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

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

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

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

Concurrent Silicosis and Pulmonary Mycosis at Death

To examine risk for mycosis among persons with silicosis, we examined US mortality data for 1979–2004. Persons with silicosis were more likely to die with pulmonary mycosis than were those without pneumoconiosis or those with more common pneumoconioses. Health professionals should consider enhanced risk for mycosis for silica-exposed patients

Relapse Associated with Active Disease Caused by Beijing Strain of Mycobacterium tuberculosis1

Risk for relapse was higher among persons of Asian–Pacific Islander descent

Guidelines for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020.

Comprehensive guidelines for treatment of latent tuberculosis infection (LTBI) among persons living in the United States were last published in 2000 (American Thoracic Society. CDC targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-47). Since then, several new regimens have been evaluated in clinical trials. To update previous guidelines, the National Tuberculosis Controllers Association (NTCA) and CDC convened a committee to conduct a systematic literature review and make new recommendations for the most effective and least toxic regimens for treatment of LTBI among persons who live in the United States.The systematic literature review included clinical trials of regimens to treat LTBI. Quality of evidence (high, moderate, low, or very low) from clinical trial comparisons was appraised using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. In addition, a network meta-analysis evaluated regimens that had not been compared directly in clinical trials. The effectiveness outcome was tuberculosis disease; the toxicity outcome was hepatotoxicity. Strong GRADE recommendations required at least moderate evidence of effectiveness and that the desirable consequences outweighed the undesirable consequences in the majority of patients. Conditional GRADE recommendations were made when determination of whether desirable consequences outweighed undesirable consequences was uncertain (e.g., with low-quality evidence).These updated 2020 LTBI treatment guidelines include the NTCA- and CDC-recommended treatment regimens that comprise three preferred rifamycin-based regimens and two alternative monotherapy regimens with daily isoniazid. All recommended treatment regimens are intended for persons infected with Mycobacterium tuberculosis that is presumed to be susceptible to isoniazid or rifampin. These updated guidelines do not apply when evidence is available that the infecting M. tuberculosis strain is resistant to both isoniazid and rifampin; recommendations for treating contacts exposed to multidrug-resistant tuberculosis were published in 2019 (Nahid P, Mase SR Migliori GB, et al. Treatment of drug-resistant tuberculosis. An official ATS/CDC/ERS/IDSA clinical practice guideline. Am J Respir Crit Care Med 2019;200:e93-e142). The three rifamycin-based preferred regimens are 3 months of once-weekly isoniazid plus rifapentine, 4 months of daily rifampin, or 3 months of daily isoniazid plus rifampin. Prescribing providers or pharmacists who are unfamiliar with rifampin and rifapentine might confuse the two drugs. They are not interchangeable, and caution should be taken to ensure that patients receive the correct medication for the intended regimen. Preference for these rifamycin-based regimens was made on the basis of effectiveness, safety, and high treatment completion rates. The two alternative treatment regimens are daily isoniazid for 6 or 9 months; isoniazid monotherapy is efficacious but has higher toxicity risk and lower treatment completion rates than shorter rifamycin-based regimens.In summary, short-course (3- to 4-month) rifamycin-based treatment regimens are preferred over longer-course (6-9 month) isoniazid monotherapy for treatment of LTBI. These updated guidelines can be used by clinicians, public health officials, policymakers, health care organizations, and other state and local stakeholders who might need to adapt them to fit individual clinical circumstances

Study of chemotherapy regimens of 5 and 7 months duration and the role of corticosteroids in the treatment of sputum-positive patients with pulmonary tuberculosis in South India

A controlled clinical trial of 3 short-course chemotherapy regimens was undertaken in patients with bacteriologically positive, newly diagnosed pulmonary tuberculosis. The patients were allocated at random to receive one of 3 regimens: rifampicin, streptomycin, isoniazid and pyrazinamide daily for 2 months, followed by streptomycin, isoniazid and pyrazinamide twice weekly for 3 months (R/5) or for 5 months (R/7), and the same regimen as R/7 but without rifampicin (Z/7). Further, half the patients in each series, selected at random, were prescribed daily prednisolone for the first 8 weeks. Of the 509 patients admitted to this phase of the trial, 390 had pre-treatment sputum cultures sensitive to isoniazid and streptomycin. At 2 months, in 92 % of R/5 and R/7 patients (combined) and in 72% of Z/7 patients all cultures were negative (P<0.00001). All 390 patients had a favourable response at the end of chemotherapy. At follow up for 24 months from the time of admission a bacteriological relapse requiring retreatment was observed in 5.4 % of R/5, 0.0 % of R/7 and 3.9 % of Z/7 patients. The differences between R/7 and each of the other 2 series were significant (P < 0.03). Including a second phase of the study to increase the numbers in the Z/7 series, a total of 269 patients with drug-sensitive sputum cultures received the Z/7 regimen. All of them had a favourable response to treatment and only 2.6 % had a bacteriological relapse requiring retreatment. These results demonstrate that in patients with drug-sensitive cultures, good results can be achieved with a shortcourse regimen that does not include rifampicin. Among patients with sputum cultures resistant to both isoniazid and streptomycin, 6 of 23 in the R/5 and R/7 series had an unfavourable response to treatment, compared with 13 of 16 in the Z/7 series (P<0.01). These results demonstrate that in patients with drug-resistant cultures, short course regimens that do not include rifampicin may be unsatisfactory. Prednisolone given for the first 8 weeks did not influence the speed of sputum conversion or the response to chemotherapy in patients with drug-sensitive cultures and it had no effect on the rate of bacteriological relapse. However, in patients with cultures resistant to streptomycin and isoniazid the response to chemotherapy was less favourable in those who had taken prednisolone than in those who had not. Thus, 4 of 12 receiving prednisolone in the R/5 and R/7 series had an unfavourable response compared with 2 of 11 not receiving it (P>0.2), and all of 10 and 3 of 6, respectively, in the Z/7 series (P =0.04). The most common adverse drug reaction was arthralgia, which was complained of by 24 % of patients in the R/5 and R/7 series and 46 % in the Z/7 series (P<0.001) ; all except 5 continued their normal activities without any interruption or modification of the regimen. Hepatitis occurred in 17 (2.5 %) patients