Very Basic and Important topic for all T.B & Chest Residents

1. Short Course Chemotherapy
DR. NEELU CHUGH
PGY3
PULMONARY MEDICINE
GGSMCH, FARIDKOT.

2. Evolution of TB Control in India
• 1950s-60s Important TB research at TRC and NTI
•1962 National TB Programme (NTP)
• 1992 Programme Review
• 1993 RNTCP pilot began
• 1998 RNTCP scale-up
• 2006 Entire country covered by RNTCP

3. In the late 1960s, the introduction of rifampicin as part of a combination
of anti-TB drugs reduced treatment to six to eight months—known as
short-course drug treatment. With short-course treatment, patients feel
better more quickly as the bacterial load decreases dramatically during
an intensive initial two month phase of treatment. Within these few
weeks (appx. 8weeks), patients are rendered noninfectious,
aymptomatic and are no longer able to spread the disease to family,
friends and co-workers.

4. Monumental work done by the British Medical Research Council &
partners around the world led to the development of standard short-
course chemotherapeutic regimens. The studies established a number
of key points that provided the framework for the development of
modern treatment. These points include the following:
1. Regimens of 6 and 8 months’ duration are extremely effective in
achieving a high cure rate with a low relapse rate.
2. Rifampicin-containing regimens allow effective short-course
treatment even of patients with smear-positive cavitary disease.

5. 3. For 6 and 8-month regimens, both rifampicin and pyrazinamide are
necessary, pyrazinamide is required only for the initial phase of
treatment.
4. Relapses with short-course treatment generally occur within the first
year and relapses that occur following multidrug therapy are usually
caused by organisms that retain their original susceptibility.
5. Multiple drugs can be given with minimal toxicity.

6. The discovery in the late 1960s of rifampicin as perhaps the most
effective medication for tuberculosis. Rifampicin is a broad-spectrum
antibiotic used predominantly for the treatment of tuberculosis. Use of
rifampicin led to the emergence of modern and effective short-course
regimens.
Studies in the 1980s that evaluated regimens with a treatment duration
of less than 6 months demonstrated high relapse rates (11–40%) in
patients with sputum smear-positive pulmonary tuberculosis.

7. 1. Two groups of investigators in France and India, in search of a shorter
duration of treatment for pulmonary tuberculosis, tried daily regimens
of 3 months’ duration (90 doses of HRZS). A regimen of HRZS given daily
for 3 months in India achieved almost 100% culture conversion at 3
months, but 20% of patients had bacteriologically confirmed relapse.
2. Similarly, 4-month regimens studied in Singapore also had high
relapse rates (8–16%).
3. Two 5-month regimens (2HRZS/3HZS and 3HRZS/2H2Z2S2) tried in
Madras were effective and had low relapse rates (4–5%). However, this
is the only study that investigated 5-month regimens and acceptable
results were achieved only by using streptomycin for the entire 5
months of treatment.
Thus, there is at present no practical regimen of less than 6 months’
duration that
has given acceptable results in smear-positive tuberculosis.

8. History of DOT
• The history of directly observed therapy presents us
with a remarkable global journey, which begins in
Europe, and takes us through Asia, America, and Africa,
before finally emerging as a truly international
approach to improving treatment concordance.
• A more conventional form of supervised treatment was
introduced in the 1840s, with the establishment of the
sanatorium movement in Europe. Patients who were
admitted to these mountain sanatoria were isolated for
long periods of time, and subjected to diverse and
disciplined regimens of treatment

9. Perhaps because of the long history of sanatorium treatment, the first
patients to be treated with streptomycin and later PAS, were all
hospitalized for the full course of treatment .
In the late 1950s the focus shifted to Asia, and Bayer and Wilkinson take
the story up from here in their history of DOT. The British Medical
Research Council studies conducted by Wallace Fox in TRC, Madras
(1956) demonstrated that hospitalization was not necessary to prevent
transmission of disease. These findings led to a shift to ambulatory
chemotherapy for people with TB in most parts of the world.

10. Dr Karel Styblo, who developed the DOTS strategy based in
large part on the principles discovered in India, wrote about
this phenomenon: “Well-organized outpatient chemo-
therapy, especially if provided free of charge, will attract
symptomatic cases from far and wide”.

11. From Asia we return to Europe, where the principle of
supervised treatment was adopted by Stradling and Poole in
London, and then travel further west- wards to America,
where the call for supervised treatment was taken up by
Sbarbaro (40), which he termed “directly administered”
treatment.
These observations that influenced the development of a
programme of supervised ambulatory care in Hong Kong.
The studies from India therefore, provide the earliest example
of modern conventional DOT utilising effective treatment to
ensure high cure rates in people with TB. The ambulatory
treatment that was rapidly adopted around the developing
world was often unsupervised.

12. The developed world still has much to learn from developing countries.
In 1974 WHO published the 9th report of the Expert Committee on
Tuberculosis, which proposed the use of a supervised regimen of
intermittent streptomycin and isoniazid, as a means for ensuring patient
compliance.
However, the next major step forward in the history of DOT was the
development of SCC regimens given under direct supervision in the
International Union Against Tuberculosis and Lung Disease [IUATLD]
supported programme in Tanzania, which was subsequently expanded
to a further six countries in Africa, and to Nicaragua (49).

13. The Styblo/IUATLD Model of TB Control
The Tanzania model, developed by Dr Karel Styblo, was based on
hospitalization of TB patients for the intensive phase of treatment. The
reasons for doing so were significantly different from the early days; the
emphasis was now on supervision of therapy, and continuation of
treatment until the patient was cured.
Over the last two decades, universal hospitalization of patients has been
largely abandoned due to a massive increase in the incidence of TB
resulting from HIV/AIDS.
The principle that has been established is, therefore, not hospitalization,
but supervision of drug-taking.

14. The principles which evolved here were later adapted and promoted by
WHO as DOTS, and adopted in places as diverse as China, Nepal, New
York, and India as the Revised National Tuberculosis Control Programme
[RNTCP] from the early 1990s.
We have, therefore, come full circle. The principles of modern TB
control first developed in India in the late 1950s have travelled around
the world, and finally returned home nearly 40 years later, as DOTS.

15. The Five fundamental principles of the WHO-recommended DOTS are:
1. Political and administrative commitment.
2. Case finding primarily by sputum smear microscopy of patients
atttending health facilities.
3. Uninterrupted supply of good quality drugs.
4. Short course chemotherapy by Directly observed treatment (DOT).
5. Systemic monitoring and Accountability.

16. Advantages and Disadvantages of DOT
Advantages
• It ensures that the patient
completes an adequate regimen
• It lets the health care worker
monitor the patient regularly
for
side effects and response to
therapy
• It helps the health care worker
solve problems that might
interrupt treatment
• By ensuring the patient takes
every dose of medicine, it helps
the patient become
noninfectious sooner
Disadvantages
• It is time consuming
• It is labor intensive
• It can be insulting to some
patients
• It can imply that the patient is
incapable or irresponsible
• It can be perceived as
demeaning or punitive

17. Advantages of DOTS strategy in the control of TB : The Indian experience
1. More than doubles the accuracy of TB diagnosis
2. Results in success rates of up to 95%
3. Cuts down TB deaths by seven fold
4. Doubles the cure rate
5. Reduces the incidence and prevalence of TB
6. Helps in alleviating poverty by saving lives
7. reducing the duration of illness and preventing new infectious cases
8. Improves the quality of care and overcomes stigma
9. Prevents treatment failure and the emergence of MDRTB

18. Intermittent treatment and what
is the scientific basis for intermittency?
The “lag period” factor
In vitro experiments have shown that, when tubercle bacilli are
exposed to a drug for a short time (6–24 hours) and, after careful
removal of the drug, are transferred to a drug-free medium, the
surviving bacilli start to grow again after an interval of several
days. This interval is called the “lag period”, and varies with the
type and concentration of the drug and with the length of
exposure.
All tuberculosis drugs have been tested for their ability to produce
a lag period, in order to determine whether they are suitable for
intermittent regimens.

19. Lag in growth of Mycobacterium tuberculosis after temporary exposure to drugs
Drug Concentration Lag (days) after exposure for:
(mg/litre) 6 hours 24 hours
Isoniazid 1 0 6–9
Rifampicin 0.2 2–3 2–3
Pyrazinamide 50 5–40 40
Ethambutol 10 0 4–5
Streptomycin 5 8–10 8–10
A series of experiments in an animal model demonstrated that
intermittent dosing actually increased the efficacy of treatment with
isoniazid, rifampicin and Pyrazinamide.

20. The intermittent regimen was highly successful and perhaps slightly
more effective than the daily regimen. The potency of intermittent
treatment is all the more striking as most of the patients admitted to the
study had extensive, bilateral cavitary disease with sputum heavily
positive by direct smear. This feature was common to all the studies in
Chennai in which the patients had severe disease.
The relapse rates in a 2-year period were 8% for the twice-weekly
regimen and 12% for the daily regimen; after 4 years, they were 12%
and 15% respectively.
In 4 out of 5 patients who relapsed on the intermittent regimen, the
bacilli were susceptible to both isoniazid and streptomycin. This
suggests that, had there been an intensive phase at the start of
treatment, the susceptible bacilli would probably have been eliminated.

24. PRINCIPLES
The aims of treatment regimens are to:
1. cure the patient
2. prevent death from active disease or its late effects
3. prevent the emergence and spread of drug-resistant organisms
4. minimize relapse
5. protect the community from continued transmission of infection.
All treatment regimens have two phases – an initial intensive phase
and a continuation phase.

25. Initial intensive phase
The initial intensive phase of treatment is designed to kill actively
growing and semi dormant bacilli. This means a shorter duration of
infectiousness, usually with rapid smear conversion (80–90%) after 2–3
months of treatment.
At least two bactericidal drugs, such as isoniazid and streptomycin
or isoniazid and rifampicin, are required in the initial phase.
Pyrazinamide given in the initial intensive phase allows reduction in
treatment duration from 9 to 6 months. Ethambutol is of benefit when
initial drug resistance may be present or if the burden of organisms is
high

26. The initial phase of rifampicin-containing regimens should always be
directly observed in order to ensure adherence. That phase usually
involves four drugs.
Use of a four-drug regimen reduces the risk both of drug resistance,
failures and relapses. If a patient defaults on treatment after the initial
intensive phase, relapse is less likely.
Continuation phase
The continuation phase eliminates most residual bacilli and reduces
failures and relapses. At the start of the continuation phase, numbers of
bacilli are low and there is less chance of selecting drug-resistant
mutants: fewer drugs are therefore needed.

27. Bacilli types:
1. Rapid growing --------------------H, R & S.
2. Slowly growing -------------------RIF , PZA (For Acidic medium ie.
Intracellular)
3. Persisters --- Rifamipicin
4. Dormant – No drug effective.
Good penetration is of H, R and Z,, not STM.

28. CURRENT REGIME
INTENSIVE PHASE ---------------------- 2 (HRZE)
CONTINUATION PHASE ---------------- 4 (HRE)
Drugs Used : Isoniazid, Rifampicin, Pyrazinamide and Ethambutol.
Sputum Examination at end of 2 months and at the end of 6 months.