TB Notes 1, 2005
No. 1, 2005
Updates from the Clinical and Health Systems Research
Why the TB Trials Consortium Needs Your Support
The year is 2024. You are called to the public health clinic to
consult on a TB case; its disposition is remarkably speedy and successful.
A middle-aged woman and her three children (aged 5 to 12) who recently
emigrated from another country are brought in for evaluation. The
woman’s husband was diagnosed with TB the week before, when he presented
to a local hospital with cough, fever, and weight loss. Genetic
testing of his sputum confirmed that his illness is caused by drug-susceptible
TB. The woman and her children have latent TB infection that was
detected by a rapid assay for gamma interferon response performed
on a fingerstick sample of blood; they are feeling well and have
normal chest radiographs. You place these four family members on
the standard regimen for LTBI: 12 weekly doses of a single pill
(INH and rifapentine combined) delivered by DOT. You assure the
family that they will all be protected from the disease affecting
their husband and father. The woman is relieved to learn that she
and her children will be able to take such a simple regimen of medicines.
Her husband is now at home and has been started on the standard
4-month regimen for drug-susceptible TB: thrice-weekly DOT with
three drugs, including a rifamycin and a quinolone.
Sound like an unrealistic fantasy? Perhaps not, and you and your
patients may have an opportunity to help make these fantasies come
true. Read on.
Consider the advances in TB therapy that have been made in the
last 50 years. Standard TB regimens in the 1950s and 1960s consisted
of daily therapy with multiple medications, often including injectables,
for 18 to 24 months. Clinical trials conducted in the 1960s and
1970s by the British Medical Research Council in collaboration with
groups in Africa, India, and Hong Kong established the effectiveness
of 6-month “short course” therapy with rifampin-based regimens.1
Many practitioners in the United States were not willing to adopt
the use of regimens that had not been studied in a domestic population
and were concerned about the possible toxicity of rifampin. In the
early 1970s, public health clinics across the United States enrolled
822 patients in a United States Public Health Service (USPHS) trial
comparing three rifampin-based regimens. The results of this trial
helped establish 600 mg as the effective dose of rifampin for use
in combination chemotherapy and demonstrated acceptably low toxicity
of the isoniazid and rifampin combination.2
The results of two clinical trials published in 1990 established
the basis for our current standard of care for TB in the United
States. USPHS Study 21 enrolled over 1400 patients
from 22 clinics in 13 states in the 1980s and demonstrated the effectiveness
and tolerability of a 6-month INH/RIF regimen (supplemented with
PZA for the first 2 months) compared with a 9-month INH/RIF regimen.3
The other trial of 125 patients studied by the Denver Department
of Health demonstrated the effectiveness of the largely intermittent
6-month “Denver short course” delivered by DOT, a regimen used by
the majority of U.S. public health clinics today.4
During the 1970s, public health and Veterans Administration (VA)
clinics across the United States enrolled patients in much greater
numbers in studies of the effectiveness and safety of INH for prophylaxis
of TB in PPD-positive individuals.5,6 The many clinical
trials conducted in the United States and abroad provide the evidence
to support our current successful approach to the therapy of latent
and active TB.
But, as the reader well knows, we have the need for simpler, shorter,
safer, and even more successful regimens for all TB patients. Additionally,
TB/HIV coinfection and the growing prevalence of MDR TB in some
global areas bring new challenges to the treatment and control of
TB. How can we arrive at the fantasy described above? New regimens
will only result from careful design and conduct of clinical trials.
The Tuberculosis Trials Consortium (TBTC) is an investigator-driven
consortium funded by CDC since 1995. The purpose of the TBTC is
to continue earlier work done by the USPHS and the VA by conducting
programmatically relevant research that expands treatment and prevention
options for TB control worldwide. CDC and 28 clinical sites across
the United States, Canada, and abroad (Uganda, South Africa, Brazil,
and Spain) share overall consortium leadership in the conduct of
1) studies to evaluate the safety and efficacy of new TB treatment
regimens; 2) pharmacokinetic studies of TB and HIV medication interactions;
3) studies of nucleic acid amplification methodologies in the diagnosis
and management of active TB; and 4) studies of treatment for latent
You may not know that U.S. TB treatment guidelines have already
been informed by the results of TBTC studies. The first two TBTC
trials studied intermittent regimens using rifapentine (in HIV-infected
and HIV-uninfected patients) and rifabutin in HIV-infected patients.
TBTC Study 22 results set the standard and limitations for the use
of rifapentine-based regimens for low-risk TB patients and alerted
the TB community to rifampin-resistance developing in HIV-infected
persons, resulting in rifapentine contraindications in this population.7
TBTC Study 22 also identified TB patients at high-risk for TB treatment
failure or relapse based on the combined finding of cavity on initial
chest x-ray and persistently positive sputum cultures after the
first 8-weeks of therapy. This led to the new emphasis on the timing
of sputum conversion and prolonging therapy in those at highest
risk. This should significantly reduce the number of re-treatment
cases we all have to deal with.
TBTC Study 23 determined that rifamycin-based intermittent therapy
of persons with HIV-TB and low CD4 counts resulted in unacceptable
rates of rifampin-resistant TB. These research results shaped the
majority of changes made in the 2003 TB treatment guidelines.8
Currently the TBTC is enrolling patients into five TB treatment
and prevention trials. The U.S. clinical sites comprise public
health departments, academic medical centers, and VA Medical Centers.
Over the next 4 years, TBTC sites will enroll over 300 patients
per year in studies of active TB and over 1500 patients per year
in Study 26, a study of treatment for latent TB infection. Study
26 is a trial of treatment of LTBI comparing 3-month once-weekly
isoniazid and rifapentine (the short regimen referred to in the
2024 “fantasy” above) vs. standard 9-month isoniazid therapy. This
large study will have a total enrollment of 8,000 high risk PPD-positive
patients; over 3,500 have been enrolled to date. History has taught
us the powerful impact of clinical trials. TBTC investigators hope
you and your clinic will continue or begin to participate in these
important opportunities to improve the future of TB treatment.
Many of the clinics participating in TBTC work have found there
are also more immediate benefits to participation. Claire Murphy,
RN, a former public health nurse and current study coordinator for
the Boston TBTC, writes the following about TBTC:
"It enhances patients’ involvement through active participation
in their own plan of care. Patients who feel they are part of
the ‘process’ actively contribute to laying the groundwork for
those future regimens of safe and effective short-course chemotherapies.
Ongoing collaboration with the TBTC allows for more opportunities,
strategies, and resources to target those 'hard-to-reach' patients.
A partnership with your local TBTC site will facilitate optimum
completion of therapy rates. To our local public health departments,
these high-risk patients who are sought out for treatment are
waiting for more improved and tolerable regimens. The question
is, ‘Are you ready for them?’ Come, work with us!”
For further information, contact the Clinical and
Health Systems Research Branch, DTBE, National Center for HIV, STD,
and TB Prevention, CDC, Mailstop E-10, Atlanta, GA, 30333. Elsa
Villarino, MD, MPH, is the Team Leader for the TB Trials Consortium.
Tel: (404) - 639-8123
Fax: (404) - 639-8961
—Reported by Susan M. Ray, MD
- Iseman MD, Sbarbaro JA. Short course chemotherapy of tuberculosis:
Hail Britannia (and friends). Am Rev Resp Dis 1991;143:697-8.
- Long MW, Snider DE, Farer LS. USPHS cooperative trial of three
rifampin-isoniazid regimens in the treatment of pulmonary tuberculosis.
Am Rev Resp Dis 1979;119:879-94.
- Combs DL, O’Brien RJ, Geiter LJ. USPHS tuberculosis short-course
chemotherapy trial 21: effectiveness, toxicity, and accepatability.
Ann Intern Med 1990;112;397-406.
- Cohn DL, Catlin BJ, Peterson KL, Judson FN, Sbarbaro JA. A
62-dose, 6-month therapy for pulmonary and extrapulmonary tuberculosis:
a twice-weekly, directly observed, and cost-effective regimen.
Ann Intern Med 1990;112:407-415.
- Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis:
a general review. Adv Tuberc Res 1970;17:28--106.
- Kopanoff DE, Snider, Jr., DE, and Caras GJ. Isoniazid-related
hepatitis: a U.S. Public Health Service cooperative surveillance
study. Am Rev Respir Dis 1979;117:991-1001.
- TB Trials Consortium. Once-weekly rifapentine and isoniazid
versus twice-weekly rifampin and isoniazid in the continuation
phase of therapy for drug-susceptible pulmonary tuberculosis:
a prospective, randomized clinical trial. Lancet 2002;360;528-34.
- American Thoracic Society, CDC, and Infectious Diseases Society
of America. Treatment
of tuberculosis. Am J Respir Crit Care Med 2003;167:603-662.
TBTC Studies and Publications
- Safety and Efficacy Trials
Study 22: Efficacy trial of once-weekly isoniazid and
rifapentine in the continuation phase of therapy for pulmonary
TB (TB Trials Consortium. Lancet 2002; 360: 528-34.)
Study 23: Single-arm trial evaluating twice-weekly rifabutin
for treatment of HIV-associated TB (completed; manuscript submitted)
Study 24: Efficacy of intermittent therapy for patients
with isoniazid -resistant TB or isoniazid intolerance (enrollment
Study 25: Phase I-II dose escalation study using same
design as Study 22, randomizing to 600, 900, or 1200 mg of once-weekly
rifapentine (Bock N, et al. Amer J Respir Crit Care Med 2002;
Study 27: Phase II study of activity and tolerability
of moxifloxacin vs. ethambutol in 1st 8 weeks of
TB treatment (enrollment completed March 8, 2005)
Study 28: Phase II evaluation of moxifloxacin-based,
isoniazid-sparing regimen in 1st 8 weeks of TB treatment
(anticipated start in April 2005)
- Pharmacokinetic Studies
Study 22 PK: Evaluate isoniazid, rifampin, and rifapentine
PK in Study 22 (Weiner et al. Am J Respir Crit Care Med 2003;
167: 1341-7; Weiner M et al. Am J. Respir Crit Care Med 2004;
Study 23A, B & C: Evaluate rifabutin and isoniazid,
efavirenz and nelfinavir interaction in persons with HIV-TB
- Diagnostic Studies
NAA Substudy: Study of the performance of several nucleic
acid amplification methodologies in diagnosis and management
of active TB (Ongoing)
- Prevention Trials
Study 26: Trial of treatment of latent TB infection
comparing 3-month once-weekly isoniazid + rifapentine vs. 9-month
isoniazid therapy (Ongoing)
A Rapid HIV Test for Use in the Field with Oral
Following the period of large TB outbreaks among persons infected
with the human immunodeficiency virus (HIV) in the late 1980s and
early 1990s, CDC recommended that all TB patients and suspects be
offered voluntary HIV counseling and testing to improve patient
management, to prevent further HIV transmission, and to better track
disease trends in this highly susceptible population.1,2
Once highly active antiretroviral treatment (HAART) for HIV became
available beginning in 1996, referral of HIV-infected persons to
assess the need for and to facilitate initial contact with care
and support service providers was added to HIV counseling and testing.3
Over time, the percentage of all TB patients having known HIV status
has risen from 30% in 1993 to approximately 52% in 2002.4
Some TB programs know the HIV status of over 90% of patients, but
others less than 25%. There is still room for improvement. In addition,
knowledge of the HIV status of persons being assessed for latent
TB infection (LTBI) can help in decision-making for TB screening
and LTBI treatment and, through referrals, can link newly diagnosed
HIV-infected persons to HIV care.
Many persons do not return for the results of standard HIV tests:
during 2000, 30% of persons who tested HIV positive and 39% of persons
who tested HIV negative did not return.6 Rapid diagnostic
HIV tests provide results within 20 minutes of specimen collection.
Although slightly more expensive to purchase than standard HIV enzyme
immunoassays, rapid HIV diagnostic tests increase receipt by patients
of their HIV test results and have been shown to be cost-effective.5
In a client satisfaction survey in New York state, 97% of 500 clients
chose rapid HIV tests over other tests, with 24% stating that they
would not have accepted HIV testing if the rapid test were not being
OraSure Technologies Inc. manufactures the only rapid HIV test
approved by the Food and Drug Administration for use on oral fluid
specimens, the OraQuick Advance HIV 1 / 2 Antibody Test. The test
uses oral fluid, which is slightly different from saliva. A device
to collect oral fluid is swabbed between the lips and gums and then
inserted into a vial containing a developer solution. After 20 minutes,
the presence of HIV antibodies is indicated by a display of two
reddish-purple lines. This test can also be used on plasma or whole
blood specimens. The two other FDA-approved rapid tests for nonclinical
settings require whole blood specimens obtained through fingerstick
or venous blood draw. These are the Uni-Gold Recombigen HIV test
for HIV 1 produced by Trinity Biotech and the OraQuick Rapid HIV-1
Antibody test.8 The OraQuick Advance test can be performed
in a wider range of operating temperatures (59°F to 99°F) than other
rapid tests.9 In addition, the OraQuick Advance HIV 1
/ 2 test can detect HIV 2, which is prevalent in persons from West
Reactive test results using rapid HIV testing technologies are
considered preliminary positives and need to be confirmed by Western
blot or immunofluorescent assay (IFA). If such confirmatory testing
yields negative or indeterminate results, follow-up testing should
be performed on a blood specimen collected four weeks after the
initial reactive rapid HIV test result.10
For clients tested with a rapid HIV test, counseling should include
the same types of information recommended for those tested with
a standard EIA:
- Information about the HIV test, its benefits and consequences.
- Ways HIV is transmitted and how it can be prevented.
- The meaning of the test results in explicit, understandable
- Where to obtain further information and, if applicable, HIV
- Where to obtain other services including, if applicable, treatment.
In addition, clients tested with rapid HIV tests should be
- Advised that their rapid test results will be available during
the same visit.
- Informed that confirmatory testing is needed if the rapid test
result is reactive.11
Waivers of the Clinical Laboratory Improvements Amendments of 1988
(CLIA) have been granted for the OraQuick Advance HIV 1 / 2 (on
June 25, 2004), the Uni-Gold Recombigen HIV test (November 5, 2004),
and the OraQuick Rapid HIV-1 Antibody test (January 31, 2003).12
These waivers permit their use in nonclinical settings, rather than
only in traditional laboratories. For instance, waived tests can
be done in settings such as doctor’s offices, HIV counseling and
testing sites, mobile vans, health fairs, or other nonclinical settings.
Rapid tests have been particularly useful for testing pregnant
women of unknown HIV status during labor and delivery to prevent
mother-to-child HIV transmission. For TB programs, settings where
the rapid HIV test may be particularly useful include sites for
targeted TB testing of populations with high HIV prevalence such
as at homeless shelters, substance abuse clinics, or correctional
institutions, or even for contact investigations in home-based settings.
For all waived rapid HIV testing, programs must obtain a certificate
of waiver from the CLIA program, follow manufacturer’s instructions
for the test procedure, and maintain an adequate quality assurance
program. Quality assurance guidelines can be found online.
—Reported by Suzanne Marks, MPH
Div of TB Elimination
- CDC. Tuberculosis and human immunodeficiency virus infection:
recommendations of the Advisory Committee for the Elimination
of Tuberculosis (ACET). MMWR 1989; 38 (17): 236-238, 243-250.
- CDC. Essential components of a tuberculosis prevention and
control program: recommendations of the Advisory Council for the
Elimination of Tuberculosis. MMWR 1995; 44 (RR-11): 13.
- CDC. Revised guidelines for HIV counseling, testing, and referral
and revised recommendations for HIV screening of pregnant women.
MMWR 2001; 50(RR-19): 36.
- CDC. Reported Tuberculosis in the United States, 2003.
Atlanta, GA: US Department of Health and Human Services, CDC;
September 2004. Table 13, page 23.
- CDC. Unpublished analysis by Dr. Paul Farnham and colleagues,
- CDC. HIV CT Client Record Report, 2000 U.S. Total. Unpublished
- Branson B, Burstein G. Retarding HIV Prevention: Initial results
from OraQuick postmarketing surveillance. Presentation, August
National Center for HIV, STD, and TB Prevention, Division of HIV/AIDS
- CDC, NCHSTP, DHAP. OraQuick
Rapid HIV Test for Oral Fluid – Frequently Asked Questions.
- CDC. Notice
to Readers. Protocols for confirmation of reactive rapid HIV test.
MMWR 2004; 53 (10): 221-222.
NCHSTP, DHAP website.
- FDA. Tests
waived by FDA from January 2000 to present.