Threefold Increase in the Number of Drug Resistant TB Cases after Introduction of Universal Drug Susceptibility Testing: Experiences from Two South India Districts

Background: In India, tuberculosis (TB) is a major public health problem, and the advent of drug resistance TB (DR-TB) has worsened the situation. The Revised National TB Control Programme (RNTCP) has introduced universal drug susceptibility testing (UDST) for all diagnosed TB cases in 2018. We conducted this study to know the advantage of implementing UDST when compared to selective testing existent in 2017 on key diagnostic cascade parameters and to identify the challenges in the implementation of UDST. Methods: The study was conducted in two districts of Karnataka, India during January 2017-December 2018. The quantitative part consisted of before-and-after design and the qualitative part consisted of descriptive design. Results: In 2017 (during selective testing/“before” period) out of the 2440 TB patients, 80 (3%) were diagnosed with Isoniazid and Rifampicin resistance patients; in contrast in 2018 (during UDST/“after” period) of the 5129 TB patients 258 (5%) were diagnosed with Isoniazid and Rifampicin resistance. However, the proportion of eligible patients tested for rifampicin resistance during the “after” period was 60% when compared to 100% during the “before” period and median turnaround time for testing was also longer during the “after” period when compared to the “before” period (32.5 days vs 27.5 days). How to cite this paper: Krishnamurthy, S.K.G., Nagaraja, S.B., Anand, T., Sagili, K.D., Gowda, C., Shailaja, Poojar, B. and Satyanarayana, S. (2020) Threefold Increase in the Number of Drug Resistant TB Cases after Introduction of Universal Drug Susceptibility Testing: Experiences from Two South India Districts. Journal of Tuberculosis Research, 8, 42-52. https://doi.org/10.4236/jtr.2020.82005 Received: March 12, 2020 Accepted: May 24, 2020 Published: May 27, 2020 Copyright © 2020 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access S. K. G. Krishnamurthy et al. DOI: 10.4236/jtr.2020.82005 43 Journal of Tuberculosis Research Major reasons for these two gaps were found to be difficulties in collecting sputum specimens and transportation. Conclusion: The rollout of UDST has led to a three-fold increase in a number of DR-TB cases detected in the region. There is a need for the programme to increase the proportion tested for DST by increasing the laboratory capacity and address the challenges in sputum collection and transportation.


Introduction
Globally, tuberculosis (TB) is a major public health problem and India accounts for more than 27% of the world's TB burden [1]. Worldwide, the estimated proportion of drug-resistant TB among new and retreatment cases is 4% and 19% respectively. And, there are an estimated 0.14 million drug-resistant tuberculosis (DR-TB) cases in India accounting for one-fourth of global TB burden [2].
To tackle the problem of drug resistance in TB, the Revised National TB Control Programme (RNTCP) of India initiated the programmatic management of drug-resistant TB (PMDT) in 2007. Initially, the programme was dependent on solid culture for drug susceptibility testing (DST), and there were a limited number of RNTCP accredited laboratories to perform the tests. Gradually, the programme expanded its horizon in a phased manner and included the line probe assay (LPA), liquid culture and cartridge-based nucleic acid amplification (CBNAAT or Xpert TB MTB/Rif) to detect DR-TB patients. By the end of 2018, the country had 74 Culture and drug susceptibility testing (CDST) laboratories, 106 LPA sites and 1135 CBNAAT sites across the country [3]. In view of identifying and diagnosing DR-TB patients the PMDT had laid down three different selective testing criteria namely A, B and C to prioritize presumptive DR-TB cases, keeping in consideration the availability of certified laboratories, necessary logistics and human resources [4].
The state of Karnataka in south India with 60 million population and 31 administrative districts was implementing criteria C/selective testing till 2017 [5].
The presumptive DR-TB cases in criteria C included: 1) any sputum smear positive follow-up of new cases at the end of intensive phase, 2) all re-treated TB cases (sputum smear positive and negative) at the time of diagnosis, 3) all the contacts or presumptive TB cases of family to a known drug-resistant TB case and 4) All HIV-TB co-infected patients. During 2017, the state had 4 CDST laboratories, 4 LPA laboratories and 54 CB-NAAT sites delivering the services [3].
In January 2018, the state of Karnataka rolled out the policy of "universal drug susceptibility testing" (UDST) in which all the sputum smear-positive TB pa-  The intent of the initiative was to detect the   drug-resistant TB patients early and reduce loss to follow-up and deaths. Implementation of the policy was a challenge to the programme staff and managers as it involved the transportation of sputum from designated microscopy centers in the field to the drug susceptibility testing (DST) sites which were located at far-away places.
We conducted this study in two districts of Karnataka, India to know the advantage of implementing UDST in 2018 ("after" period) when compared to the selective testing existent during 2017 ("before" period). We compared the key diagnostic cascade parameters that include the number (proportion) of eligible presumptive DR-TB cases, number (proportion) of eligible presumptive DR-TB tested, number (proportion) of DR-TB cases detected and drug resistance patterns, loss to follow-up and deaths and the median time taken for a presumptive TB case for DR-TB treatment initiation. We also explored the challenges in implementing UDST as perceived by the health care providers at these districts.

Methods
The quantitative part consisted of before-and-after design and the qualitative part consisted of descriptive design.

Settings
The study was conducted at two districts of Karnataka, namely Tumkur (2.     Diagnostic cascade under Universal drug susceptibility testing (after) All the presumptive TB cases are subjected to sputum smear examination. If found positive, the sputum is sent to CBNAAT site for testing.
1) If the sputum is found to be sensitive to rifampicin (R), the sputum is subjected to first line LPA: a) If found to be sensitive to Isoniazid (H), the patient is initiated on first line anti-TB treatment; b) If found to be resistant to Isoniazid, the patient is initiated on Isoniazid mono resistant TB.
2) If the sputum is found to be resistant to rifampicin, the sputum is subjected

Study Population, Sources of Data and Data Collection
The quantitative data on presumptive DR-TB cases were obtained from the la- The KIIs were conducted at district TB centre in local vernacular language (Kannada) at a time and place convenient to them after taking prior appointment.
Each interview lasted for 8 -10 minutes, and all the participants were purposively selected.

Study Population, Sources of Data and Data Collection
The quantitative data on presumptive DR-TB cases were obtained from the la-

Data Analysis
The quantitative variables were double entered and validated using EpiData data entry software version 3.

Ethics Approval
Ethics approval was obtained from the Institutional Ethics Committee of the

Quantitative
The annual presumptive TB case load were 68735 and 71438 for the year 2017 and 2018. The comparison of the cascade of patients under selective testing (before) and UDST (after) is shown in Table 1. The sputum positivity rate among both the districts was found to be 10.7% both under selective testing and UDST.
The proportion of death and loss to follow up before and during the first line anti-TB treatment were 16% and 12% respectively for selective testing and UDST. in Table 2. Majority of the DR-TB patients were males in the age group of 26 to 55; there was no statistically significant difference between the two groups. The median time required for a presumptive TB case to be initiated on DR-TB treatment under selective testing (before) was 27.5 days (IQR: 18 -38.5) and 32.5 days (IQR: 9 -59) under UDST (after).

Qualitative
The challenges perceived by the health care providers in implementation of UDST were broadly categorized as: 1) collection and transportation of samples and 2) costs for transportation.

Collection and Transportation of Sputum Samples
The health care providers opined that tracing the presumptive TB case who is found to be smear positive TB for drug sensitive TB is a difficult task. The patient either comes to collect the sputum results next day or the health care provider informs the paramedical staff of the area through WhatsApp (social media mobile application freely available) or phone call. The provider also has to visit the house of the patient to collect the sample and send it to DMC. The cumulatively collected such sputum containers are transported to the DST site once in two days either by a courier or a human carrier. The time taken to transport sample from field to CBNAAT site and then to LPA testing at DST laboratory is 7 -10 days. Many a times the sputum samples are inappropriately packed and leads to spillage. Hence, the providers are reluctant to transport the samples.

Costs of transportation
The providers incur the costs of at least INR 20 -50 to visit the patients for collection of sputum which is usually not reimbursed by the peripheral health centers; and to avoid this cost, the providers insist on patients to provide the sputum samples at DMC. This enforcement on patients indirectly affects the daily earnings of the patients.

Discussion
It is the first study conducted in the country to know the benefits of UDST implementation. The study findings suggest that the roll out of UDST has led to three-fold increase in number of DR-TB cases detected in the region. The im- and UDST (after) in India. Third, the median turnaround time from being a presumptive TB case to initiation DR-TB treatment was 27.5 days in selective testing (before) and 32.5 days in UDST (after). A systematic review suggests that the time to treatment initiation for second line TB treatment is 38 days (95% CI 27 -49) for genotypic susceptibility testing [12]. The reason for longer duration in UDST could be related to: 1) delay in collection of sputum from patient site and sending it to DMC; 2) flooding of sputum samples from peripheries to CBNAAT site at the district; 3) overburdening of DST sites by influx of samples from the catchment area of zonal districts. The programme should consider destressing the laboratories by placing CBNAAT machines at sub-district levels and providing LPA sites at district level.
Fourth, there remains a challenge of sputum transportation at sub-district level. Innovative strategies need to be developed and the non-governmental organizations are to be encouraged to participate by providing attractive incentives. Mechanisms have to be developed to re-imburse the cost incurred for sputum transportation by the health providers at the level of peripheral health centers.
The study has following strengths and limitations. The strengths are: 1) the study is conducted under field conditions and hence reflects the ground reality; 2) the data is considered verified as the quantitative data was double-entered and validated for discrepancies; 3) the qualitative component of the study has helped in identifying the challenges pertaining to diagnosis. The limitations are: 1) there were few missing and incomplete data which is considered to be normal for quantitative studies under programmatic conditions; 2) the interviewer for the key informants of Belgaum district was the district TB officer from Tumkur district and there could be a possibility of introducing bias among the interviewees; 3) the findings of the study is contextual to this situation and should be generalized to other regions with caution.
To conclude, the rollout of UDST has led to a three-fold increase in a number of DR-TB cases detected in the region. There is a need for the programme to increase the proportion tested for DST by increasing the laboratory capacity and address the challenges in sputum collection and transportation.