High relapse rate in RNTCP: An increasing concern and time to intervene.

Sir,

I congratulate Dr. Azhar for his systematic review of trials from India to demonstrate the high relapse rate among new cases of pulmonary tuberculosis (TB) patients treated with DOTS regimen (RNTCP).[1] The entire India is covered under the RNTCP program since 2006 and the program have consistently achieved an 85% treatment success rate among new smear-positive cases for last few years; but, the registration of relapse cases are progressively increasing.[2] The relapse of TB is either due to reactivation or exogenous reinfection. Areas where the prevalence of TB is high, the likelihood of getting reinfection from the environment is more. However, a study from India had shown that majority of the relapse cases (69%) are actually due to re-activation.[3]

The major risk factors for relapse of TB are irregularity in treatment and presence of initial drug resistance. The presence of initial drug resistance is responsible for increased risk of failure, relapses and acquired drug resistance. The risk of amplification of rifampicin resistance is high among those have initial Isoniazid (INH) resistance and were smear positive at initiation of the continuation phase.[4] The Global data showed that 32% of the relapse cases are actually multidrug-resistant TB (MDR).[5] Therefore, reduction in relapses among those who received RNTCP category I treatment may also reduce the total number of MDR cases in India.

Regularity in treatment is essential to achieve high cure and low relapse rate among TB patients. Those patients who take irregular treatment are twice more likely to have relapse than those who take regular treatment (19.8% vs. 8.5%) and the extent of treatment irregularity has a linear relationship with the rate of relapse.[6] The regularity in TB treatment can be addressed by early retrieval mechanism and proper implementation of RNTCP.

Thomas et al. observed that 6% of their study population had initial INH resistance, and 26.6% of them had relapse after completing RNTCP category I treatment.[6] The adjusted odds ratio of relapse for those with initial drug resistance (OR 4.8; 95% CI 2.0–11.6) was higher than those who took irregular treatment. In patients with initial INH resistance, thrice-weekly intensive phase was associated with significantly higher risk of failure and acquired drug resistance than in those treated with daily dosing during the intensive phase.[5] In populations with known or suspected high levels of INH resistance, the WHO recommended that new pulmonary TB patient may receive a daily intensive phase followed by thrice-weekly INH, rifampicin and ethambutol as an acceptable alternative to INH and rifampicin during the continuation phase.[5] However, the concerns are that evidences to add ethambutol along with INH and rifampicin in the continuation phase are weak and the risk of ethambutol toxicity (though ethambutol is used for 24 months in the treatment of MDR). The American Thoracic Society also recommended 7 months continuation phase for TB patients with cavities in chest X-ray and when the culture remained positive after 2 months of intensive phase.[7] Metaanalysis had demonstrated that in the presence of initial INH resistance, adjusted relapse rates are lower with regimens using rifampicin for at least 8 months than with using rifampicin for 6 months.[8] Another meta-analysis to evaluate the dosing schedule and treatment outcome of TB also documented high level of evidence in favor of daily dosing schedules, especially during the intensive phase in the presence of cavity, INH resistance and HIV co-infection, to reduce the risk of treatment failure, relapse and acquired drug resistance.[9] If Mycobacterium tuberculosis (M tb) was initially sensitive to all drugs, the cumulative incidence of relapse was 6.2% (95% CI: 5–7), whereas the incidence of relapse was 12% (95% CI: 8–17) in the presence of single drug resistance.[10] In areas with high prevalence of initial drug resistance, development of high level of amplification of drug resistance under well-functioning DOTS program has been demonstrated.[11]

Resistance to INH is the common form of primary drug resistance seen among M tb isolates from India. The high prevalence of initial INH resistance is probably due to earlier introduction of INH as an anti-tubercular drug and relatively high spontaneous mutation rate. Drug resistance studies carried out in different part of India after 1997 showed that the initial INH resistance among study population varied from 15% to 23.4%, and was higher than the initial rifampicin resistance.[12] A study conducted in a district of south India had demonstrated increase in initial INH resistance from 12.5% to 20.7% over a period of 20 years, with an average annual rise of 3.1%.[13] Global studies also documented progressive increase in the prevalence of initial INH resistance.[12]

In the absence of adequate logistics to diagnose the pre-treatment initial drug resistance pattern and prevalence of high initial INH resistance in a country like India, a prospective multicenter randomized trial is required to compare the relapse rate among new TB patients who had received supervised daily regimen during the intensive phase followed by the thrice-weekly regimen during the continuation phase versus the thrice-weekly regimen during the entire treatment. The effect of inclusion of ethambutol along with rifampicin and INH in the continuation phase should also be examined especially those who remained smear positive at the end of intensive phase. The analysis of previous treatment cards of relapse cases in RNTCP will be helpful to identify risk factors responsible for relapse. In areas with high prevalence of TB, the effectiveness of any regimen should also be assessed by molecular techniques to differentiate between reactivation and reinfection. However, the unanswered questions are optimal duration of daily supervised intensive phase and operational difficulties in implementing daily supervised treatment.