Review Article

Management and control of multidrug-resistant tuberculosis (MDR-TB): Addressing policy needs for India Sachin R. Atrea,b,* and Megan B. Murraya,* a Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA 02115, USA b Maharashtra Association of Anthropological Sciences, Centre for Health Research and Development (MAAS-CHRD), Pune, and Savitribai Phule Pune University, Pune, 411007, India

*Corresponding authors. E-mails: [email protected]; [email protected]

Abstract

Multidrug-resistant tuberculosis (MDR-TB) challenges TB control efforts because of delays in diagnosis plus its long-term treatment which has toxic effects. Of TB high-incidence countries, India carries the highest burden of MDR-TB cases. We describe policy issues in India concerning MDR-TB diagnosis and management in a careful review of the literature including a systematic review of studies on the prevalence of MDR-TB. Of 995 articles published during 2001–2016 and retrieved from the PubMed, only 20 provided data on the population prevalence of MDR-TB. We further reviewed and describe diagnostic criteria and treatment algorithms in use and endorsed by the Revised National TB Control Program of India. We discuss problems encountered in treating MDR-TB patients with standardized regimens. Finally, we provide realistic suggestions for policymakers and program planners to improve the management and control of MDR-TB in India. Journal of Public Health Policy advance online publication, 6 May 2016; doi:10.1057/jphp.2016.14 Keywords: MDR-TB; policy; India; pathways to care; primary; acquired

Introduction Multidrug-resistant tuberculosis (MDR-TB) threatens to undermine global TB control efforts. MDR-TB refers to tuberculosis caused by bacilli resistant to at least two of the most effective first-line anti-TB drugs—isoniazid, and rifampicin. It requires 18–24 months of treatment compared to 6 months for drug-sensitive TB. The second-line drugs used

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in its treatment are more expensive, toxic, and less effective than the standard short course chemotherapy of first-line anti-TB drugs.1 MDR-TB is of particular concern for India, that accounted for 27 per cent of global TB notifications in 2014 and was estimated to have the highest number of MDR-TB cases in the world.2 India is home to a vast poorly regulated private medical sector. Although the Revised National Tuberculosis Control Program (RNTCP) has since 1997 endorsed and implemented the World Health Organization’s (WHO) Directly Observed Treatment, Short-course (DOTS) strategy, private health providers, who often deviate from standard TB treatment guidelines (as well as from MDR-TB treatment guidelines), manage a substantial number of India’s TB cases.3–5 In 2012 The Government of India took a bold step, launching a mandatory TB notification policy, mainly to increase TB notification from the private sector. It then launched a web-based TB case notification system, ‘NIKSHAY’. These initiatives contributed to a 29 per cent increase in TB notifications from India.2 A first ever surveillance of antiTB drug resistance is also now underway with completion expected in 2016. However, the scale of the problem is huge; success will require holistic thinking to guide more concerted and effective efforts. Several articles attempted to address the problem of MDR-TB in India, but as yet none provides a complete picture of the MDR-TB situation in India or suggests specific operational strategies for its control. We attempt to offer an overview of the MDR-TB situation in India and discuss policy needs by analyzing the burden of disease, pathways to care including ‘health seeking’ (patient's behavior/actions towards seeking care during the illness experience), diagnosis and treatment in the public and private sectors, and the acquisition and spread of drug resistance. Finally, we discuss possible operational measures to tackle this menace.

Burden of TB and MDR-TB The WHO regularly produces national estimates of the burden of TB based on routinely collected case notification data. These are adjusted for country-specific case detection rates. Surveillance systems capture these data through case notifications and death registrations and in special surveys designed to estimate disease prevalence.6 Although the WHO estimated the incidence of TB in India to be between 2 and 2.3 million cases per year, only 1 683 915 cases were notified to WHO in 2014.2 Several studies estimate that the private sector manages nearly

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half of TB cases; 3,4,7,8 but the WHO 2015 report reveals that the private sector’s contribution to total case notification reached only 12 per cent.2 The number of TB cases under treatment in private sector remains unknown. The gap between estimated and notified cases likely reflects underreporting from the private sector. Although India has not conducted a national prevalence survey since 1958,9 the periodic Demographic and Health Surveys (DHS) include questions on participants’ TB diagnoses. The DHS 2005–2006 report yielded a prevalence of a self-reported TB diagnoses of 445 per 100 000 and of self-reported medically treated TB of 418 per 100 000.10 These estimates were substantially higher than the WHO estimates of prevalence of 299 per 100 000 for 2005.11 Data from a few subnational prevalence surveys are also available. One conducted in a rural sub-district in South India between 2008 and 2010 reported a point prevalence (proportion of persons with disease on a particular date) of 196 per 100 000.12 Another conducted in Jabalpur district in the Central Indian State of Madhya Pradesh in 2009–2010, reported 255.3 per 100 000.13 Importantly, the Jabalpur study found that prevalence in rural areas was significantly higher than in urban ones (348.8 versus 153.9 per 100 000). The study was not designed to reflect the proportion of urban and rural dwellers in the population. While it is clear that a large number of cases are not notified, there are only a few data sources available to derive the actual case detection rate. Thus, there is a large margin of uncertainty in any estimates of the actual burden of TB. To estimate the prevalence of MDR-TB, the WHO organizes periodic surveys of drug resistance in countries that do not carry out and report routine drug susceptibility testing (DST) for all TB cases.14 These surveys typically ensure representativeness by using a cluster sampling method with a minimum of 30 clusters, each including 10–40 patient isolates. To date, reports from the drug resistance surveys (during 2007–2009) covered only three states: Maharashtra, Gujarat, and Andhra Pradesh.15 On the basis of these, the WHO estimates that in India 2.2 per cent (95 per cent CI 1.9–2.6) of new pulmonary TB cases and 15 per cent (95 per cent CI 11–19) of total retreatment cases are MDR-TB.2 This translates to an estimated 61 000 incident cases of MDR-TB of which 24 000 (95 per cent CI 21000–29000) are new cases and 47 000 (95 per cent CI 35000–59000) retreatment cases. Unfortunately, there was no separate reporting of the proportions of laboratory confirmed MDR-TB cases among new and previously treated cases.2

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To determine whether other states have similar proportions of MDRTB, we systematically reviewed the literature to identify studies reporting the prevalence of MDR-TB among new and/or previously treated cases at any site in India and published in the English language from 1 January 2001 through 15 February 2016. Panel 1 describes the search strategy: Panel 1: Search strategy in PubMed PubMed MeSH terms: 1. ‘multidrug-resistant’/‘drug-resistant’ 2. ‘tuberculosis’ 3. ‘India’ 4. ‘prevalence’ Text terms: 1. ‘survey’ 2. ‘surveillance’ 3. ‘proportion’ Search strings (all inclusive): 1. 1 AND 2 AND 3 AND 4 2. 1 AND 2 AND 3 AND 5 3. 1 AND 2 AND 3 AND 6 4. 1 AND 2 AND 3 AND 7 5. 1 AND 2 AND 3

Selection Criteria We included studies that measured resistance in a random sample of all presenting patients (>18 years age) and that reported the proportion of MDR-TB among new and previously treated cases separately. We excluded any studies that: ● ● ● ● ●

duplicated a record already included had been conducted outside India did not report the proportion of MDR-TB cases did not include a complete or random sample of all presenting cases, or had been carried out among HIV infected individuals or among the contacts of MDR-TB cases (Figure 1)

Of 995 articles, we excluded 889 articles because they did not report on the proportion of MDR-TB, and 33 more based on studies that did not

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995 articles identified in PubMed, screened by titles and abstracts Excluded: duplicate records (2) 993 articles Excluded: geographic area outside India (39) 954 articles

Relevant articles (65)

Selected after full text review (20)

Excluded: No reports on proportion of MDR-TB (889)

Excluded: -Studies did not include random sample of all presenting patients (33) -Study among HIV positive individuals (7) -Study among contacts of MDR-TB cases (1) -No separate sample of new and previously treated cases (4)

Figure 1: Flow chart of selection of studies on MDR-TB prevalence in India.

randomly sample all presenting cases. Many of the latter were studies of suspected MDR-TB cases and conducted at tertiary care centers (mostly involving chronic cases). Others were excluded for various reasons listed as above in Figure 1. Table 1 demonstrates the findings from the 20 studies15–34 that met our inclusion criteria, including the three subnational surveys from three states noted above. The three states where most of the drug resistance surveys were conducted represent only a small minority of the 2935 States and 7 Union Territories in India, and cover about 20 per cent of India’s population. The Gross Domestic Product (GDP) is higher there than the majority of states36 and the three account for only one quarter of notified TB cases in India.37 There are a few sporadic studies available from the states such as Tamil Nadu, Delhi, Uttar Pradesh, Madhya Pradesh, Kerala, and Karnataka. Table 1 shows that even among selected studies, estimates of MDR-TB among new cases ranged from 0 per cent in Orissa to 24 per cent in Mumbai, Maharashtra, whereas among previously treated cases, it ranged from 2 per cent in Andhra

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Authors Bhat et al (2015) 16 Mynedu et al (2015)17 Selvkumar et al, (2015)18 Salvo et al (2014)19 Das et al (2013)20 Gupta et al (2013)21 Yadav et al (2013)22 Sharma et al (2011)23 Sharma et al (2011)24 DRS (2007) or Ramchandran et al (2009)25 DRS (2009)15 D’Souza et al (2009)26 Joseph et al (2009)27 Jain et al (2008)28 Joseph et al (2007)29 DRS (2007)15 Anuradha et al (2006)30 Dhingra et al (2003)31 Negi et al (2003)32 Shah et al (2002)33 Paramasivan et al (2002)34

State

New cases (n)

Percentage (CI)

Previously treated cases (n)

Percentage (CI)

Madhya Pradesh New Delhi Tamil Nadu Different states Orissa Uttar Pradesh Chandigarh New Delhi New Delhi Gujarat Andhra Pradesh Maharashtra Kerala Uttar Pradesh Kerala Maharashtra Andhra Pradesh New Delhi New Delhi Gujarat Tamil Nadu Karnataka

NA 453 1220 193 405 169 102 Not included 177 1571 NA 493 92 318 305 NA 714 157 142 Not included 282 278

2.2 4.0 1.8 (1.1-2.5) 14.5 0 4.7 5.9 Not included 1.1 2.4 (1.6–3.1) 1.8 24.0 5.4 13.2 2.0 2.7 0.14 (0.13–0.41) 2.98 11.97 Not included 2.8 2.5

NA Not included 714 71 37 Not included 69 196 Not included 1047 NA 231 104 368 Not included NA 195 Not included 92 1472 11 11

8.2 Not included 13.2 (10.7–15.6) 31.4 8.1 Not included 33.3 20.4 Not included 17.4 (15–19.7) 11.8 41.0 16.4 25.5 Not included 14.0 2.0 (0.04–3.96) Not included 42.4 9.2 69.0 100.0

Note: DRS (highlighted): Drug resistance surveys; NA: Not available; CI: Confidence intervals

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Table 1: Summary of selected studies showing the proportion of MDR-TB

Multidrug-resistant tuberculosis (MDR-TB)

Pradesh to 100 per cent in Karnataka. Lack of information on confidence intervals, small sample size, and non-availability of information either among new or previously treated cases from some states limited the results. Given these limitations, current estimates of population-based MDR-TB in India are highly uncertain, as the WHO has acknowledged.14 Nationwide anti-TB drug resistance surveillance is currently underway and expected to complete in 2016. Results from that will not be available immediately.

Routes to MDR-TB MDR-TB can be acquired through two distinct routes. First, suboptimal TB treatment can lead to within-host selection of M. tuberculosis bacilli that have acquired drug resistance mutations. This ‘acquired’ resistance occurs when bacilli are exposed to ‘functional monotherapy’ with a drug to which they are resistant.37 Patients may receive such functional monotherapy if they do not receive multi-drug therapy – either because of non-adherence or suboptimal patient management where treatment programs are poorly implemented. Functional monotherapy can also occur when patients receive multiple drugs if absorption of some of them is reduced by medical comorbidities that impair uptake from the gastro-intestinal tract or if patients carry strains already resistant to some drugs in the regimen. Genetic differences can also lead to poor absorption of drugs. Second, once a patient has a drug-resistant TB strain, he or she may spread this infection to another person who will directly become infected with that drug-resistant strain. This form of drug resistance is referred to as ‘primary’ drug resistance.38 Although conventional wisdom long held that drug resistant strains are less transmissible than drug-susceptible strains,39,40 recent molecular epidemiologic data demonstrate that many resistant strains do have the potential to spread both within households as well as communities.41–43 Empirical studies that compared reproductive fitness of drug resistant strains and drug susceptible strains revealed heterogeneity, which limits predicting behavior of the pathogen.44–46 To understand better how and where MDR-TB emerges in India, we map patients’ pathways to care. Figure 2 indicates a potential pathway to care from the onset of TB symptoms. Is based on a model of ‘pathways of ideal behaviors in TB control’ prepared jointly by the Academy of Educational Development and the Stop TB Partnership. It captures the

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First help seeking

Diagnosis

Treatment

Lack of awareness about TB; Social stigma

Use of poor diagnostics in the private sector (reliance on the chest radiographs rather than microscopy)

Private practitioners’ deviation from standard TB treatment guidelines

Lack of awareness of free anti-TB treatment (DOTS) in the government facilities/at public health centers Shopping around in poorly regulated private sector (Informal and formal) and chemists can result in partial or incomplete treatment Factors leading to delays in approaching the RNTCP, development of acquired resistance through partial treatment in the private sector and transmission of primary MDR-TB strains in the absence of effective therapy

Limitations of criteria used for MDR-TB suspects-No drug susceptibility test prior to beginning anti-TB treatment, only sputum microscopy is done

Erroneous treatment due to failure in inquiring about history of prior antiTB treatment Treatment of primary MDR-TB cases with the first-line regimen;

Limited use of methods for rapid diagnosis of MDR-TB

Standardized treatment for all MDRTB cases irrespective of their DST status and without ongoing surveillance of drug resistance

Operational difficulties in transporting sputa to DST labs and getting results

Poor treatment adherence from patients’ side; or functional monotherapy

Limited number of laboratories performing DST Factors leading to delays in diagnosis of MDR-TB, which may result in transmission of drug resistant/MDR-TB strains

Factors leading to emergence and amplification of resistance with potential further spread of resistant strains

Figure 2: Pathways to care: Factors responsible for emergence and spread of MDR-TB in India.

complex interrelationships among behavior, DOTS services, and other societal structures.47 We adopt a similar approach to consider the interplay of social, biological, and health system-related factors that could negatively affect the course of diagnosis and treatment for TB, and ultimately lead to emergence and spread of MDR-TB.

Onset of symptoms and first help seeking A recent study in Delhi found that only 29 per cent of 108 patients sought help within 30 days of first experiencing TB symptoms (cough and/or fever) and women sought it later (6.3 months) than men (3.8 months).7 These results are consistent with a previous multi-country study that included data from Chennai where the average time from the onset of symptoms to first help seeking was 57.2 days for women and 48.1 for men.48 Multiple qualitative studies have identified fear of stigmatization as a major obstacle in seeking initial help.49–52 Patients note the convenience of using the private sector care—proximity and shorter waiting times compared with government health centers. Patients also thought the

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private sector offered confidentiality and thus protection from stigma.53 Other reasons given for use of private sector services included lack of awareness about free anti-TB treatment in the government clinics, lack of trust in government services, lack of attention offered to the patient, and unhygienic conditions in government health centers. 3,4,54–57 The study in Delhi found that TB patients’ preference for private sector treatment has not changed even after several years of implementation of the RNTCP.7 This study retrospectively reconstructed pathways to TB care among 108 TB patients eventually registered in government DOTS clinics (or the RNTCP). None had approached the RNTCP as their first point for help; 62 per cent identified an ‘informal’ provider as the first point, 30 per cent identified a ‘qualified practitioner,’ and 8 per cent went directly to chemists. This last group reported that chemists are best qualified to recommend medicines and are more affordable because they rarely charge for their services, unlike medical practitioners. Diagnosis Once a patient has sought care, he or she should undergo diagnosis for TB, a process that often differs between the private and public sectors. Several studies found that Indian private practitioners rely heavily on chest radiographs rather than the sputum smear microscopy as recommended by the RNTCP.58–60 A study of the behavior and interactions of TB patients with the private for-profit sector in India in the 1990s found that private practitioners recommended sputum smear microscopy in only 20 per cent of suspects, whereas 56 per cent of patients reported that they were diagnosed with TB on the basis of chest X-rays alone.61 During this period, over 70 per cent of patients treated within India's national TB program were diagnosed by chest X-rays alone, a strategy that led to over-diagnosis and unnecessary treatment.62 Although the RNTCP incorporated sputum smear microscopy into the national guidelines in 1997, a 2010 study among 260 private practitioners in Hooghly district documented that 68 per cent of practitioners still preferred chest X-rays over sputum examination for diagnosis.60 Diagnosis of drug resistance Although sputum smear microscopy improves the specificity of TB diagnosis compared with chest X-ray, neither test provides information

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Table 2: Definition for MDR-TB suspects in India Criteria A

Criteria B Criteria C

Failures of new TB cases Failure and non-converters of smear positive re-treatment cases All pulmonary TB cases in contact of confirmed MDR-TB cases All smear positive retreatment pulmonary TB cases at diagnosis Any new or re-treatment pulmonary TB case smear positive at any follow up All smear negative re-treatment pulmonary TB cases at diagnosis & HIV-TB cases

Source: Central TB Division CTD63.

on drug susceptibility. To understand the challenge of diagnosing MDRTB, we examined the diagnostic algorithms currently used in India. Table 2 identifies criteria for suspecting MDR-TB and Figure 3 shows the algorithm from the point when a patient presents to a provider with signs and symptoms of TB until he or she is finally tested for drug resistant TB. From the algorithms and criteria in use, it is clear that unless a new case is a contact of a known MDR-TB case, he or she will not undergo DST until 2– 3 months after initiating treatment with first-line anti-TB drugs. Even if the samples are sent for DST, only some laboratories have liquid culture capacity. Thus, it can take 2 more months to get a diagnosis. Delays of nearly 4–5 months in diagnosis may occur, especially among those who may have ‘Primary’ MDR-TB. The 2015 WHO report shows that in 2014, of the 1 683 915 total of TB cases notified from India to the WHO, only 255 897 (15 per cent) were subjected to DST, of which new cases were only 2 per cent.2 This clearly reflects the gap in diagnosis of MDR-TB among new as well as previously treated cases. All three criteria are currently implemented in India; however, to address this gap sufficiently will require time and building technical capacity for diagnosis of MDR-TB. Laboratory capacity to diagnose MDR-TB We reviewed India’s laboratory capacity to perform DST in light of the projected burden of MDR-TB. As per the TB India Report 2015, 62 laboratories had been certified by the RNTCP to conduct DST for TB.64 Of these, 41 had facilities for conducting solid culture and DST, 26 had liquid culture capacity, 50 were equipped with line probe assays, and 40 more laboratories were in the process of certification. The GeneXpert (M.tb/Rif.) test for rapid diagnosis of rifampicin resistance was available at 121 sites.2 On the basis of the guidelines from the Global Plan to Stop TB for 2011–2015 that suggest one laboratory per 5 million

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Cough for >2 weeks

Two sputa samples for testing

One or both smears positive

Both smears negative

Antibiotics for 10-14 days New case Category I Regimen HRZE/4

Previously treated cases Category II Regimen

Smear positive at any follow up or After 5 months of treatment (failure)

Known contact of MDR-TB

After 5 months Smear negative

Smear positive at any follow up or After 4 months Of treatment (failure)

If cough persists, repeat two sputa

One or both smear positives

Both smear negatives CXR

After 4 months Smear negative

Suggestive of TB

No TB

Suspect MDR-TB and send the sample for culture and DST

Figure 3: Diagnostic algorithms for detecting MDR-TB cases under theRNTCP. Notes: Category I regimen: 2H3R3Z3E3/4H3R3: This includes 2 months of Intensive phase (IP) treatment with Isoniazid (H), Rifampicin(R), Pyrazinamide (Z), and Ethambutol (E) followed by the continuation phase (CP) with H and R for 4 months. Three indicates thrice weekly dose. If sputum remains positive at any follow up or after 5 months, patient will be suspected as MDR-TB and his/her sputum sample will be sent for culture and DST. Patient will be shifted to category II treatment until results are awaited. Category II regimen: 2S3H3R3Z3E3/1H3R3Z3E3/5H3R3E3: This is the same regimen as Category I with an addition of streptomycin (S) followed by HRZE for 1 month in IP and 5 months of CP with HRE. If sputum is positive after 3 months, IP is extended by 1 month of HRZE. MDR-TB is suspected at the diagnosis, or if sputum remains positive at any follow up, his/her sputum sample will be sent for culture and DST. Patient will be continued on category II treatment until DST results are reported.63,65. CXR: chest X-ray.

population,2 India should have about 240 DST laboratories. As per the TB India 2015 report, the lab capacity was only one fourth of the required number.

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Table 3: State wise distribution of drug susceptibility testing (DST) laboratories required to help the diagnosis of MDR-TB Sr.

States*

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 UT1 UT2 UT3 UT4 UT5 UT6 UT7

Uttar Pradesh Maharashtra Bihar West Bengal Andhra Pradesh Madhya Pradesh Tamil Nadu Rajasthan Karnataka Gujarat Orissa Kerala Jharkhand Assam Punjab Chattisgarh Haryana Jammu and Kashmir Uttarakhand Himachal Pradesh Tripura Meghalaya Manipur Nagaland Goa Arunachal Pradesh Mizoram Sikkim Delhi (NCT) Puducherry Chandigarh Andaman & Nicobar Dadra, Nagar Haveli Daman & Diu Lakshdweep

Population (Census 2011)

Number of DST labs required as per WHO guidelines

199 581 477 112 372 972 103 804 637 91 347 736 84 665 533 72 597 565 72 138 958 68 621 012 61 130 704 60 383 628 41 947 358 33 387 677 32 966 238 31 169 272 27 704 236 25 540 196 25 353 081 12 548 926 10 116 752 6 856 509 3 671 032 2 964 007 2 721 756 1 980 602 1 457 723 1 382 611 1 091 014 607 688 16 753 235 1 244 464 1 054 686 379 944 342 853 242 911 64 429

40 22 20 18 16 14 14 14 12 12 8 6 6 6 6 4 4 2 2 1 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0

Currently certified (any certification-solid/ liquid/LPA) (n = 62)

Percentage

6 9 3 3 4 4 4 3 2 3 2 1 1 1 1 1 1 2 1 1 0 1 0 0 1 0 0 0 4 1 1 1 0 0 0

15.0 40.9 15.0 16.6 25.0 28.5 28.5 21.4 16.6 25.0 25.0 16.6 16.6 16.6 16.6 25.0 25.0 100.0 50.0 100.0 0 >100.0 0 0 >100.0 0 0 0 >100.0 >100.0 >100.0 >100.0 0 0 0

Source: Government of India. TB India64; Census of India, State Census66. Note: 1 DST lab for 5 million population2. LPA: Line Probe Assay. UT: Union Territory. *Although India has 29 States and 7 Union territories as of 2014, the table includes 28 States based on the laboratory data available at the time of analysis.

Table 3 provides data on each state’s population and the number of TB laboratories performing DST. It shows that most states have fewer than the recommended number and that the geographic distribution of labs does not correspond to population density. The majority of states have

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fewer than a quarter of the recommended number while Delhi has more laboratories than recommended. Five of nine laboratories in Maharashtra are located in Mumbai city itself despite the fact that only 10 per cent of the current 114 million residents of that state dwell in that city. Distant locations of TB laboratories, especially for rural areas, translates directly into delays in diagnosis and in the provision of effective treatment. One study of 559 MDR-TB suspects (217 new and 331 retreatment cases, 11 smear negative cases) in the state of Andhra Pradesh reported reasons for the considerable loss to follow-up of patients: ●

● ●

samples lost during transportation from a district center to a referral laboratory (27); sample contamination (33); and an inadequate quantity of sputum (20).67

Limited courier services in the interior parts of the country and frequent electricity interruptions are also reported to hinder timely delivery of sputum samples to DST laboratories.15 Data suggest that MDR-TB cases receiving aggressive treatment with at least five or six effective drugs have better outcomes than those receiving fewer effective drugs.1 This requires DST facilities for secondline drugs, but India’s 2015 TB Report identifies only 14 laboratories certified for conducting DST for these.64 Given such limited laboratory capacity, it is obvious that in most parts of the country, patients are enrolled in MDR-TB treatment without having second-line DST. This is a serious concern.

Course of Treatment and Treatment Outcomes Once the patient is diagnosed, he or she will start treatment. Because most patients initiate care in the private sector, we sought to assess initial treatment regimens there. A previous report notes that the private sector spending on first-line anti-TB drugs in India constitutes nearly threefourths of the total: US$70 million of a total $94 million.68 Several studies document that private practitioners frequently deviate from standard guidelines for TB treatment;3,69–71 Treatment outcome data from the private sector are rarely available. One study found a higher default (treatment interrupted for 2 consecutive months or more) rate in

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the private health sector (56.3 versus 34.2 per cent) than in the RNTCP.72 These observations raise serious questions about use of firstline anti-TB drugs in the private sector of India. Treatment of MDR-TB cases in the private sector is inconsistent. A study in Mumbai reported that only 5 of 106 private practitioners surveyed were able to prescribe treatment for MDR-TB according to RNTCP guidelines,3 while another survey found that none of the 112 physicians who routinely treated MDR-TB patients could identify the standard treatment recommended by the RNTCP.5 In the latter study, practitioners prescribed 87 different treatment regimens to patients with MDR-TB. An earlier systematic review of treatment outcomes among MDR-TB patients from the private sector identified very few studies from India.73 Because patients who approach the Government/RNTCP clinics often have a history of prior anti-TB treatment in the private sector – in the absence of DST for all new cases prior to starting anti-TB treatment – most cases under the RNTCP begin treatment with the standard first-line regimen. And because prior anti-TB treatment is a major risk factor associated with MDR-TB74,75 and thus an indication to proceed directly to DST, it is important to understand how TB patients are screened, categorized, and treated when they reach the RNTCP. One large epidemiological study in Maharashtra found that RNTCP staff erroneously categorized 13 per cent (71 of 568) of cases in urban areas of Mumbai and 9 per cent (30 of 321) in rural areas as ‘new’ despite their having undergone anti-TB therapy for >1 month in the past.76 Thus, those who may have primary/initial MDR-TB are less likely to respond and more likely to amplify their initial drug resistance if they receive suboptimal care with the first-line regimen. 1,75 For MDR-TB cases, the RNTCP advocates a standardized treatment regimen with an intensive phase of 6–9 months during which 6 drugs are administered (Kanamycin, Levofloxacin, Ethionamide, Pyrazinamide, Ethambutol, and Cycloserine). Then a continuation phase of 18 months uses 4 drugs (Levofloxacin, Ethionamide, Ethambutol, and Cycloserine). This regimen is recommended for all MDR-TB cases regardless of actual resistance profiles.63 While this policy stems in part from the limited availability of second-line drug resistance testing, MDR-TB outcomes among 12 125 patients treated by RNTCP suggest that this regimen may not be optimal: only 5796 (48 per cent) had good outcomes (cure or completion) while 2682 (22 per cent) died and 19 per cent defaulted.64

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One reason for such poor outcomes among MDR-TB cases could be resistance to some of the drugs used in standardized regimen. Future studies might provide supporting evidence to accept or reject this hypothesis. Studies from different countries have shown that the prevalence of resistance to ethambutol (EMB) or Pyrazinamide (PZA) among cases with MDR-TB was about 60–70 per cent and the prevalence of simultaneous resistance to both EMB and PZA was about 50 per cent.77–80 A recent study among 668 MDR-TB patients indicated that a regimen of four effective drugs and non-effective Pyrazinamide were associated with higher mortality rates (adjusted hazard ratio [HR] 2.87; 95 per cent CI 1.35–6.09 and adjusted HR, 2.76; 95 per cent CI 0.92–2.87) as compared with the regimen with five effective drugs.81

A Way Forward Our analysis identifies six areas relevant for policymakers involved in the management and control of MDR-TB in India. First, given uncertainty about the exact burden of MDR-TB, well-designed prevalence surveys with representative sampling are needed. Such prevalence surveys are expensive. Because in India, health is a state as opposed to national responsibility, each state might conduct its own periodic prevalence surveys. This will help assemble a regional as well as national picture of MDR-TB. Active case finding would also be a helpful strategy. The burden of MDR-TB is relevant especially now that India’s first ever national anti-TB drug resistance survey is underway. Second, laboratory capacity for conducting DST should be increased. In our opinion, the decision to establish a new laboratory should be based on annual TB case notification and drug resistance survey results rather than mere ‘population density’. In view of limited laboratory capacity, the RNTCP should explore a possibility for strengthening collaboration with private efforts like The Initiative for Promoting Affordable and Quality TB (IPAQT) tests that works to bring down prices of approved tests for patients in the private sector. It has enabled 51 private laboratories to offer tests such as Gene Xpert, the Hain Genotype, MGIT, and BacT/Alert. Third, criteria for suspecting MDR-TB could be expanded to include all three listed in Table 2. Even so, operational capacity needs to be developed. Given that patients first seek help in the private sector, all so-called ‘new’ smear positive patients approaching the RNTCP

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also need to undergo DST at the beginning of anti-TB treatment. Thus stepwise testing for drug resistance should be discouraged. If a patient has any indication of drug resistance (on clinical, epidemiological, or laboratory grounds), then the full panel of anti-TB drugs should be tested right away. That will not only help achieve earlier diagnosis of MDR-TB among both new and retreatment patients, but also improve selection of appropriate regimens. Fourth, RNTCP’s current treatment strategies for MDR-TB must be carefully reviewed. Principles developed from empirical evidence suggest that a single drug should never be added to the failing regimen and MDR-TB patients should never be treated with a standard first-line regimen.82 We found that current RNTCP algorithms did not adhere to these principles. All TB patients are initially treated with first-line regimens regardless of their drug resistance status and the Category II (retreatment category) regimen includes addition of a single drug, streptomycin, to four drugs (HRZE). Debate continues about the use of ‘standardized’ versus ‘individualized’ regimens for MDR-TB.82 (That is, a ‘standard’ regimen used for all drug-resistant cases without regard to drug susceptibility versus one based on the tested drug susceptibility profile of the individual.) Clearly, results of standardized treatment in India have been disappointing and similar experiences have been noted elsewhere, including in Korea and Peru.83,84 In contrast, optimal cure rates of about 80 per cent have been seen among some MDR-TB patients in Peru and Lativia who received an individualized treatment.85,86 In countries where the standardized regimens are used, ongoing surveillance of drug resistance is needed. No such surveillance takes place in India. Fifth, the RNTCP urgently needs investment in both human and financial resources. As shown by data provided in the RNTCP report 2013, about 30 per cent of authorized posts in the RNTCP were vacant (Table 4).87 Further, at 1.3 per cent of the GDP, public health expenditure (recurrent and capital spending from government, both central and local budgets, external borrowings and grants including donations from international agencies and non-governmental organizations, and social or compulsory health insurance funds) in India is among the lowest in the world 88 and this is reflected in the allocation of funds even for TB control. Last, for preventing transmission or spread of drug resistant TB strains through a nosocomial mode (hospital-based infections), it is essential to

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Official/staff

District TB Officers Second Medical officer at District TB Centre Medical Officer-TB Control Medical Officers DOTS Plus and TB-HIV supervisor Senior Treatment Supervisor (STS) Senior TB Laboratory Supervisor (STLS) TB Health Visitor Laboratory Technician at microscopy centers Data entry operator DOT provider Total

Number of Regular Contractual Current sanctioned posts in posts number in posts Government position 698 462 2564 92513 653 2706 2697 3239 14107 698 693628 813965

628 279 2308 73694 0 202 144 366 9445 0 NA 87066

0 31 48 1299 562 2355 2395 2442 3986 676 NAV 13794

Source: Government of India. TB India87; NA: Not Applicable; NAV: Not available.

567 246 1770 58938 480 2381 2387 2650 12080 650 484672 566821

Difference between sanctioned and current number in position

Proportion of sanctioned posts that are vacant (%)

131 216 794 33575 173 325 310 589 2027 48 208956 247144

18.7 46.7 30.9 36.2 26.4 12.0 11.4 18.1 14.3 6.8 30.1 30.3

Multidrug-resistant tuberculosis (MDR-TB)

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Table 4: Human resource in the RNTCP as of December 2012

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treat the environment as well as the patient. A recent study shows the effectiveness of measures such as upper room ultraviolet germicidal irradiation89 in high burden health centers where TB cases are treated. Such measures will ultimately help to reduce the spread of infection in the society. We hope that careful attention to all of these crucial issues will be useful in MDR-TB management and control in India and find suitable applications in other settings that share similarities with India.

Acknowledgements Sachin Atre gratefully acknowledges funding support from US Department of State through the United States India Educational Foundation (USIEF) toward his one-year Fulbright-Nehru Postdoctoral fellowship at Harvard Medical School from September 2013. The authors thank Ms. Caroline McCallum for her editorial assistance.

About the Authors Sachin R. Atre, PhD, is a medical anthropologist and Study Coordinator on US-NIH funded project on TB-diabetes in collaboration with Johns Hopkins University-BJ Medical College Pune, India. He carried out the work in this article as a part of Fulbright-Nehru Post-doctoral Fellowship at the Department of Global Health and Social Medicine at Harvard Medical School 2013-14 and MAAS-CHRD. He previously served as a consultant for the Global TB Program of the World Health Organization. Megan Murray, MD, MPH, ScD, an epidemiologist, and an infectious disease physician, is a Professor of Global Health and Social Medicine at Harvard Medical School, and an Associate Professor of Medicine and the Director of Research at the Brigham, and Women’s Hospital Division of Global Health Equity and its sister organization, Partners In Health. As an Associate Professor of Epidemiology at the Harvard School of Public Health, she leads a research team conducting multidisciplinary research on MDR- and XDR-TB involving conventional and molecular epidemiology, cost-effectiveness and mathematical modeling, outcomes and operations research, and genomic epidemiology.

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Notes and References 1. Mitnick, C.D. et al (2013) Aggressive regimens for multidrug-resistant tuberculosis decrease all-cause mortality. PLoS ONE 8(3): e58664. 2. World Health Organization. (2015) Global Tuberculosis Control Report. (WHO/HTM/TB/ 2015.22) Geneva, Switzerland: World Health Organization. 3. Udwadia, Z.F., Pinto, L.M. and Uplekar, M.W. (2010) Tuberculosis management by private practitioners in Mumbai, India: Has anything changed in two decades? PLoS ONE 5(8): e12023. 4. Uplekar, M., Pathania, V. and Raviglione, M. (2001) Private practitioners and public health: Weak links in tuberculosis control. The Lancet 358(9285): 912–916. 5. Yadav, A. et al (2012) Treatment practices in pulmonary tuberculosis by private sector physicians of Meerut, Uttar Pradesh. Indian Journal of Chest Diseases and Allied Sciences 54(3): 161–163. 6. Dye, C. et al (2008) Measuring tuberculosis burden, trends and the impact of control programs. The Lancet Infectious Diseases 8(4): 233–243. 7. Kapoor, S.K., Venkat Raman, A., Sachdeva, K.S. and Satyanarayana, S. (2012) How did the TB patients reach DOTS services in Delhi? A study of patient treatment seeking behavior. PLoS ONE 7(8): e42458. 8. Satyanarayana, S. et al (2011) From where are tuberculosis patients accessing treatment in India? Results from a cross-sectional community based survey of 30 districts. PLoS ONE 6(9): e24160. 9. Indian Council of Medical Research. (1959) Tuberculosis in India-A National Sample Survey: 1955–58 ICMR Special Report Series, New Delhi, No. 34. 10. International Institute for Population Sciences (IIPS) and Macro International. (2007) National family health survey (NFHS-3), 2005–06, Vol I. Mumbai, India: IIPS; pp. 411-418, http://www .rchiips.org/NFHS/NFHS-3%20Data/VOL-1/India_volume_I_corrected_17oct08.pdf, accessed 14 November 2014. 11. WHO Report. (2007) Global Tuberculosis Control. Surveillance, Planning and Financing. Geneva, Switzerland, World Health Organization WHO/HTM/TB/2007.376. 12. Chadha, V.K. et al (2012) Prevalence of Pulmonary Tuberculosis among Adults in a Rural Sub-District of South India. PLoS ONE 7(8): e42625. 13. Rao, V.G. et al (2012) Prevalence of pulmonary tuberculosis – A baseline survey in central India. PLoS ONE 7(8): e43225. 14. World Health Organization. (2013) Global Tuberculosis Control Report. Geneva, Switzerland: World Health Organization.(WHO/HTM/TB/2013.13). 15. Institute of Medicine (USA). (2012) Facing the reality of drug-resistant tuberculosis in India: Challenges and potential solutions: Summary of a joint workshop by the institute of medicine, the Indian national science academy, and the Indian council of medical research. Washington DC: National Academies Press, http://www.ncbi.nlm.nih.gov/books/NBK92617/pdf/TOC.pdf, accessed 14 November 2014. 16. Bhat, J. et al (2015) Situation of drug resistant tuberculosis in Saharia tribe of central India. Indian Journal of Medical Research 141(5): 636–639. 17. Myneedu, V. et al (2015) First and second line drug resistance among treatment naïve pulmonary tuberculosis patients in a district under Revised National Tuberculosis Control Programme (RNTCP) in New Delhi. Journal of Epidemiology & Global Health 5: 365–373. 18. Selvakumar, N. et al (2015) High rates of ofloxacin resistance in Mycobacterium tuberculosis among both new and previously treated patients in Tamil Nadu, South India. PLoS ONE 10(3): e0117421. 19. Salvo, F. et al (2014) Survey of tuberculosis drug resistance among Tibetan refugees in India. International Journal of Tuberculosis and Lung Disease 18(6): 655–662.

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Atre and Murray

20. Das, D., Dwibedi, B. and Kar, S.K. (2014) Low levels of anti TB drug resistance in Rayagada district of Odisha, India. International Journal of Mycobacteriology 3(1): 76–78. 21. Gupta, H., Kant, S., Jain, A., Natu, S.M. and Ahluwalia, S. (2013) Initial drug resistance pattern among pulmonary tuberculosis patients. Indian Journal of Tuberculosis 60(3): 154–161. 22. Yadav, R., Sethi, S., Dhatwalia, S., Gupta, D., Mewara, A. and Sharma, M. (2013) Molecular characterization of drug resistance in Mycobacterium tuberculosis isolates from North India. International Journal of Tuberculosis and Lung Disease 17(2): 251–257. 23. Sharma, S.K. et al (2011) Prevalence of multidrug-resistant tuberculosis among category II pulmonary tuberculosis patients. Indian Journal of Medical Research 133(3): 312–315. 24. Sharma, S.K. et al (2011) Prevalence of multidrug-resistant tuberculosis among newly diagnosed cases of sputum-positive pulmonary tuberculosis. Indian Journal of Medical Research 133(3): 308–311. 25. Ramachandran, R. et al (2009) Surveillance of drug-resistant tuberculosis in the state of Gujarat. India International Journal of Tuberculosis and Lung Disease 13(9): 1154–1160. 26. D’Souza, D.T. et al (2009) High levels of multidrug resistant tuberculosis in new and treatmentfailure patients from the Revised National Tuberculosis Control Program in an urban metropolis (Mumbai) in Western India. BMC Public Health 9: 211. 27. Joseph, B.V. et al (2009) Drug resistance in Mycobacterium tuberculosis isolates from tuberculosis patients in Kerala, India. International Journal of Tuberculosis and Lung Disease 13(4): 494–499. 28. Jain, A., Mondal, R., Prasad, R., Singh, K. and Ahuja, R.C. (2008) Prevalence of multidrug resistant Mycobacterium tuberculosis in Lucknow, Uttar Pradesh. Indian Journal of Medical Research 128(3): 300–306. 29. Joseph, M.R., Shoby, C.T., Amma, G.R., Chauhan, L.S. and Paramasivan, C.N. (2007) Surveillance of anti-tuberculosis drug resistance in Ernakulam District, Kerala State, South India. International Journal of Tuberculosis and Lung Disease 11(4): 443–449. 30. Anuradha, B. et al (2006) Prevalence of drug resistance under the DOTS strategy in Hyderabad, South India, 2001–2003. International Journal of Tuberculosis and Lung Disease 10(1): 58–62. 31. Dhingra, V.K., Rajpal, S., Bhalla, P., Yadav, A., Jain, S.K. and Hanif, M. (2003) Prevalence of initial drug resistance to M. tuberculosis in new sputum positive RNTCP patients. Journal of Communicable Diseases 35(2): 82–89. 32. Negi, S.S., Gupta, S. and Lal, S. (2003) Drug resistance in tuberculosis in Delhi: A 2 year profile (2001–2002). Journal of Communicable Diseases 35(2): 74–81. 33. Shah, A.R., Agarwal, S.K. and Shah, K.V. (2002) Study of drug resistance in previously treated tuberculosis patients in Gujarat, India. International Journal of Tuberculosis and Lung Disease 6(12): 1098–1101. 34. Paramasivan, C.N., Venkataraman, P., Chandrasekaran, V., Bhat, S. and Narayanan, P.R. (2002) Surveillance of drug resistance in tuberculosis in two districts of South India. International Journal of Tuberculosis and Lung Disease 6(6): 479–484. 35. Although India has 29 States and 7 Union territories as of 2014, at the time of analysis data was only available for 28 States. 36. Government of India Planning Commission data book. (2014) http://planningcommission.nic. in/data/datatable/0814/comp_databook.pdf, accessed 9 November 2014. 37. Government of India – TB India. (2014) Revised National TB Control Program Annual Status Report, New Delhi, http://www.tbcindia.nic.in/pdfs/TB%20INDIA%202014.pdf, accessed 15 April 2014. 38. Warner, D.F. and Mizrahi, V. (2006) Tuberculosis chemotherapy: The influence of bacillary stress and damage response pathways on drug efficacy. Clinical Microbiology Review 19(3): 558–570.

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Multidrug-resistant tuberculosis (MDR-TB)

39. WHO/IUATLD. (2004) Global Project on Anti-Tuberculosis Drug Resistance Surveillance. Anti-Tuberculosis Drug Resistance in the World. Geneva, Switzerland: World Health Organization. Report No.3. 40. Dye, C. et al (2002) Erasing the world’s slow stain: Strategies to beat multi drug-resistant tuberculosis. Science 295(5562): 2042–2046. 41. Billington, O.J., McHugh, T.D. and Gillespie, S.H. (1999) Physiological cost of rifampicin resistance induced in vitro in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 43(8): 1866–1869. 42. Nardell, E. and Dharmadhikari, A. (2010) Turning off the spigot: Reducing drug-resistant tuberculosis transmission in resource-limited settings. International Journal of Tuberculosis and Lung Disease 14(10): 1233–1243. 43. Zhao, M. et al (2009) Transmission of MDR and XDR tuberculosis in Shanghai, China. PLoS ONE 4(2): e4370. 44. Grandjean, L. et al (2015) Transmission of multidrug-resistant and drug-susceptible tuberculosis within households: A prospective cohort study. PLoS Medicine 12(6): e1001843. 45. Cohen, T. and Murray, M. (2004) Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness. Nature Medicine 10(10): 1117–1121. 46. Cohen, T., Sommers, B. and Murray, M. (2003) The effect of drug resistance on the fitness of Mycobacterium tuberculosis. The Lancet Infectious Diseases 31: 13–21. 47. Waisbord, S. and Zimicki, S. http://www.popline.org/node/264997, accessed 9 November 2014. 48. Weiss, M., Auer, C., Somma, D. and Abouihia, A (2006) Gender and tuberculosis: Cross-site analysis and implications of a multi-country study in Bangladesh, India, Malawi and Colombia. Special Programme for Research and Training in Tropical Diseases (UNICEF/UNDP/World Bank/WHO), TDR/SDR/SEB/RP/06.1. Geneva, Switzerland: WHO. Report Series No. 3, http:// www.who.int/tdr/publications/documents/sebrep3.pdf, accessed 5 May 2014. 49. Atre, S. et al (2011) Gender and community views of stigma and tuberculosis in rural Maharashtra, India. Global Public Health 6(1): 56–71. 50. Somma, D. et al (2008) Gender and socio-cultural determinants of TB-related stigma in Bangladesh, India, Malawi and Colombia. International Journal of Tuberculosis and Lung Disease 12(7): 856–866. 51. Jaramillo, E. (1998) Pulmonary tuberculosis and health-seeking behaviour: how to get a delayed diagnosis in Cali, Colombia. Tropical Medicine & International Health 3(2): 138–144. 52. Liefooghe, R. et al (1997) From their own perspectiveA Kenyan Community’s Perception of Tuberculosis. Tropical Medicine & International Health 2(8): 809–821. 53. Portero, L.J. and Rubio, M. (2003) Private practitioners and tuberculosis control in the Philippines: Strangers when they meet? Tropical Medicine & International Health 8(4): 329–335. 54. Pinto, L.M. and Udwadia, Z.F. (2010) Private patient perceptions about a public programme; what do private Indian tuberculosis patients really feel about directly observed treatment? BMC Public Health 10: 357. 55. Jaggarajamma, K., Balambal, R. and Muniyandi, M. (2009) Perceptions of tuberculosis patients about private providers before and after implementation of Revised National Tuberculosis Control Program. Indian Journal of Tuberculosis 56(4): 185–190. 56. Uplekar, M. et al (1998) Tuberculosis patients and practitioners in private clinics in India. International Journal of Tuberculosis and Lung Disease 2(4): 324–329. 57. Pathania, V., Almeida, J. and Kochi, A. (1997) TB Patients and Private for Profit Health Care Providers in India. Geneva, Switzerland: World Health Organization, WHO/TB/ 97.223.1997.

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21

Atre and Murray

58. Srivastava, D.K. et al (2011) An assessment of knowledge and practices regarding tuberculosis in the Context of RNTCP among non-allopathic practitioners in Gwalior District. Online Journal of Health and Allied Sciences 10(2): 5. 59. Bhargava, A., Pinto, L. and Pai, M. (2011) Mismanagement of tuberculosis in India: Causes, consequences, and the way forward. Hypothesis 9(1): e7. 60. Datta, K., Bhatnagar, T. and Murhekar, M. (2010) Private practitioners’ knowledge, attitude and practices about tuberculosis, Hooghly district India. Indian Journal of Tuberculosis 57(4): 199–206. 61. Uplekar, M., Juvekar, S. and Morankar, S. (1996) Tuberculosis patients and practitioners in private clinics, Bombay [Research Newsletter]. Foundation for Research in Community Health. 62. Jagota, P. (1998) Case finding policy for national tuberculosis program. Indian Journal of Tuberculosis 45(1): 3–7. 63. Central TB Division (CTD). (2012) Guidelines on programmatic management of drug resistant TB (PMDT) in India. Ministry of Health & Family Welfare, Nirman Bhavan, New Delhi, http:// tbcindia.gov.in/WriteReadData/l892s/8320929355Guidelines%20for%20PMDT%20in% 20India%20-%20May%202012.pdf, accessed 21 February 2016. 64. Government of India – TB India. (2015) Revised National TB Control Program Annual Status Report, New Delhi, http://tbcindia.gov.in/showfile.php?lid=3166, accessed 25 November 2015. 65. Sachdeva, K. (2013) Management of tuberculosis: Indian Guidelines 2013, http://www .apiindia.org/medicine_update_2013/chap105.pdf, accessed 25 November 2015. 66. Census of India (State Census). (2011) http://www.census2011.co.in/states.php, accessed on 25 November 2015. 67. Chadha, S. et al (2011) Operational challenges in diagnosing multi-drug resistant TB and initiating treatment in Andhra Pradesh, India. PLoS ONE 6(11): e26659. 68. Global Alliance for TB drug development. (2007) Pathway to Patients: Charting the Dynamics of the Global TB Drug Market. New York: TB Alliance. 69. Greaves, F., Ouyang, H., Pefole, M, MacCarthy, S. and Cash, R.A. (2007) Compliance with DOTS diagnosis and treatment recommendations by private practitioners in Kerala, India. International Journal of Tuberculosis and Lung Disease 11(1): 110–112. 70. Pathania, V.S. (2001) Why the Indian TB control program must stop ignoring private practitioners. International Journal of Tuberculosis and Lung Disease 5(2): 201–203. 71. Uplekar, M.W. and Shepard, D.S. (1991) Treatment of tuberculosis by private general practitioners in India. Tubercle 72(4): 284–290. 72. Gupta, S., Gupta, S. and Behera, D. (2011) Reasons for interruption of anti-tubercular treatment as reported by patients with tuberculosis admitted in a tertiary care institute. Indian Journal of Tuberculosis 58(1): 11–17. 73. Atre, S. (2015) Notification of multidrug-resistant tuberculosis cases and their treatment outcomes from the private sector. International Journal of Tuberculosis and Lung Disease 19(9): 1126. 74. Sharma, S. and Mohan, A. (2006) Multidrug-resistant tuberculosis: A menace that threatens to destabilize tuberculosis control. Chest 130(1): 261–272. 75. Farmer, P. and Kim, J.Y. (1998) Community based approaches to the control of multidrugresistant tuberculosis: Introducing ‘DOTS-plus’. BMJ 317(7159): 671–674. 76. Atre, S., D’Souza, D.T.B., Dholakia, Y.N. and Mistry, N.F. (2007) Observations on categorization of new TB cases: Implications for controlling drug resistance. International Journal of Tuberculosis and Lung Disease 11(10): 1152–1153. 77. Mphahlele, M. et al (2008) Pyrazinamide resistance among South African multidrugresistant Mycobacterium tuberculosis isolates. Journal of Clinical Microbiology 46(10): 3459–3464.

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Multidrug-resistant tuberculosis (MDR-TB)

78. Khurram, M., Khaar, H.T. and Fahim, M. (2012) Multidrug-resistant tuberculosis in Rawalpindi, Pakistan. The Journal of Infection in Developing Countries 6(1): 29–32. 79. Whitfield, M.G. et al (2015) A global perspective on pyrazinamide resistance: Systematic review and meta-analysis. PLoS ONE 10(7): e0133869. 80. Otu, A., Umoh, V., Habib, A., Ameh, S., Lawson, L. and Ansa, V. (2013) Drug Resistance among Pulmonary Tuberculosis Patients in Calabar. Pulmonary Medicine, doi:101155/2013/ 235190. 81. Franke, M. et al (2015) Counting pyrazinamide in regimens for multidrug – Resistant tuberculosis. Annals of American Thoracic Society 12(5): 674–679. 82. Laniado-Laborin, R. (2010) Multidrug-resistant tuberculosis: standardized or individualized treatment? The question has already been answered. Expert Review of Respiratory Medicine 4(2): 143–146. 83. Suárez, P. et al (2002) Feasibility and cost – effectiveness of standardized second-line drug treatment for chronic tuberculosis patients: A national cohort study in Peru. The Lancet 359(9322): 1980–1989. 84. Park, S., Lee, W.C., Lee, D.H., Mitnick, C.D., Han, L. and Seung, K.J. (2004) Self-administered, standardized regimens for multidrug-resistant tuberculosis in South Korea. International Journal of Tuberculosis and Lung Disease 8(3): 361–368. 85. Mitnick, C. et al (2003) Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. The New England Journal of Medicine 348: 119–128. 86. Leimane, V. et al (2005) Clinical outcome of individualized treatment of multidrug-resistant tuberculosis in Latvia: A retrospective cohort study. The Lancet 365(9456): 318–326. 87. Government of India. TB India. (2013) Revised national TB control program annual status report, New Delhi, http://www.tbcindia.nic.in/pdfs/TB%20India%202013.pdf, accessed 15 April 2014. 88. World Bank. (2013) Public health expenditure data, http://data.worldbank.org/indicator/SH. XPD.PUBL.ZS, accessed 5 March 2014. 89. Escombe, A.R. et al (2013) Upper-room ultraviolet light and negative air ionization to prevent tuberculosis transmission. PLoS Med 6(3): e1000043.

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