4. 3. Era of short course chemotherapy

4.3.1 Collaboration with TRC

After the advent of rifampicin there was a new hope of reducing the total duration of treatment. The clinical trials, which are time consuming and painstaking, were urgently required to develop SCC regimens. NTI was not entrusted with the responsibility of conducting clinical trials, as TRC already existed to carry out the research. It was felt that there was an urgent need to find out a suitable SCC regimen for the programme and if two institutions join, then required number of patients would be intaken into the study in half of the time. The early visionaries who created NTI and TRC as enshrined in the plan of operations had also assumed that these two institutions along with the UMTS would work in close coordination. All the three institutions were in the south. No joint ventures ensued for a long time. Perhaps the very objectives of the three institutions were different. When Dr NK Menon took over as Director of NTI in 1976, because of his earlier association with TRC, collaborative studies in SCC began to take shape. In 1978, TRC did a collaborative study with NTI on three SCC regimens in first phase, six in the second phase. The collaboration lasted upto 1983. The results of 5 and 3 month regimens tested in the first phase showed 99% and 93% bacteriological negativity and relapse rates after two years were 4% and 20%. In 3 month regimen relapses were very high98. The collaboration helped NTI in many ways. Like a longitudinal study, it had a very committed work discipline and this enabled all the staff involved to learn another research discipline. After five years of work, when the study was wound up, the staff was well versed with this methodology and attained a new expertise that NTI could carry out some important operational studies on SCC with great ease. In his Ranbaxy Robert Koch Oration - 1989, Dr Wallace Fox recalls: I went to NTI, Bangalore in 1977 specifically to discuss direct collaboration in a controlled clinical trial of SCC. This was readily agreed by Dr Menon and the NTI participation was in the LWSTC. The staff members of the two units worked side by side and in harmony with the clinic’s staff. The research on bacteriology was centred in the TRC, ensuring standardised bacteriological tests. The collaboration was a great success. Dr P Jagota of the NTI proved a gifted team leader with a special talent for clinical research but unfortunately, it was unexpectedly terminated, for unforeseen administrative reasons which arose in Bangalore. Thus the NTI could only contribute a two-year period of observation of its patients99.....

In 1983, TRC was given the responsibility of implementing three different SCC regimens in 18 pilot districts in the country. It reported in 1990 a wide spectrum of treatment completion rates ranging from 30% to 80%100. The problem of non-compliance as envisaged earlier could not be overcome with the implementation of SCC in the programme.

From the time it was resolved to include SCC regimens, the NTI began to study the operational aspects of implementing SCC in the programme. It may not be difficult to treat patients with SCC in trial conditions where careful selection of cases, adequate organisational set up and efficient default retrieval could be maintained. But, this seemingly simple set up is hard to achieve in the programme conditions. As Dr Jagota puts it: There is a wide difference between clinical trial and programme organisational resources...SCC alone will not solve the problem of TB…. An efficient treatment organisation is required for the management of the TB patients during the therapy leading to the actual consumption of drugs for the required period101. Aneja summarised in 1982: Based on the clinical trials and operational studies in actual working conditions, a sea change in the understanding of chemotherapy has occurred. The right type of chemotherapy and the right type of organisation for its delivery at the distribution points near the patients homes have emerged to be the key factors. The drug default nevertheless, continues to be the major problem and efforts are being made to tackle it at the operational level. Meanwhile, the introduction of SCC and MPW scheme are some of the recent developments which are likely to influence the outcome of chemotherapy. However, for deciding about feasibility of the application of SCC and involvement of MPWs in operational conditions, the available knowledge requires to be supplemented with scientific operational studies in actual working conditions of NTP102.

Dr. KS Aneja TB Specialist I/c Control Section, 1976

A study on "acceptability of two, six month SCC regimens i.e., 1SHRZ/7TH and 2SHR/6TH" was conducted by NTI in 1989. It was seen that around 80% of patients starting on either regimen completed optimum treatment. The bacteriological conversion in either regimen was of the order of 91% as against almost 100% obtained in controlled clinical trials with a relapse rate of the order of 12% and 17% respectively. These regimens have shown a relapse rate of about 7% under controlled trial conditions. Thus, it could be seen that both bacteriological conversion and relapse rates are quite close to rates observed in clinical trials103.

Since 1986-87, the GOI began the implementation of SCC in the DTPs in a phased manner. Therefore, it became necessary to carry out a study on adverse reactions to two regimens of SCC. Sputum positive patients attending the LWSTC, Bangalore without history of anti-TB treatment, who agreed to attend the centre regularly, were selected for this purpose. Published in 1989, Sudha Xirasagar concluded that adverse reaction was not by itself a major difficulty but a manageable one104. For the SCC to succeed in NTP, additional resources and trained human power are needed. In another study of operational factors published in 1989, the paper revealed that domiciliary SCC proved feasible and advantageous in an urban TB programme. The study examined the following factors: necessary willingness, drug default, treatment completion pattern, adverse drug reactions and initial drug resistance with their potential harmful effects on the treatment outcome as well as the work load and additional cost involved in providing SCC regimens under DTP105.

There were other problems associated with SCC. For e.g., what is the fate of resistant cases treated with three different regimens of SCC under programme conditions? In 1990, Jagota and others investigated the fate of 100 INH resistant patients. They found: (i) a high, favourable response among patients with INH resistant strains but with no history of treatment, (ii) emergence of drug resistance to rifampicin was directly related to the duration of its use, (iii) fewer deaths occurred by the end of 24th, 36th month of follow up in comparison with conventional regimens106.

In 1993 Chaudhuri and others carried out a study in Kolar district and reported: of the 382 patients put on unsupervised SCC regimen under the existing DTP conditions, only 33.2% completed over 75% drug collections in both intensive and continuous phases. The pattern of compliance did not vary with the place of treatment viz., DTC or PHI. Due to robustness of the SCC regimen, nearly 72-75% of the total cases attained smear negative status at the end of treatment. However, low compliance was a very disturbing finding107.

In a good programme, case holding is as important as case finding. In 1992, Balasangameshwara and others have shown through a mathematical model that if any of the two components was given less importance, the overall purpose of DTP, as a system gets defeated108. This important mathematical model is yet to be clearly understood. Mathematical models, look simple; but are enigmatic. Hence, they are more often ignored. Once understood, they could be used freely. The history of science is replete with ignored models coming to life long after the discoverer was gone. Galileo, Newton and Einstein are some examples.