Controlled Clinical trial of fully oral sort-course chemotherapy in the treatment of smear positive pulmonary tuberculosis

A prospective study to investigate three fully oral regimens of 6 or 8 months’ duration, with varying frequencies of attendance and different rhythms of drug intake is reported

Limitations of conducting community surveys to access the epidemiological impact of TB control programmes on the incidence of TB

Tuberculosis (TB) remains a major health problem in India, and accounts for nearly 20-30% of the global TB burden. A comprehensive review1 in 1993 of the National TB Control Programme (NTP), present in our country for four decades, documented the failure of NTP due to various drawbacks. These included poor management of the TB control programme, over-reliance on X-rays, poor treatment adherence, under-utilization of laboratory services, poor supply of quality drugs, inadequate funding and lack of proper documentation and case reporting. The Revised National Tuberculosis Control Programme (RNTCP), an application of the globally accepted WHO recommended Directly Observed Treatment Short-course (DOTS) strategy, was implemented in 1993 on a pilot basis, rapidly expanded from 1997 and achieved nation-wide coverage in March 2006

Trends in initial drug resistance over three decades in a rural community in south India

programme. Aims: To study trend of initial drug resistance over a period of three decades in a rural community in five panchayat unions in Chingleput district in south India. Methods: A total population survey of tuberculosis in the area was undertaken in 1968-70, comprising radiographic examination of all individuals aged 10 years or more and sputum examination of those with abnormal shadows. Subsequently, the total population survey was repeated on 6 occasions at intervals of 2.5 years along with new entrants found at each survey, and on two more occasions (1991-92, 1994-96) in a subset of two panchayat unions. Prevalence cases and (new) incidence cases of culture-positive tuberculosis were identified in each survey, and their susceptibility to Isoniazid and Streptomycin was determined. Results: Between 1968 and 1986, initial drug resistance to Isoniazid increased from 12.5% to 20.7% in prevalence cases, at an average annual rate of 3.1%. For Streptomycin, the increase was from 6.4% to 12.1%, at the rate of 4.9% per annum. In incidence cases, the corresponding annual rate of increase was 3.8% for Isoniazid and 7.4% for Streptomycin. In the subset of the population, that was surveyed in 1991-92 and 1994- 96, there was some evidence of a decline in the proportion of resistant cases after 1984-86. Conclusion: There was a steady increase in the magnitude of initial drug resistance in the community between 1968 and 1986, which probably indicates an unsatisfactory tuberculosis programme during the period

Shortening short course chemotherapy: a randomized clinical trial for the treatment of smear positive pulmonary tuberculosis with regimens using ofloxacin in the intensive phase

the setting of clinical trials, yet cumbersome to implement under practical conditions. Shorter treatment regimens would ease drug administration for both patients and providers: an effective. regimen of 3 or 4 months’ duration would have significant practical advantages for tuberculosis control. Methods: The study subjects were HIV negative adults with newly diagnosed. sputum smear and culture positive pulmonary tuberculosis. Eligible patients were randomly allocated to one of four regimens: (a) Ofloxacin. Isoniazid. Rifampicin. and Pyrazinamide daily for 3 months; (b) regimen(a). followed by Isoniazid and Rifampicin twice a week for 1 month: (c) regimen(a). followed by Isoniazid and Rifampicin twice a week for 2 months: or (d) Ofloxacin. Isoniazid. Rifampicin, and Pyrazinamide daily for 2 months, followed by Isoniazid and Rifampicin twice a week for 2 months. Each dose was administered under direct observation. The patients were assessed clinically and bacteriologically every month during and after treatment. Follow up will continue for 5 years; the results up to 24 months after treatment are presented here. Results :A total of 529 patients were admitted to the study. Data for efficacy analysis are available for 416 patients: 113 were excluded primarily because of limited compliance. At the end of treatment, only 4 (1%) of 360 patients with initially drug-susceptible tuberculosis had an unfavourable bacteriological response (> 1 positive culture in the last 2 months of treatment). one patient in each regimen. Over a follow-up period of 2 years, 7 (8%) of 83, 3 (4%) of 81. 2 (2%) of 86. and 12 (13%) of 91 patients relapsed in regimens (a) through (d), respectively. Most (79%) of the relapses occurred in the 6 months following the cessation of treatment. Of the 47 patients with tuberculosis initially resistant only to Isoniazid. 2 (4%) had an unfavourable bacteriological response at the end of treatment. However, bacteriological relapse occurred in 8 (19%) of 43 such patients who were assessed for relapse. Intention to treat analysis i.e. after including those who had inadequate therapy. of 469 patients (which had 53 patients who received inadequate chemotherapy). showed that only 4 (3%) of 120. 6 (5%) of 115, 5 (4%) of 118 and 3 (3%) of I16 patients in the 4 regimens had an unfavourable bacteriological response at the end of treatment. Adverse reactions attributable to the anti-tuberculosis medications were observed in 3 1% (regimen d) to 44% (regimen c) of the patients. but a majority of the reactions were mild and manageable with symptomatic measures. Only 5% of patients had a reaction that required modification of the regimen. Corrclusions: Regimens of 4 or 5 months’ duration that contain Ofloxacin and other first-line anti-tuberculosis agents for at least three months can achieve high cure rates and low 24-month relapse rates in newly diagnosed patients with smear positive pulmonary tuberculosis without causing significant adverse reactions. These results indicate that Ofloxacin containing regimens of 4-5 months achieve >95% efficacy with no increased incidence of adverse reactions and minimal relapses. permitting shortening of short-course chemotherapy

Seven year findings of short-course chemotherapy in 18 districts in India under district tuberculosis programme

The ICMR undertook a study project to find out the feasibility of introducing Short-Course Chemotherapy (SCC) under the existing programme conditions and evaluate its acceptability. Sputum positive pulmonary tuberculosis patients aged 15 years or more who had not received more than two months of anti-tuberculosis chemotherapy, belonging to 18 districts spread over 9 states and one union territory of India, were treated with one of the following regimens: Regimen 1 : Rifampicin, Isoniazid and Pyrazinamide for 2 months and Rifampicin and Isoniazid for the next 4 months, the drugs being given twice a week under supervision. Regimen 2 : Rifampicin, Isoniazid and Pyrazinamide daily for 2 months and Thioacetazone and Isoniazid for the next 6 months drugs being self-administered. Regimen 3 : As in regimen 2 for 2 months and Rifampicin and Isoniazid for the next 4 months, the drugs being given twice a week under supervision. In all, a population of 40 million was covered. Of the Peripheral Health Institutions where District Tuberculosis Programme had been implemented, 66% in 1985 and 93% in 1991 had implemented SCC. Of the newly diagnosed patients, 83% were eligible for SCC and 62% of these were started on SCC. Of the remaining patients, with data available, the reasons for not starting SCC were `patient-related' in 58% and had organisational/ administrative related aspects in 35%. Of those who were started on SCC, 49% in regimen I, 54% in regimen 2 and 61% in regimen 3 received 80% or more of chemotherapy. Concurrent cohort analysis of SCC and standard regimens showed that the overall treatment completion for SCC was fairly constant (51-55%), but ranged from 29% to 45% for the standard regimen. Conclusion : It is feasible to employ SCC under the existing programme conditions. However, additional efforts have to be made to improve case finding and case holding further

Evaluation of a Non-Rifampicin Continuation Phase (6HE) Following Thrice-Weekly Intensive Phase for the Treatment of New Sputum Positive Pulmonary Tuberculosis

Setting: Tuberculosis Research Centre, Chennai and Madurai, South India. Objective: To assess response to treatment, relapse and emergence of MDR TB in newly diagnosed patients with sputumpositive tuberculosis using an intermittent intensive phase followed by a non-rifampicin continuation phase. Design: Patients were treated in a controlled clinical trial with 2HRZE3/6HE with thrice-weekly direct dosing in the intensive phase and once-weekly with six doses self-administered in the continuation phase. Clinical and bacteriologic evaluation was done every month for 24 months. Results: The overall outcome was good, with 92% favourable response (cure) and 4.8% relapse in 450 patients including 103 who did not receive extension of intensive phase for positive smear, 38 with initial H-resistant cultures, 4 with MDR TB and 15 who received less than 75% of chemotherapy. In 392 patients with drug-susceptible cultures, 96%were cured and only 4% relapsed. There was no emergence of MDR TB among failures and relapses; toxicity was low. Conclusion: Newly-diagnosed Category I patients can be effectively treated with this regimen without emergence of MDR TB. It has immense potential in programmes where directly observed therapy cannot be ensured throughout, and when rifampicin is contraindicated in HIV-TB patients who require concomitant therapy with anti-retroviral drugs

Influence of sex, age & nontuberculous infection at intake on the efficacy of BCG: re-analysis of 15-year data from a double-blind randomized control trial in south India

Background & objectives: To estimate the efficacy of BCG in preventing tuberculosis over a 15-year period, and also to assess the impact of infection with nontuberculous environmental mycobacteria in a rural community in Chingleput district in Tamil Nadu in south India. We re-analysed the 15-year follow up data of a large randomized trial conducted earlier. Methods: A double-blind randomized control trial was initiated in 1968, in which over 100,000 uninfected subjects with a normal radiograph were allocated to placebo, BCG in low dose (0.01 mg) or BCG in high dose (1.0 mg); two widely used strains of BCG were employed, each in one half of the vaccinated subjects. Sensitivity to purified protein derivative (PPD-B) was also determined. The study population was followed for 15 yr by radiographic surveys of the total population once every 2.5 yr, selective case finding in suspects once in 10 months, and investigation of those reporting voluntarily with chest symptoms. Results: Coverage by radiography was of the order of 80 per cent throughout, while coverage by sputum examination of suspects was usually 90 per cent or above. The annual incidence of culturepositive tuberculosis (irrespective of smear) was estimated to be 55 per 100,000, and neither strain of BCG had any effect. The failure to protect was seen in both males and females, and in children and adults. However, in a subset of over 40,000 subjects who were also nonreactors to PPD-B, BCG had a low level of protection, i.e., 32 per cent (95% CI=3-52%), 29 per cent with the Danish strain and 34 per cent with the French strain. Interpretation & conclusion: Our findings reaffirm that BCG was of little value in preventing sputumpositive cases of pulmonary tuberculosis

Interim findings on the evaluation of split drug regimens for pulmonary tuberculosis – A randomized controlled clinical trial

A randomized controlled clinical trial of three fully oral short course chemotherapy regimens of 6 month duration is being conducted to evaluate split-dose double drug combinations for the treatment of sputum positive pulmonary tuberculosis. Split I and Split II regimens consist of Rifa mpicin and Ethambutol on one day and lsoniazid and Pyrazinamide on the next day, each combination given thrice a week during the initial intensive phase of 2 or 3 months, respectively, followed by Rifampicin and Isoniazid given twice a week during the continuation phase for the next 4 and 3 months; respectively. The control regimen consists of all the four drugs, Rifampicin, Isoniazid, Pyrazinamide and Ethambutol, given together in a single dose thrice a week during the intensive phase of first 2 months, and Rifampicin and Isoniazid twice a week during the continuation phase of next 4 m o n t h s . D r u g s w e r e g i v e n u n d e r f u l l supervision during the entire chemotherapy period of 6 months. The findings upto the end of chemotherapy for 750 patients suggest that the response is similar in split and control regimens among patients with sensitive organisms and those with resistance to Isoniazid alone. Among patients with organisms resistant to both Isoniazid and Rifampicin, almost all had an unfavourable response. Adverse reactions were low and similar in both split and control regimens

Fifteen year follow up of trial of BCG vaccines in south India for tuberculosis prevention

A large scale community-based double blind randomized controlled trial was carried out in Chingleput district of south India to evaluate the protective effect of BCG against bacillary forms of pulmonary tuberculosis. From among 366,625 individuals registered, 281,161 persons were vaccinated with BCG or placebo by random allocation. Two strains of BCG were used, the French and Danish, with a high dose (0.1mg/0.1ml) and a low dose (0.01 mg/0.1 ml) in each strain. The entire population was followed up for 15 years by means of resurveys every 30 months, and selective follow up every 10 months and continuous passive case finding. There were 560 cases (189,191 and 180 from the high dose, low dose and placebo groups respectively) arising over 15 years, among 109,873 persons who were tuberculin negative and had a normal chest X-ray at intake. This represents a small fraction of the total incidence of 2.6 per 1000 person-years most of which came from those who were initially tuberculin positive. The incidence rates in the three “vaccination” groups were similar confirming the complete lack of protective efficacy, seen at the end of 7% years. BCG offered no overall protection in adults and a low level of overall protection (27%; 95% C.I. -8 to 50%) in children. This lack of protection could not be explained by methodological flaws, or the influence of prior sensitisation by non specific sensitivity, or because most of the cases arose as a result of exogenous re-infection. The findings at 15 years show that in this population with high infection rates and high nonspecific sensitivity, BCG did not offer any protection against adult forms of bacillary pulmonary tuberculosis. Key words BCG trials - community based trials - tuberculosi