|Year : 2018 | Volume
| Issue : 2 | Page : 112-121
Epidemiology of multi-drug-resistant tuberculosis in Northern India
Ankur Kumar, Amresh Kumar Singh, Vandana Upadhyay, Jayesh Pandey
Department of Microbiology, Baba Raghav Das Medical College, Gorakhpur, Uttar Pradesh, India
|Date of Web Publication||14-Jun-2018|
Dr. Amresh Kumar Singh
Department of Microbiology, Baba Raghav Das Medical College, Gorakhpur - 273 013, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
India is the world's second most populous country, accounting for a quarter of the world's annual incidence of tuberculosis (TB). Every year around 2 million people develop TB in India and 300,000 die due to the TB. The emergence of drug-resistant-TB (DR-TB) has become a major public health concern in India. This situation is worsened by the appearance of multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis. We sought to determine the characteristics and relative frequency of transmission of MDR-TB in North India and their association with the clinical and epidemiological characteristics of TB-patients and to mitigate the impeding drug-resistant TB epidemic in the country; it will help to established TB surveillance system effectively in the country. Diagnosis of MDR-TB prompts an appropriate treatment for patients with presumptive MDR-TB or rifampicin resistance in TB patients who have failed treatment with first-line drugs. If left undiagnosed or poorly treated, MDR-TB patients suffer for months to years before succumbing to the disease; hence, transmission of MDR-TB continues MDR-TB patients were found to be significantly higher in previously treated patients in comparison to newly diagnosed patients. The emerging drug susceptibility testing patterns and enlisting the help of an expert in DR-TB should be sought sooner rather than later through more than 100 established DR-TB centers across the country. To control the primary transmission of MDR-TB in Northern India, we recommend that improving the social support, living standards, and medical security of each patient should become a priority.
Keywords: Drug sensitivity testing, multi-drug resistant tuberculosis, rifampicin
|How to cite this article:|
Kumar A, Singh AK, Upadhyay V, Pandey J. Epidemiology of multi-drug-resistant tuberculosis in Northern India. Biomed Biotechnol Res J 2018;2:112-21
|How to cite this URL:|
Kumar A, Singh AK, Upadhyay V, Pandey J. Epidemiology of multi-drug-resistant tuberculosis in Northern India. Biomed Biotechnol Res J [serial online] 2018 [cited 2020 Dec 1];2:112-21. Available from: https://www.bmbtrj.org/text.asp?2018/2/2/112/234454
| Introduction|| |
Tuberculosis (TB), a well-known bacterial disease from the past 5000 years, is still infecting nearly one-third of world population with daily addition of 5000 new cases and loss of two lives every 3rd min. In India, 1.9 million new cases are reported every year, of which 0.8 million new cases are “infectious smear-positive TB cases.” According to the World Health Organisation (WHO), the death rate due to TB in India is nearly 28/100,000 population, which is the highest among all other communicable diseases and accounts for 26% of all avoidable adult deaths.
Multidrug-resistant TB (MDR-TB) is the most serious problem among the pandemic of antibiotic resistance because TB patients that fail treatment have a high risk of death. According to a study of MDR-TB patients from 2005 to 2008 conduct in several countries, had 43.7% resistance to least one second-line drug (SLD). About 9% of MDR-TB cases also have resistance to two other classes of drugs and are labeled as extensively DR-TB (XDR-TB). However, the WHO revised the case definition of XDR-TB as “TB with resistance to at least H and R as well as further resistance to any FQs (ofloxacin [Ofx], levofloxacin [Lfx], or moxifloxacin [Mfx]) and second-line injectable drugs (kanamycin [Km], amikacin [Amk], or capreomycin [Cm]) in Global XDR-TB Task Force. This definition was considered given the difficulty in testing some SLDs and less treatability of some forms of drug resistance as compared to others. Further, two new terminologies pre-XDR-TB and extremely DR-TB (XXDR-TB) also called total drug resistance (TDR-TB) had been introduced recently based on SLDs resistance pattern.
First XDR-TB case was described in 2006, drew attention to the emergence of TDR-TB in a cohort of 15 patients from Iran, resistant to all SLDs. Since the first cases of XDR-TB in India were reported from the P. D. Hinduja National Hospital and Medical Research Centre, Mumbai. They have described the first patients from India with TDR-TB.
As per the WHO Global Report on TB 2013, India accounts for highest burden of MDR-TB cases, i.e. 64,000 MDR-TB cases out of 300,000 cases estimated globally occur among the notified pulmonary TB cases annually.
The prevalence of MDR-TB was found at a very low level among most of the countries, where it has been studied. Data from studies conducted by NIRT Chennai (erstwhile TRC) and National Tuberculosis Institute Bangalore have found MDR-TB levels of 1% to 3% in new cases and around 12% in retreatment cases.
MDR-TB, defined as resistance to both isoniazid (INH) and rifampicin (RIF), is a worldwide problem and it is one of the greatest challenges facing public health, particularly in resource-poor settings where adequate diagnosis and treatment are often unavailable. MDR-TB reduces responses to standard short-course chemotherapy with first-line anti-TB drugs, leads to higher mortality and treatment failure rates, and increases the period of transmissibility of the disease resulting super-resistant strains have emerged. India ranks first out of the 22 countries with the highest burden of the disease. Unfortunately, sufficient information on the magnitude of MDR-TB in the country is largely unavailable at the root level.
The prevalence of drug resistance TB is an important epidemiological indicator to assess the amount of transmission of resistant bacteria in the community, as the patients harboring resistant bacilli and remain infectious for a prolonged period and may be more likely to infect others. Hence, there is a need to strengthen the surveillance for DR-TB to ensure continuous monitoring of the epidemiological profile of MDR-TB and XDR-TB. In India, it is difficult to determine the exact magnitude of the problem of DR-TB as the majority of the laboratories providing services for microscopic diagnosis of TB, and there are only a limited number of laboratories capable of conducting quality assured the first-line and second-line drug susceptibility testing (DST) in India.
| Types of Drug Resistance|| |
Drug resistance may be of two types as follows: primary and acquired. Primary drug resistance may be defined as drug resistance in a patient who has not received any anti-tubercular treatment in the past. The resistance that develops in a patient who has received prior chemotherapy is defined as acquired drug resistance. Recently, the terms “resistance in new cases” and “resistance in previously treated cases” have been proposed for use because of the difficulty to confirm the validity of the patients' history of treatment. Combined resistance is defined as sums of primary and acquired resistance.
The transmission of DR-TB strains is increasing and playing an important role in emergence of MDR-TB. However, from the available data, it is not feasible to comment on the trend of MDR among new TB cases. The proportion of previously treated cases with MDR-TB varied from 8% to 67%; although, these studies have been conducted in different locations, which indicate an increasing trend of MDR among previously treated cases over the period.,
MDR and XDR-TB are serious forms, and the management of MDR-TB is difficult, much expensive, challenging, and leads to therapeutic failures. Not only that MDR-TB is a potential threat to control of TB but also it is full of challenges starting from diagnosis to treatment, drug delivery.
The emergence of DR TB has become a major public health concern in India. This situation is worsened by the appearance of MDR-TB strains of Mycobacterium tuberculosis; therefore, we have reviewed the studies/information available in the public domain and data from various indexed research papers and attempt to provide an overview of epidemiology in MDR-TB. Simultaneously, we have reviewed current knowledge in the management of MDR-TB and relative frequency of transmission of MDR-TB in North India to elaborate on prospects of control of the disease in the future.
The present review is based on the Medline search performed using the keywords TB, DR-TB, MDR-TB, XDR-TB, and XXDR-TB covering the period up to December 2016 including the morbidity and mortality, annual report of the Revised National TB Control Programme (RNTCP) was searched from 2009 to the 2016 on MDR-TB and XDR-TB. The articles identified on the basis of epidemiology, prevalence, incidence, risk of infection, sources and causes, outcome of DR-TB, and management of the MDR-TB/XDR-TB, including disease prevention and control, improved diagnostic tools and new drugs regimens and HIV seropositivity in TB cases and MDR-TB among new and previously treated TB cases. A total of 11 studies on MDR-TB in North India among the new cases of TB, previously treated cases and annual status report of RNTCP-TB India from 2009 to 2015 and the WHO updates were included in the present review study.
| Epidemiology of Multidrug-Resistant Tuberculosis|| |
In a population of M. tuberculosis, random mutation that results in resistance to anti-tubercular drugs occurs at a relatively low frequency. Clinically, significant drug resistance in TB can develop during anti-TB treatment (acquired resistance). Anti-TB drugs impose selection pressure in a population of M. tuberculosis in which resistant mutants gradually outnumber susceptible bacilli and emerge as the dominant strains. Monotherapy of TB resulting in emergence of resistance to the drug was noted since 1940s when streptomycin (SM) was used alone in the treatment of the disease. Para-aminosalicylic acid (PAS) and subsequently INH were incorporated into the drug regimen to prevent the development of SM resistance. Once resistant bacillary strains emerge during treatment, these could be transmitted in a community. Those who are infected with drug-resistant strains may develop DR-TB before treatment (primary resistance).
The first national drug resistance survey in the world, which involved 974 clinical isolates cultured from newly diagnosed cases of TB in Britain, (1955–1956) showed strains resistance to SM (2.5%), PAS (2.6%), and INH (1.3%). Similar data from the United States showed that INH resistance increased from 6.3% (between 1961 and 1964) to 9.7% (between 1965 and 1968) among patients with newly diagnosed TB. Between 1970 and 1990, there were numerous outbreaks of drug-resistant TB involving strains resistant to two or more drugs. In subsequent years, when strains with resistance to an even greater number of antibiotics were discovered, the term “extensively drug-resistant TB” (XDR-TB) was coined. In March 2006, the first data were published on the worldwide occurrence of TB with resistance to SLDs, termed XDR-TB.
In 2013, an estimated 9 million incident cases of TB among which 1.5 million people died due to the TB (1.1 million deaths among people those were HIV-negative and 360,000 among people those were HIV-positive). Among these deaths, an estimated 210 000 people died due to the MDR-TB, high mortality rate in 480,000 cases of MDR-TB. Following a systematic review of evidence about mortality caused by MDR-TB undertaken in 2013 (Global TB Report) and consensus about which indicators for reporting on the burden of MDR-TB. This report includes updated global estimates of MDR-TB incidence and mortality. The best estimate was 480,000 (350,000–610,000) new cases of MDR-TB worldwide in 2013. This includes total cases of primary and acquired MDR-TB.,,
The number of incident TB cases relative to population globally, 3.5% of new and 20.5% of previously treated TB cases were from MDR-TB in 2013. This translates into an estimated 480,000 people having developed MDR-TB in 2013. On an average, an estimated 9% of patients with MDR-TB had XDR-TB.,
TB remains one of the major public health concerns in the Southeast Asia region according to the WHO, this region accounts for 38% of the global burden of TB regarding incidence. It is estimated that about 3.4 million new cases of TB occur each year and about 440,000 people died of this disease in 2013, most of these cases reported in five countries, namely, Bangladesh, India, Indonesia, Myanmar, and Thailand, which are among the 22 high-TB-burden countries in the world. The prevalence of MDR-TB is lower than 2.2% among new cases and 16% among retreatment cases; however, this translates into nearly 89,000 estimated MDR-TB cases among all TB cases notified in 2013.
Present status in India
India is one of the nations in the world which has the highest burden of MDR-TB. India has 22% (64,000) global MDR-TB cases which are highest in the world according to the WHO 2012 TB report. As per the WHO Global TB Report 2013, India accounts for 64,000 MDR-TB cases out of which 300,000 cases notified as pulmonary TB cases. In 2013, an estimated 480,000 new cases of MDR-TB were reported among which an estimated 190,000 people died of MDR-TB (“Global TB Control 2015, WHO”) worldwide.,
In 2014, the WHO estimated the prevalence of TB was 3.1%, and the estimated percentage of new TB cases of MDR-TB was 2.1% subsequently overall notified cases of MDR-TB cases were 4237 among which 3384 cases on MDR-TB treatment in India. According to the RNTCP-TB Status report 2015, 2016, and 2017 an increasing order 29,057 <36,000 <53,460 of MDR-TB was found in India.,,, In 2014, the cumulative outcomes of 12,125 MDR-TB cases were reported out of which 5796 (48%) were successfully treated, whereas 2682 (22%) died and 2277 (19%) defaulted and 4%–7% progressed to XDR-TB.
During the past four quarters, out of 1, 38, 585 MDR-TB suspects were tested with new rapid TB diagnostic methods and 19,017 MDR-TB cases were diagnosed., Various studies have found MDR-TB prevalence about 3% in new cases and around 12%–17% in retreatment cases as shown in [Table 1].
|Table 1: Present status of pulmonary multi-drug resistant-tuberculosis cases in India|
Click here to view
Multidrug-resistant-tuberculosis burden in North India
According to RNTCP, the burden of TB has been studied in six zones (North, West, and East, South 1 and South 2, and North East) in India. Punjab, Haryana, Chandigarh, Delhi, Himachal Pradesh, UP, and Uttarakhand states come under the North zone of India as per the RNTCP program. North zone of India is the second highest MDR-TB prevalent zone after the West zone of India, As per the RNTCP status report, a total of 25652 MDR-TB cases were detected in 2014, of which 6184 were reported in North India. In 2013, significantly increasing MDR-TB cases were found in North India, especially Delhi (11%), Haryana (14%), and UP (35%) reported a high burden of MDR-TB in North zone.
RNTCP annual report 2015 TB India 255408 “MDR-TB suspects” subjected to C-DST out of which 25652 MDR-TB cases were detected in India and also reported 10% prevalence rate in 2014. In the same period, out of 37958 TB cases, 6184 MDR-TB cases were detected in North India with the 16% prevalence rate in 2014 which is higher than National MDR-TB prevalence rate. In 2015, numbers of laboratory increase under RNTCP for TB-DST in north India; therefore, 67,443 patients were tested for C-DST of which 8729 (13%) cases were found to be positive for MDR-TB strains which were lower than previous year according to the RNTCP annual report 2016 TB India , as shown in [Table 2] and [Figure 1].
|Table 2: Status of multi-drug resistant-tuberculosis in North India between 2014 and 2015 (source of data: Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India 2017)|
Click here to view
|Figure 1: Prevalence of multidrug-resistant-tuberculosis in North India state wise|
Click here to view
The trend of MDR-TB and non MDR-TB was observed from 2010 to 2015 RNTCP annual report. A total cases of 640/1786 (35%), 687/3173 (21%), 947/3782 (25%), 2750/16,301 (16%) and 4879/26,330 (18%), 6184/37,958 (16%), and 8729/6,7443 (13%) were identified as MDR-TB cases in 2009, 2010, 2011, 2012, 2013, and 2014, respectively, in different states of North India ,,,,,,, as shown in [Table 3] and [Figure 2].
|Table 3: Detection and prevalence rate of multi-drug resistant-tuberculosis under Revised National Tuberculosis Control Programme 2009-2016 (RNTCP- PMDT North India)|
Click here to view
|Figure 2: Prevalence of multidrug-resistant-tuberculosis in North India year wise|
Click here to view
Overall, MDR-TB cases gradually decreased from 2009 to 2015 in both new and previously treated cases in North India, but still, the prevalence rate was higher in North India than National prevalence rate of MDR-TB. According to RNTCP, a decreasing number of MDR-TB in North India was noted from 2009 to 2015 as per the RNTCP annual status report ,,,,,,,,, is shown in [Figure 2].
According to a research article based on 4 years retrospective study conducted in Lucknow, UP, a continuous increasing trend of MDR-TB was observed from 2007 to 2010. A total cases of 16 (36.4%), 18 (36.7%), 25 (39.1%), and 38 (40.8%) were identified as MDR-TB cases in 2007, 2008, 2009, and 2010, respectively. Overall MDR-TB gradually increased from 2007 to 2010 in both new and previously treated cases. They found a total of 97 (38.8%) MDR-TB strains from 250 MTB culture isolates tested for first-line anti-tubercular drugs. Of which 97 MDR-TB strains, 80 (82.5%) were from PTB, and 17 (17.5%) were from EPTB cases. Among these, 23 (22%) were new MDR-TB cases, and 74 (77.3%) previously treated cases. They reported a high prevalence (38.8%) of MDR-TB at a tertiary care referral center both in new cases (29.1%) and previously treated cases (43.3%). The prevalence was the most common in the PTB (32%) cases as compared to EPTB (6.8%) cases., Some other studies which were conducted in Delhi also showed a high prevalence of MDR-TB, i.e. 53% MDR-TB combined (new and previously treated cases and 67% in previously treated cases, represents a high burden of MDR-TB in North India.,
Direct nucleic acid amplification tests (NAAT) are playing an increasingly important role in the diagnosis of TB as well as MDR-TB having turnaround time of 2-3 hours, with the WHO endorsing the Xpert MTB/RIF test in 2010.
In another study conducted in Varanasi out of 101 TB isolates, 55 were found to be MDR-TB both INH and RIF resistance. This study showed the bulk of ongoing transmission of MDR-TB strains in Varanasi; Northern India was linked to Beijing genotype followed by the CAS1_Delhi lineage. The study showed that a total of 123 (58.5%) strains were identified as resistant to one or more than one anti-tubercular drug and 86 (41.5%) strains were pan-susceptible (SS). Out of 123 resistant cases, 55 (44.7%) strains were identified as MDR-TB, and 68 (55.3%) strains were mono-resistance either for INH or RIF. In further findings of MDR-TB in Uttar Pradesh (UP) shown greatly increased the prevalence of MDR-TB.,, Similar findings were also reported from Dehradun (UK) showed 57% prevalence of MDR-TB in previously treated cases in North India. Since then, we observed several studies had been conducted in others cities in North India. A Study of Chandigarh, in this study, MDR-TB found with an overall prevalence of 17.8% (39/219). Of which 9.9% new MDR-TB was observed which was higher than the WHO estimated the prevalence of 2.1% of MDR-TB among the notified newly diagnosed pulmonary TB cases in India in 2010. However, the reports of prevalence of MDR-TB in newly diagnosed cases vary from 0.6%–24% from different regions of the country.
In a combined study from Himachal Pradesh and Chandigarh, out of 910 PTB cases, only 52 cases were enrolled as MDR-TB as per definition. Fifty-two (5.7%) cases of MDR-TB were identified, among which 8 (15.3%) were diagnosed with XDR-TB on the basis of drug susceptibility testing (DST).
Similarly, a study of Kashmir, out of 910 PTB cases 52 (5.7%) cases of MDR-TB were identified, among which 8 (15.3%) were diagnosed with XDR-TB on the basis of DST, using the standard definition. The study identified 19 (36.5%) cases with initial resistance and 33 who had interrupted anti-TB therapy (63.4%) with secondary resistance. Results of the drug-susceptibility testing showed the highest resistance to four drugs (53%), lowest resistance was against PAS and amikacin.
The trends of MDR-TB in a Delhi based study showed, 353 TB cases subjected to DST, 239 (68%) were detected as MDR-TB, i.e., resistant to both INH and RIF). Among the MDR patients (67.7%), the proportion of resistance to three or more drugs including HR (86.1%) was greater than that of resistance to HR only (13.8%).
According to the programmatic management of drug-resistant tuberculosis (PMDT) till March 2010 out of 446 MDR suspects, 87 MDR cases were detected under RNTCP-DST laboratory in Haryana. Finally, the findings of this report highlight the strong need to implement better and rapid diagnostic methods, which will be useful in early detection of MDR-TB and to minimize the risk of transmission of DR-TB strains.
According to a multicentered study conducted in different part of North India from Chandigarh, Himachal Pradesh, Punjab, Jammu and Kashmir, and Haryana reported the prevalence of MDR-TB was found to be 9% in newly diagnosed cases, which is higher than 3%–5% global prevalence rate. A new case of TB was defined as a patient who has never had treatment for TB or who has taken anti-TB drugs for less than a month. There were 121 newly diagnosed and 98 previously treated MDR-TB patients, of which MDR-TB was found to be associated with 9.9% and 27.6% of cases, respectively. This was an Indian Council of Medical Research-funded-study for over 3 years, a revealed high prevalence of DR-TB among PTB isolates from north India as compared to the WHO estimates in India in 2010.
Another study from Punjab reported, the prevalence rate of 26% MDR-TB in newly diagnosed cases showing the high burden of MDR-TB in Punjab as compared to another state of North India.
We collected the data of MDR-TB cases from Annual Status report of RNTCP, and several original studies were conducted in different part of north India as shown in [Table 4].
|Table 4: Prevalence of multi-drug resistant-tuberculosis in different part of north India|
Click here to view
Management of multidrug-resistant-tuberculosis
Recommendations for the management of patients with MDR-TB and XDR-TB have recently been reviewed. A method for grouping anti-TB drugs, based on potency, the experience of use and drug classes can be used to design an empirical regimen. Treatment outcomes are optimized if patients with MDR-TB or XDR-TB receive timely and adequate empirical therapy including multiple drugs such patient has not been treated before initiation of treatment for MDR-TB cases.
Timely identification of MDR-TB cases and adequately administered treatment regimens are essential to stop primary transmission of MDR-TB. WHO endorsed thrice weekly anti-tubercular treatment regimen, administered under the directly observed treatment-short course (DOTS), after its use for two decades, was questioned for its effectiveness in the treatment of MDR-TB and it was realized that the treatment of MDR-TB cases is very complex therefore RNTCP of India introduced the internationally recommended PMDT services since 2007 but now, daily regimen for the treatment of TB patients are widely accepted and started in India.,,
PMDT is an integrated program which encompasses diagnosis, treatment, and management of MDR-TB, previously known as DOTS-plus. Major emphasis is given on registering, monitoring, and reporting of MDR-TB cases, under new guidelines of PMDT. This program is run jointly by the WHO-Stop TB and Green Light Committee (GLC). Hence reaching to remotest area of the country, providing a rapid diagnosis, and appropriate category of treatment are integral objectives of this program.,
For PMDT to be successful, special attention is laid on the following:
(i) Efficient and timely identification of patients who require DST; (ii) quality-assured laboratory capacity (smear, culture-DST, and rapid molecular test); (iii) efficient drug procurement and supply chain management; (iv) adherence to difficult-to-take regimens for long periods; (v) prompt identification and management of side-effects; (vi) recording and reporting; and (vii) human and financial resources., Thus, the emergence of drug-resistant strains is known to reduce the efficacy of treatment. Strains resistant to INH and/or SM neither pose a major problem nor affect the result of treatment in a big way provided proper regimens are used. The currently available short-course regimens of 6 months duration cure 94%–97% of patients with resistance to SM, INH or both drugs. On the contrary, the outcome of treatment of patients infected with organisms resistant to RIF and INH MDR-TB have a high rate of treatment failure.,,
A clinical diagnosis of XDR-TB is difficult, however, the strongest risk factors to suspect XDR-TB include; failure of an MDR-TB treatment regimen and close contact with an XDR-TB patient or an individual for whom treatment with SLDs has failed. A detailed evaluation of the history of previous exposure to ATT including first-line drugs as well as SLDs is essential. XDR-TB cases constitute two major subgroups as follows: (i) MDR-TB at diagnosis (not exposed to SLDs) and (ii) MDR-TB therapy failure (exposed to SLDs). The classification is important as it is a major variable for XDR-TB therapy response as XDR-TB patients belonging to the latter group are difficult to treat as compared to former one.
Control and prevention
The primary aim in the control of drug-resistant and MDR-TB is to prevent its development in the first phase. This can be done by DOTS, which are the most cost-effective way of treatment and prevention of MDR-TB. At the same time, since MDR-TB cases respond poorly to short-course chemotherapy, careful introduction of reserve drugs to treat MDR-TB cases to reduce further transmission of such strains will be required. Since new drugs for TB are unlikely to come up shortly, the key to success remains in the prompt and correct diagnosis and effective treatment. Apart from a strong TB control program, there is also a need for a continuous and periodic survey of drug resistance, instead of current and past MDR-TB chemotherapy programs.
It is well known that poor treatment practices breed drug resistance. Areas with a poor TB control tend to have higher rates of DR-TB. It has been acknowledged that good treatment is a prerequisite to the prevention of emergence of resistance. Prevention of emergence of MDR-TB in the community is more imperative rather than its treatment. It is impossible to tackle the problem of DR-TB through treatment alone; each MDR-TB case costs more than 20 times the cost of a simple drug-susceptible TB case, therefore, basic TB diagnostic and treatment services would be prioritized as per PMDT. In PMDT services, for the management of MDR-TB, are supplementary services under the expanded framework of the DOTS package. This should be a protocol for every hospital treating TB patients in India.
There are two main approaches to prevent multi-drug resistance as follows: (a) Identification and treatment of patients with multi-drug resistant TB. (b) Identification of persons with tubercular infection and their proper initiation of treatment to prevent the 5%–10% risk of subsequent development of the disease.,
Patterns of drug resistance should be evaluated regularly in the community. Therefore, detection and treatment of all forms of TB, including MDR-TB, should be integrated into national TB control programs. The framework for PMDT treatment of MDR-TB cases presented in this document is to be integrated into the TB free strategy.
MDR-TB cannot be cured by the two major TB drugs, INH and rifampin. XDR-TB is resistant to those drugs as well as three or more of the second line TB drugs. Treating these resistant forms of TB is far more costly than is treating non resistant TB. Treatment of DR-TB requires taking a “cocktail” of at least four drugs, including first-line medications that are still effective and several second-line medications, for 18 months to 2 years or longer. If treatment is successful, you may need surgery to remove areas of persistent infection or repair lung damage.
Treatment of XDR-TB is difficult and expensive. Less powerful agents (second-line and Group V agents) are required because R and H cannot be used and drugs have to be used for a longer duration. According to the WHO Global Report, (2016) 2130 XDR-TB cases were prescribed SLD under PMDT of RNTCP with treatment success rate of 37% in 2013. There is a need to introduce new classes of ATT that can be used for treating XDR-TB. Linezolid is one of the drugs, which has been utilized in managing XDR-TB cases.
| Treatment under Programmatic Management of Drug-Resistant-Tuberculosis in India|| |
The RNTCP-PMDT vision is to promptly diagnose and effectively treat all TB patients with DR-TB, through decentralized DST and PMDT treatment services integrated into RNTCP. Given the complexity, scale and cost, a phased approach has been developed, focusing first on those most likely to have DR-TB.
The treatment is given in two phases, the intensive phase (IP) and the continuation phase (CP). The total duration of treatment for regimen for MDR-TB is 24–27 months, depending on the IP duration. IP should be given for at least 6 months and thereafter, the patient will be reviewed and the treatment changed to CP if the 4th or 5th month culture result in solid or liquid culture is negative, respectively. If the 4th or 5th month culture result remains positive, the treatment is extended by 1 month. Extension of IP beyond 1 month will be decided on the results of sputum culture of 5th or 6th and 6th or 7th months. If the result of the 4th month culture is still awaited after 6 months of treatment, the IP is extended until the result is available, with further treatment being decided according to the culture result. The IP can be extended up to a maximum of 3rd month after which the patient will be initiated on the CP irrespective of the culture result. The recommended duration for CP is 18 months.,,
| Regimen for Multidrug-Resistant-Tuberculosis|| |
This regimen comprises 6 drugs-kanamycin, levofloxacin, ethionamide, pyrazinamide, ethambutol, and cycloserine during 6–9 months IP and four drugs levofloxacin, ethionamide, ethambutol, and cycloserine during the 18 months of CP. In the treatment of patients with MDR-TB, four second-line anti-TB drugs likely to be effective (including a parenteral agent), as well as pyrazinamide and ethambutol should be included in the IP,, the duration of that should be at least for 6 to 9 months. Consider extending treatment at least 18 months beyond the last evidence of mycobacteria in a culture from the patient. Thus, the total duration of treatment should be at least 24 months up to a maximum of 27 months in patients newly diagnosed with MDR-TB (i.e., not previously treated for MDR-TB). Doses are recommended as per the PMDT guideline as shown in [Table 5].,
|Table 5: Drug susceptibility testing guided regimen with or without newer drugs for initiating treatment of drug-resistant tuberculosis patients with additional resistance to fluoroquinolone class and/or second-line injectable class, at NDR-TBC based on SL-LPA|
Click here to view
In the treatment of patients with MDR-TB, regimens should thus include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), either cycloserine or PAS if cycloserine cannot be used., Treatment regimen may be suitably modified in case of ofloxacin and/or kanamycin resistance detected early at the initiation of MDR-TB treatment or during early IP, preferably not <4–6 weeks. However, for patients on MDR-TB regimen that are found to be resistant to at least ofloxacin and/or kanamycin during the later stage of MDR-TB treatment; they should be treated with a suitable regimen for XDR-TB using SLDs including group 5 drugs as per the PMDT guideline to which the organisms are known or presumed to be susceptible.,
The MDR-TB patients diagnosed with baseline FQ and injectable aminoglycosides resistance are treated with modified category IV (CAT-IV) regimen, whereas the same resistance patterns among nonresponders and failures of CAT-IV are treated with CAT-V regimen for up to 24–30 months daily regimen. The standardized regimen for CAT-V consists of seven drugs, with two reserve/substitute drugs. The IP (6–12 months) consists of seven drugs-Cm, PAS, Mfx, high-dose H, Cfz, Lzd, and amoxyclav, whereas CP (18 months) consists of six drugs–PAS, Mfx, high-dose H, Cfz, Lzd, and amoxyclav. The dosages of the drugs would vary as per the weight bands of the patient. All drugs are to be given on a daily basis under supervision of a directly observed treatment provider.
Majority of these pre-XDR cases was due to resistance to fluoroquinolones (66.3% [95% confidence interval (CI) =58.2; 74.4, n = 5]). Prevalence of XDR-TB was notified in 14 studies and the countrywide prevalence was (1.9% [95% CI = 1.2; 2.6]). Due to limited data from published studies for pre-XDR and XDR-TB, a subgroup analysis stratified by regions and decades could not be performed.
However, the recently published ATS/CDC/IDSA guidelines suggest that among the fluoroquinolones, levofloxacin is the most suited for the treatment of MDR-TB and XDR-TB. These observations need to be confirmed in prospective studies with a large sample size. When administering ATT by the parenteral route, proper precautions should be taken. This is particularly relevant in resource limited countries like India would be a health hazard, especially in patients with HIV.,,
The study found that the frequency of drug resistance in previously treated TB is higher than those of newly diagnosed patients for a single drug as well as for all first-line anti-TB drugs, as stated earlier in several studies.,,
We observed that North zone of India is the second highest MDR-TB prevalent zone after the West zone of India among 25,652 total case detected in 2014 of which 6184 (24%) were found in North India which is 4% is high than previous year. In North India, especially Delhi (11%), Haryana (14%), and UP (35%) had a high burden of MDR-TB (RNTCP Annual status Report 2015).,,,
| Conclusion|| |
In this review, based on ten studies from North India conducted in different cities, RNTCP status report from 2009 to 2015 and PMDT guideline showed high prevalence rate of MDR-TB in North India. To control primary transmission of MDR-TB in India, we recommend that improving the social support, living standards, and medical security of the lower social class should be a priority. Efforts should be focused on the effective use of first-line drugs in every category I and category II patients as practiced in the RNTCP to prevent the ultimate emergence of MDR-TB. Most importantly, treatment of MDR-TB is a challenge which should be undertaken by experienced clinicians at centers equipped with reliable laboratory service for mycobacterial culture and in vitro sensitivity testing.
It is high time to establish modern laboratories with a molecular diagnostic facility in each district to diagnose MDR-TB in the early stage to prevent the spread of MDR-TB. Implementation of the new mycobacteriology laboratory to be capable for DST at the district level was a historical step taken by RNTCP to achieve the target of preventing drug resistance TB in India, with CBNAAT available in almost all district level facilities. India achieved complete geographical coverage for diagnostic and treatment services for MDR-TB in 2013, with a remarkable 93,000 persons with MDR-TB diagnosed and treated with treatment until 2015 by the RNTCP's efforts. Availability of new drugs, regimens, diagnostics approaches, and strategies to end TB should be employed in the current MDR-TB control program, and operational research mechanisms should be strengthened.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Myneedu VP, Visalakshi P, Verma AK, Behera D, Bhalla M. Prevalence of XDR TB cases – A retrospective study from a tertiary care TB hospital. Indian J Tuberc 2011;58:54-9.
World Health Organization. Global Tuberculosis Control Surveillance, Planning, Financing; WHO Report 2010. WHO/HTM/TB/. Geneva: World Health Organization; 2010. p. 393.
Sharma SK, Mohan A. Multidrug-resistant tuberculosis. Indian J Med Res 2004;120:354-76.
Raviglione CM, O'Brien RJ. Antimycobacterial agents. Harrison's Principles of Internal Medicine. Medical. Vol. 18e. Ch. 168. Available from: http://www.accessmedicine.mhmedical.com
. [Last retrieved on 2016 Jul 12].
Velayati AA, Farnia P, Masjedi MR. The totally drug resistant tuberculosis (TDR-TB). Int J Clin Exp Med 2013;6:307-9.
Prasad R, Singh A, Balasubramanian V, Gupta N. Extensively drug-resistant tuberculosis in India: Current evidence on diagnosis & management. Indian J Med Res 2017;145:271-93.
] [Full text]
Rowland K. Totally drug-resistant TB emerges in India 'Discovery of a deadly form of TB highlights crisis of 'mismanagement'. Nature News by Springer Nature. 2012 doi:10.1038/ nature.2012.9797.
Central TB Division, Directorate General of Health Services Ministry of Health and Family Welfare. TB Annual Report 2014. Nirman Bhavan, New Delhi: Central TB Division, Directorate General of Health Services Ministry of Health and Family Welfare; 2014. [Last accessed on 2018 Mar 18].
Central TB Division, Directorate General of Health Services, Ministry of Health & Family Welfare. Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India: Revised National Tuberculosis Control Programme. Central TB Division, Directorate General of Health Services, Ministry of Health & Family Welfare; May, 2012.
Gupta A, Kulkarni S, Rastogi N, Anupurba S. A study of Mycobacterium tuberculosis
genotypic diversity & drug resistance mutations in Varanasi, North India. Indian J Med Res 2014;139:892-902.
] [Full text]
Sethi S, Mewara A, Dhatwalia SK, Singh H, Yadav R, Singh K, et al.
Prevalence of multidrug resistance in Mycobacterium tuberculosis
isolates from HIV seropositive and seronegative patients with pulmonary tuberculosis in North India. BMC Infect Dis 2013;13:137.
Prasad R. MDR TB: Current status. Indian J Tuberc 2005;52:121-31.
Jain RC. Tuberculosis – Challenges and opportunities. Indian J Tuberc 2011;58:148-54.
Chiang CY, Centis R, Migliori GB. Drug-resistant tuberculosis: Past, present, future. Respirology 2010;15:413-32.
Keshavjee S, Farmer PE. Tuberculosis, drug resistance, and the history of modern medicine. N Engl J Med 2012;367:931-6.
Basu S, Andrews JR, Poolman EM, Gandhi NR, Shah NS, Moll A, et al.
Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: An epidemiological modelling study. Lancet 2007;370:1500-7.
World Health Organization. Global Tuberculosis TB Report 2014. WHO/HTM/TB/2014.08. Geneva, Switzerland: WHO; 2014. Available from: apps.who.int/ iris/bitstream/10665/137094/1/9789241564809_eng.pdf. [Last accessed on 2017 Nov 26].
World Health Organization. Global tuberculosis report 2015, 20th
ed. WHO/HTM/TB/2015.22. Geneva Switzerland: WHO; 2015. Available from: apps.who.int/iris/ bitstream/ 10665/191102/1/9789241565059_eng.pdf. [Last acceseed on 2017 Nov 26].
Central TB Division, Directorate General of Health Services, Ministry of Health with Family Welfare. National Strategic Plan for Tuberculosis Elimination 2017–2025. Revised National Tuberculosis Control Programme. Nirman Bhavan, New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health with Family Welfare; March, 2017.
Central TB Division, Ministry of Health and Family Welfare. Revised National TB Control Program Annual Status Report TB India 2013. New Delhi, India. Ministry of Health and Family Welfare; 2013. Available from: https://tbcindia.gov.in/showfile.php?lid=3163
[Last accessed on 2017 Sep 11].
Central TB Division, Ministry of Health and Family Welfare. Revised National TB Control Program Annual Status Report TB India 2015. New Delhi, India. Ministry of Health and Family Welfare; 2015. Available from: https://tbcindia.gov.in/showfile.php?lid=3166
[Last accessed on 2017 September 11]
Central TB Division, Ministry of Health and Family Welfare. Revised National TB Control Program Annual Status Report TB India 2009. New Delhi, India: Ministry of Health and Family Welfare; 2009. Available from: https://tbcindia. gov.in/showfile.php?lid=2921
. [Last accessed on 2017 Dec 17].
Central TB Division, Ministry of Health and Family Welfare. Revised National TB Control Program Annual Status Report TB India 2010. New Delhi, India: Ministry of Health and Family Welfare; 2010. Available from: https://tbcindia. gov.in/showfile.php?lid=2921
. [Last accessed on 2017 Dec 17].
Central TB Division, Ministry of Health and Family Welfare. Revised National TB Control Program Annual Status Report TB India 2011. New Delhi, India: Ministry of Health and Family Welfare; 2011. Available from:https://tbcindia. gov.in/showfile.php?lid=3141
. [Last accessed on 2017 Dec 17].
Central TB Division, Ministry of Health and Family Welfare. Revised National TB Control Program Annual Status Report TB India 2012. New Delhi, India: Ministry of Health and Family Welfare; 2012. Available from: https://tbcindia. gov.in/showfile.php?lid=3141
. [Last accessed on 2017 Dec 17].
Maurya AK, Singh AK, Kumar M, Umrao J, Kant S, Nag VL, et al
. Patterns and trends of multidrug-resistance tuberculosis. Indian J Med Microbiol 2013;31:40-6.
] [Full text]
Maurya AK, Umrao J, Singh AK, Kant S, Kushwaha RA, Dhole TN, et al.
Evaluation of GenoType® MTBDRplus assay for rapid detection of drug susceptibility testing of multi-drug resistance tuberculosis in Northern India. Indian J Pathol Microbiol 2013;56:139-43.
] [Full text]
Singh N, Sidiq Z, Bhalla M, Myneedu VP, Sarin R. Multi-drug resistant tuberculosis among category I treatment failures – A retrospective study. Indian J Tuberc 2014;61:148-51.
Khanna A, Raj VS, Tarai B, Sood R, Pareek PK, Upadhyay DJ, et al.
Emergence and molecular characterization of extensively drug-resistant Mycobacterium tuberculosis
clinical isolates from the Delhi region in India. Antimicrob Agents Chemother 2010;54:4789-93.
Jeanes C, O'Grady J. Diagnosing tuberculosis in the 21st
century – Dawn of a genomics revolution? Int J Mycobacteriol 2016;5:384-91. [Full text]
Rawat J, Sindhwani G, Juyal R, Dua R. Five-year trend of acquired antitubercular drug resistance in patients attending a tertiary care hospital at Dehradun (Uttarakhand). Lung India 2009;26:106-8.
] [Full text]
Sethi S, Mewara A, Dhatwalia KS, Singh H, Yadav R, Singh K, et al
. TB genotypic diversity in Northern India. Indian J Med Res 2014;139:892-902.
Phageshwar, Wani I, Chander J. Incidence of multidrug-resistant (MDR) and extensively drug resistant (XDR) Tuberculosis among different age groups in tertiary care hospitals of Chandigarh, India. Biol Forum Int J 2013;5:21-6.
Datta BS, Hassan G, Kadri SM, Qureshi W, Kamili MA, Singh H, et al.
Multidrug-resistant and extensively drug resistant tuberculosis in Kashmir, India. J Infect Dev Ctries 2009;4:19-23.
Central TB Division, Directorate General of Health Services, Ministry of Health & Family Welfare. Revised National Tuberculosis Control Programme: Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India. Nirman Bhavan, New Delhi: Central TB Division, Directorate General of Health Services, Ministry of Health & Family Welfare; May, 2012.
Kumar P, Kumar P, Balooni V, Singh S. Genetic mutations associated with rifampicin and isoniazid resistance in MDR-TB patients in North-West India. Int J Tuberc Lung Dis 2015;19:434-9.
Gopal M, Padayatchi N, Metcalfe JZ, O'Donnell MR. Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. Int J Tuberc Lung Dis 2013;17:1001-7.
Bhowmik D, Chiranjib. B, Chandira R, Jayakar BKP. Sampath Kumar. Recent trends of drug used treatment of tuberculosis. J Chem Pharm Res 2009;1:113-33.
Ministry of Health & Family Welfare. Revised National Tuberculosis Control Programme: Guidelines on Programmatic Management of Drug Resistant TB (PMDT) in India. Central TB Division, Directorate General of Health Services. New Delhi: Ministry of Health & Family Welfare; 2017. p. 1-190.
Ministry of Health & Family Welfare, and Government of India. Standards for TB Care in India under the Central TB Division, (STCI Book Final) New Delhi. MoH & FW, Government of India & World Health Organization; 2014.
Prasad R. Management of multi-drug resistant tuberculosis: Practitioner's view point. Indian J Tuberc 2007;54:3-11.
Prakash R, Kumar D, Gupta VK, Jain S, Chauhan DS, Tiwari PK, et al.
Status of multidrug resistant tuberculosis (MDR-TB) among the Sahariya tribe of North central India. J Infect Public Health 2016;9:289-97.
Sinha P, Srivastava GN, Gupta A, Anupurba S. Association of risk factors and drug resistance pattern in tuberculosis patients in North India. J Glob Infect Dis 2017;9:139-45.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]