Issues in the management of drug resistant tuberculosis in India.

Emergence of drug resistant tuberculosis (TB), particularly multidrug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB) is a matter of great concern world over including India. India has the second highest burden of MDR-TB cases following China and it is reported that the country has approximately 66,000 MDR-TB cases among notified pulmonary TB cases in 2011 (new cases - 21,000 with a range of 15,000-27,000 and retreatment cases — 45,000 with a range of 40,000-50,000).[1] Various surveys carried out in India by well-qualified and accredited laboratories revealed that MDR-TB in new cases is about 2.1% (1.5-2.7) and is about 15% (13-16) in retreatment cases.[12] In the global scenario, about 9% of all MDR cases are XDR-TB. Although, the exact extent of XDR-TB in India is not known, the Gujarat survey carried out by the Central TB Division through National Institute for Research in Tuberculosis (NIRT), Chennai showed that of 1,571 isolates from new patients, 1,236 (78.7%) were susceptible to all first-line drugs, 173 (11%) had any isozniazid (INH) resistance and MDR-TB was found in 37 (2.4%, 95% confidence interval (CI) 1.6-3.1). Of 1,047 isolates from previously treated patients, 564 (54%) were susceptible to all first-line drugs, 387 (37%) had any INH resistance, and MDR-TB was found in 182 (17.4%, 95% CI 15.0-19.7%). Among 216 MDR-TB isolates, 52 (24%) were ofloxacin (OFX) resistant; seven cases of XDR-TB were found, all of whom were previously treated cases.[2] A recent study from Delhi region reported that 3.7% were XDR-TB cases among 483 MDR-TB cases, most of which were previously treated.[3] Thus, DR-TB is an important issue as far as our TB control efforts are concerned.

The currently recommended approach to TB care and control by World Health Organization (WHO) is the Stop TB Strategy, launched in 2006. This strategy was linked to new global targets for reductions in TB cases and deaths that were set for 2015 as part of the Millennium Development Goals (MDGs) and by the Stop TB Partnership. The targets are that TB incidence should be falling by 2015 (MDG Target 6.c) and that prevalence and death rates should be halved compared with their levels in 1990. Further, the goal is to halt and begin to reverse the incidence, prevalence and death rates associated with TB. Another important indicator was proportion of TB cases detected and cured under directly observed treatment, short-course (DOTS). The initial target and goals set by the Revised National Tuberculosis Control Program (RNTCP) of 70% case detection and cure has already been achieved and being sustained over years by the program.[456] However, the true success or otherwise of any national TB control program rests on three important parameters: Success rate, relapse rates after successful completion/cure of cases, and the extent of drug resistance observed and various steps being taken by the program to diagnose and treat these cases, particularly the MDR- and XDR-TB cases. While the RNTCP of India, has achieved the case detection and cure rates as envisaged originally (the target has since been revised for 90/90), we do not have an exact idea of relapse, whether the incidence is decreasing or increasing as there is no comparator at the baseline. Some believe that the relapse is increasing. A recent meta-analysis showed that relapse rate is around 10% in India[4] and the risk factors for relapse included drug irregularity, initial drug resistance, smoking, and alcoholism. The outcome of relapse cases put on treatment is positive, but less effective than new cases. In fact the success rates for relapse cases (Cat II) are more than 70% if we include the treatment completion cases.[5] The matter is further complicated by the fact that such relapses can either be due to reinfection or reactivation, for which one need to do genotyping studies.[6] Such information unfortunately is not available in India, although the Central TB Division has planned such a study in the near future. Thus, it cannot be said for sure that such relapses, if occur, under the program is not entirely due to the fault of the program or the intermittent regimen currently used by the RNTCP of India. Further, it must be realized that most of these relapse/retreatment or failure cases get enrolled into the program from private sector or from outside the program, at least 50% of these cases are not initially in the RNTCP. They have received multiple courses of antituberculosis treatment (ATT), with varying dosages, combinations and variable periods of treatment. Thus, the outcome will not be very satisfactory. The regimen used for Cat II patients is further criticized by many as the program is adding one new drug to an already failing regimen in these cases. But the point is what the new alternative is? Have we got any other available drug at present so that we are at liberty to add more than two drugs? Fluoroquinolones are reserved for treating MDR/XDR-TB cases. The option is either to use a daily therapy instead of intermittent regimen or treat such cases as per their drug susceptibility. As mentioned above about 15% of these retreatment cases are MDR-TB or some of them are XDR-TB. Singla, et al., in a study of 42 cases of Cat I treatment failure cases reported that among these failure patients at 5 months, 17 (40.5%) had negative sputum culture for Mycobacterium tuberculosis although they were smear positive, and only six (14.3%) had MDR-TB. When put on retreatment, patients with smear-positive, culture-negative sputum had cure rates of 88.2% compared to 28.6% among culture-positive patients.[7] Drug resistance, including poly-, MDR-, and XDR forms of tuberculosis are expected in retreatment cases of pulmonary tuberculosis. In a recent review of national MDR-TB data for the last decade with respect to MDR-TB in Zambia, it is reported that the total number of drug susceptibility tests (DSTs) performed during an 11-year period was 2,038 and accounted for 2.6% (2,038/78,639) of all the retreatment cases notified. The total number of diagnosed MDR-TB cases for this period was 446. Only one child was found to have MDR-TB. Polydrug resistance accounted for 18.9% (172/911) of the DR-TB cases and 8.4% of the total DSTs. 8.8% (80/911) of the DR-TB cases showed either rifampicin mono- or polyresistance other than MDR-TB. No XDR-TB was reported. There were no data available on DR-TB and human immunodeficiency virus syndrome (HIV) coinfection.[8] The proportion of previously treated TB cases with MDR-TB at country level ranged from 0 to 65.1%. Countries or subnational areas with the highest reported proportions were Azerbaijan (Baku city, 55.8% in 2007), Belarus (75.6% in 2011), Estonia (57.7% in 2011), Kazakhstan (51.3% in 2011), Kyrgyzstan (51.6% in 2011; preliminary results), the Republic of Moldova (63.5% in 2011), Tajikistan (53.6% in 2011; preliminary results), and Uzbekistan (62.0% in 2011). In the Russian Federation, even if the average proportion of cases with MDR-TB does not exceed 50%, the proportion is above 50% in several Oblast (with Arkhangelsk Oblast at the highest level: 58.8% in 2008). These data confirm that eastern European and central Asian countries continue to represent hot spots for MDR-TB, with nearly one-third of new and two-thirds of previously treated TB cases affected by MDR-TB in some settings.[1] Fortunately for India, the percentage of retreatment TB cases with MDR-TB is 15 with a limit of 13-16%.[12] Although, it is not a matter of great satisfaction, as many countries have 0% in these cases, it seems the RNTCP is performing reasonably well although one expects it should be much better with an aim for 0% prevalence as far as possible taking into consideration all constraints.

While daily therapy may not be the best option (as intermittent therapy has proven efficacy), DST at the beginning to find out MDR/XDR seems a logical option. Then why this was not followed by the program? The question is of capacity and availability of sufficient number of accredited and qualified laboratories in the country. It is a pity that in India which has the highest number of TB cases of the world had not even a single qualified accredited laboratory for Mycobacterial culture and drug susceptibility testing except in one or two National TB Institutes only. With the initiatives taken by the program a number of laboratories, which are accredited and qualified to take care of these issues, has been set up at different parts of the country (over 40 laboratories now) with a network of Intermediate Reference Laboratories (IRL) and National Reference Laboratories (NRL) and with further effort to increase the number and strengthening. Such, so called Cat II patients are now offered DST at the beginning after the built up of laboratory network, so that drug resistance is taken care at the beginning.

The third important issue is that of emergence of drug resistance. It is to be realized that drug resistance is not a new phenomenon in India. It has been reported even much before the era of RNTCP[9] and also it is natural that drug resistance will occur by any biological agent. However, attention is given by the program on the issues of drug resistance few years back and therefore, there is the issue of grave concern. Besides, the subnational level data collected by the program from the states of Gujarat, Maharashtra, Andhra Pradesh, and Orissa through accredited and qualified laboratories, a number of other studies from the country has focused on the issue of drug resistance,[101112131415161718] although there are issues of quality assurance of laboratories and other methodological issues in some of these reports. In another relatively recent study, culture and drug susceptibility testing results of 2,816 TB patients from across India who had failed repeated treatments from 2001 to 2004 were retrospectively analyzed at the Tuberculosis Research Centre, Chennai. Of 1,498 (53%) identified as having MDR-TB, 671 (44.8%) were resistant to one second-line drugs (SLDs): 490 (32.7%) to ethionamide, 245 (16.4%) to ofloxacin, and 169 (11.3%) to kanamycin; 69 (4.6%) were XDR-TB. It must, however, be remembered that these samples were from a highly select and nonrepresentative patient group. However, such high SLD resistance levels, including XDR-TB, among MDR-TB patients is of concern.[19]

It further needs to be stressed that when we are talking of incidence and prevalence of DR-TB, the assessment should be made by quality assured laboratories as DST is highly technical and accuracy of results is the key factor. As mentioned above, at present we do not have many such laboratories in the country to give us a true picture and helping in patient management. Issue of methodology and sampling of cases for such estimates are also crucial. Definite guidelines have been developed by WHO.

In the current issue of the journal, there are two publications:[2021] One by Dr. Dholakia and Shah and the other one by Kandi, et al. The later article reports their experience of 100 patients reporting to their hospital. The problem is that the sample size they have chosen is not adequate and more over it is a hospital based study. It is also not clear whether these retreatment cases are from the program and have they ever been treated outside the program and then come to RNTCP. The conclusion drawn by them that ethambutol is to be included in the continuation phase of all new TB cases as there is high incidence of INH in their retreatment cases is not proper as they have not studied this aspect in their report, but have made this observation which is not scientifically correct. Their worry about 28% of MDR-TB in retreatment cases is justified, and the possible solution is rapid DST at the start of treating these cases, which the program is doing in anyway after expansion of laboratory infrastructure and other logistics and of course the prevention of such cases by strengthening the existing DOTS. The second article by Dholakia and Shah has similar limitations about the sample size (small sample size of 34 only), quality assurance of their laboratory, and a large number of their cases are also from outside the program. They have concluded that “there is an urgent need for Indian RNTCP to introduce daily DOTS for susceptible cases, DST for all new cases, and scaling up DST for second-line drugs; there is also a need to use individualized treatment for DR-TB”. They have not studied any one of these conclusions, yet are recommending the same for the program. There is no head on comparison between daily therapy versus intermittent therapy to prevent emergence of retreatment cases or development of MDR/XDR-TB. These are only personal opinions and anticipations. One must understand success or otherwise of a program is not solely dependent on regimen, which is only one component. We have issues of proper management by program personnel, continuous supply of quality assured drugs, implementation of DOTS in its true spirit, political commitment in form of finances, maintenance of quality assurance diagnostics, and proper reporting and recording of cases. Nonetheless, there is a growing demand and belief that the program should change over to daily therapy. Before that the program should pilot test the operational feasibility, difficulties if any, patient adherence/acceptance, financial implications, handling of possible side effects, etc., viz-à-viz intermittent therapy. Hepatotoxicity alone has been reported to be quite high from different Indian studies varying from 8 to 36%.[22] The program is initiating such a study about the feasibility of daily therapy. The poor outcome of MDR/XDR-TB is a worldwide phenomenon. Overall, treatment success is 48%, while 28% of cases were reported as lost to follow-up or had no outcome information from data available from 60 countries of the world including 10 high burden countries, although the global target is 75% treatment success rates.[1] Fortunately, majority of contacts of MDR-TB patients will have drug-susceptible TB and the rate of MDR-TB was very low in them.[23] The initial pilot study of the RNTCP about the success rates of MDR-TB treatment success rates have been 61%.[24] The initial preliminary results of programmatic management of drug resistant tuberculosis (PMDT) started by the RNTCP reports a success rate of around 50%. Fortunately those who are treated successfully, showed no bacteriological relapse even if are left with other respiratory morbidity[25]. Starting all MDR cases on an individual basis based on their individual DST may not be an ideal and feasible option under the program. Doing DST of all freshly diagnosed cases is again not an option at this juncture because of lack of infrastructure and sufficient number of laboratories with capabilities doing such tests in all such cases in addition to cost factors even if one adopts new diagnostic methods (we do not have such a method validated as of now!). Program in any way is developing the capacity of second-line DST not only in its four NRL, but also in some of its IRLs.

Taking all these factors into consideration, we should have a pragmatic approach to manage TB, both fresh and drug resistant cases under the program. Prevention of MDR/XDR-TB through quality DOTS services, however, remains the priority. In addition, rapid scale-up of quality programmatic management under the RNTCP is needed, with more control and rational use of second-line anti-TB drugs outside the program.[262728]