supplementary Table S4 [Additional file 4]]. This supports findings from a previous study showing the potential role of the smear conversion rate as a surrogate of culture conversion, especially in resource-limited high-burden countries like India as early decision regarding transition from IP to CP can be made resulting in reduction in cost of drugs to health system as well as patients, duration of hospitalization, and AEs related to drugs. However, findings of smear examination need to be interpreted cautiously as it has less sensitivity than culture and does not differentiate between live and dead bacilli or other species such as atypical mycobacterial species leading to false positives. Reducing follow-up cultures might delay the confirmation of bacteriological conversion and could delay the diagnosis of possible treatment failure before conversion. Therefore, these findings need to be confirmed with more studies involving larger number of samples. Our study has adopted modified DOTS strategy and reported satisfactory treatment outcome of MDR-TB patients at that point of time when the national DOTS-Plus program was in expansion phase and genotypic tests were to be included for diagnosis. However, the study was hospital based involving small number of patients. Further community-based studies are required to validate these findings.
| Conclusion|| |
There is no doubt that the current PMDT program has expanded its services throughout the nation and is rigorously providing every effort to manage more and more DR-TB cases effectively by scaling up laboratory facilities with genotypic tests and appropriate regimens including newer drugs. Despite this effort, an enormous burden of DR-TB cases in high-burden countries like India, especially in private sector, still remains uncovered. This can be considered to be a great hurdle in achieving the ambitious goal of elimination of TB by 2025. The modified DOTS-Plus strategy adopted in our study can support national programs in the reduction of burden of DR-TB cases in resource-limited settings, especially in private sector. It should be made flexible as well as less stringent according to local needs but should be kept aligned to the existing national PMDT guidelines. A systematic approach is required for curbing down the epidemic of DR-TB cases by implementing cost-effective and sustainable interventions in the near future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]