CDC History of Tuberculosis Control - Medical and Public Health ...

appear to be more efficacious than the combinations
of any two of the drugs. However,
the combination of isoniazid and PAS was
much better tolerated. Evidence from an
MRC study indicated that initial streptomycin
did contribute to treatment efficacy in patients
with advanced disease. Another MRC study
determined that the optimal duration of
therapy with these drugs was 2 years.
With the scientific basis for TB chemotherapy
firmly established, the PHS turned its attention
to the next drugs that became available
for clinical study, pyrazinamide and cycloserine.
However, initial evaluation of pyrazinamide
at much higher dosages than are currently
used suggested that the drug was too
toxic for use in initial treatment, although it
appeared to have a role in the treatment of
drug-resistant disease. Subsequently, through
a series of elegant studies in Africa and Asia,
the MRC defined the critial role of that agent
in modern short-course therapy.
While continuing to conduct treatment efficacy
studies, the USPHS also embarked on
pioneering studies of isoniazid for the prevention
of TB in persons with latent TB infection
(LTBI). Between 1955 and 1959, nearly 65,000
persons including children with primary TB,
contacts of infectious TB patients, patients in
mental institutions, and Alaskan villagers,
were entered into placebo-controlled trials that
demonstrated the efficacy of isoniazid for
treatment for LTBI.
In 1960, CDC was given responsibility for TB
control and research. However, the research
division resisted pressure to move to Atlanta
and continued its work from Washington. In
USPHS studies 12 to 16, the role of ethambutol
as a first-line drug replacing PAS was
defined. In 1969, the USPHS began the first of
a series of studies of rifampin, ushering in the
modern era of short-course therapy. Study 18
found that the combination of isoniazid and
rifampin was superior to the best regimen that
had been evaluated up to that time. USPHS
TB Control at the Millennium
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Study 19 evaluated various dosages of rifampin
and found that the optimal daily dosage was 10
mg/kg or 600 mg for most adults.
As rifampin-based short-course therapy became
firmly established, support for therapy
trials in the US began to wane. Study 20, the
first USPHS study initiated after the research
division moved to CDC, attempted to duplicate
a smaller MRC study of a 6-month regimen
of isoniazid and rifampin and found that
the relapse rate of 10% was unacceptably high.
Study 21, which began enrollment in 1981,
was plagued by continuing shortages in financial
support such that the study was nearly
terminated several times before it successfully
completed enrollment. That study confirmed
the results found by the MRC and led to the
adoption of 6-month therapy in the US. It
was not until the resurgence of TB in the US,
with the concomitant increased support for
TB research, that the capacity of the USPHS
to conduct high-quality TB treatment trials
was restored.
Current TB Drug Trials:
The Tuberculosis Trials Consortium
(TBTC)
by Andrew Vernon, MD, MHS
Research and Evaluation Branch, DTBE
The USPHS and the Veterans Administration
(VA) have a distinguished history of conducting
clinical trials to evaluate new drug regimens
for both the treatment and prevention of
TB. In 1960, CDC assumed a major role in
these studies when the USPHS Tuberculosis
Division was transferred to CDC. Subsequently,
CDC coordinated a series of