Gordin F, Chaisson RE, Matts JP, Miller C, Garcia MDL, Hafner R, Valdespino JL, Coberly J, Schechter M, Klukowicz AJ, Barry MA, O'Brien RJ, for the Terry Beirn Community Programs for Clinical Research on AIDS,
the Adult AIDS Clinical Trials Group, the Pan American Health Organization,
and the Centers for Disease Control and Prevention Study Group . Rifampin and Pyrazinamide vs Isoniazid for Prevention of Tuberculosis in HIV-Infected PersonsAn International Randomized Trial. JAMA. 2000;283(11):1445-1450. doi:10.1001/jama.283.11.1445
Author Affiliations: Veterans Affairs Medical Center and Georgetown University, Washington, DC (Dr Gordin); the Department of Medicine, School of Medicine (Dr Chaisson), and Department of International Health, School of Hygiene and Public Health (Dr Coberly), Johns Hopkins University, Baltimore, Md; the Community Programs for Clinical Research on AIDS Statistical Center and Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis (Dr Matts and Ms Miller); the National Institute of Public Health, Cuernavaca, Mexico (Drs Garcia and Valdespino); the Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Md (Dr Hafner); Infectious Diseases Service, Hospital Universitário Clementino Fraga Filho, Department of Preventive Medicine, Universidade Federal do Rio de Janeiro, Brazil (Dr Schechter); Pulmonary Division, Saint Michael's Medical Center, Newark, NJ (Dr Klukowicz); Communicable Disease Control, Boston Public Health Commission, Boston, Mass (Dr Barry); and the Division of Tuberculosis Elimination, National Center for HIV, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Ga (Dr O'Brien).
Context Because of problems with adherence, toxicity, and increasing resistance
associated with 6- to 12-month isoniazid regimens, an alternative short-course
tuberculosis preventive regimen is needed.
Objective To compare a 2-month regimen of daily rifampin and pyrazinamide with
a 12-month regimen of daily isoniazid in preventing tuberculosis in persons
with human immunodeficiency virus (HIV) infection.
Design Randomized, open-label controlled trial conducted from September 1991
to May 1996, with follow-up through October 1997.
Setting Outpatient clinics in the United States, Mexico, Haiti, and Brazil.
Participants A total of 1583 HIV-positive persons aged 13 years or older with a positive
tuberculin skin test result.
Interventions Patients were randomized to isoniazid, 300 mg/d, with pyridoxine hydrochloride
for 12 months (n = 792) or rifampin, 600 mg/d, and pyrazinamide, 20 mg/kg
per day, for 2 months (n = 791).
Main Outcome Measures The primary end point was culture-confirmed tuberculosis; secondary
end points were proven or probable tuberculosis, adverse events, and death,
compared by treatment group.
Results Of patients assigned to rifampin and pyrazinamide, 80% completed the
regimen compared with 69% assigned to isoniazid (P<.001).
After a mean follow-up of 37 months, 19 patients (2.4%) assigned to rifampin
and pyrazinamide and 26 (3.3%) assigned to isoniazid developed confirmed tuberculosis
at rates of 0.8 and 1.1 per 100 person-years, respectively (risk ratio, 0.72
[95% confidence interval, 0.40-1.31]; P = .28). In
multivariate analysis, there were no significant differences in rates for
confirmed or probable tuberculosis (P = .83), HIV
progression and/or death (P = .09), or overall adverse
events (P = .27), although drug discontinuation was
slightly higher in the rifampin and pyrazinamide group (P = .01). Neither regimen appeared to lead to the development of drug-resistant
Conclusions Our data suggest that for preventing tuberculosis in HIV-infected patients,
a daily 2-month regimen of rifampin and pyrazinamide is similar in safety
and efficacy to a daily 12-month regimen of isoniazid. This shorter regimen
offers practical advantages to both patients and tuberculosis control programs.
Chemoprophylaxis of tuberculosis in individuals with latent Mycobacterium tuberculosis infection is an important component of tuberculosis
control.1 Isoniazid has been proven effective
in preventing tuberculosis in tuberculin-positive persons, both human immunodeficiency
and HIV-positive.4- 6
The American Thoracic Society and the Centers for Disease Control and Prevention
(CDC) currently recommend 6 months or longer of isoniazid daily for tuberculosis
preventive therapy.7 Difficulties with isoniazid
preventive therapy, however, include poor adherence,8
hepatotoxicity,9 and organisms with isoniazid
resistance, both in the United States and globally.10,11
Given these limitations, the development of alternative, shorter regimens
for the prevention of tuberculosis has become a high priority.12,13
This study evaluated the safety and efficacy of a 2-month regimen of
daily rifampin and pyrazinamide for prevention of tuberculosis in tuberculin-positive,
HIV-infected persons (a group selected because of its high risk for reactivation
of tuberculosis infection [eg, 7.9 cases per 100 person-years]).14
The comparison regimen was 12 months of daily isoniazid, the standard at the
start of the study.8
Patients were enrolled at 15 units of the Terry Beirn Community Programs
for Clinical Research on AIDS (CPCRA 004), at 33 units of the Adult AIDS Clinical
Trials Group (ACTG 177), and at 5 units sponsored by the CDC. One unit each
in Haiti and Brazil was also sponsored by the CDC Prevention Study Group,
and 1 unit in Mexico was sponsored by the Pan American Health Organization.
Patients were required to be 13 years or older, have been diagnosed
with HIV infection, have a reaction of 5 mm or more of induration to 5 U of
purified protein derivative (or a documented history of a positive test),
a hemoglobin level of more than 80 g/L, a neutrophil count of more than 0.75
× 109/L, platelet count of more than 50 × 109/L, total bilirubin of 42.7 µmol/L (2.5 mg/dL) or less, and aspartate
aminotransferase and alkaline phosphatase levels of less than 5 times the
normal level. Exclusions were clinical or radiological evidence of active
tuberculosis at enrollment; current treatment with fluoroquinolones or other
agents active against M tuberculosis; history of
more than 2 months of continuous treatment with antituberculous agents; past
intolerance to study medications; acute hepatitis or peripheral neuropathy;
or pregnancy. The study protocol was approved by an institutional review board
at each site and all patients gave written, informed consent.
Patients were randomized to receive 300 mg/d of isoniazid with 50 mg/d
of pyridoxine hydrochloride for 12 months or 600 mg/d of rifampin (or 450
mg/d for those who weighed less than 50 kg) and 20 mg/kg of pyrazinamide per
day for 2 months. Patients who did not receive the study drug continuously
were encouraged to complete a 6-month course if in the isoniazid arm and a
60-day course if in the rifampin and pyrazinamide arm.
The study was designed to enroll 2000 patients with follow-up for an
average of 36 months. The study, as designed, had a power of 80% to detect
a 35% difference (12% vs 7.8%) at 36 months in the risk of tuberculosis (2-sided α
level, .05) between treatment groups. The rate of expected tuberculosis was
based on prior data on the development of tuberculosis in HIV-infected persons14 and on the efficacy of isoniazid.1
It was assumed that 5% of patients in each group would crossover to the other
treatment group outside of the protocol, and that 10% in each group would
die or become lost to follow-up without tuberculosis. A stratified 1:1 randomization
with permuted blocks was used, with the study unit as the stratification factor.
The primary end point was active tuberculosis, confirmed by M tuberculosis culture from any source. Cultures and susceptibility
tests were performed at participating certified laboratories. Secondary end
points were the combination of confirmed and probable tuberculosis, adverse
events, and death. The diagnosis of probable tuberculosis required clinical
evidence; specimens positive by smear test for acid-fast bacilli were insufficient
for a diagnosis of tuberculosis.
Death and clinical progression of HIV disease were also reported. Clinical
progression was defined as the first occurrence of an acquired immunodeficiency
syndrome (AIDS)–defining condition15
or as a recurrence of Pneumocystis carinii pneumonia,
esophageal candidiasis, herpes simplex infection, disseminated herpes zoster,
or septicemia due to nontyphoidal salmonella. Progression of HIV disease was
not reliably diagnosed in Haiti.
Treatment was usually self-administered. Study visits for both treatment
groups were scheduled at months 1, 2, 3, 6, 9, and 12, and then every 6 months
thereafter. All patients received follow-up regardless of study drug status
until the close of the study. At months 1 and 2, a complete blood cell count,
uric acid, aspartate aminotransferase, total bilirubin, and alkaline phosphatase
levels were measured; and at all follow-up visits, clinical assessment was
performed. Patients thought to have active tuberculosis were studied by chest
radiography, sputum evaluation, and other tests. Adverse events were categorized
using the Division of AIDS Table for Grading Severity of Adult Adverse Experiences.
The treatment groups were compared with χ2 or Fisher
exact tests for categorial variables and with t and
Wilcoxon rank sum tests for continuous variables. Time-to-event analyses were
performed with proportional-hazards regression to estimate risk ratios (RRs).
The assumption of proportionality was not formally tested. Patients lost to
follow-up were censored at the last time they were known to be event-free.
Analyses were stratified by geography: United States, Haiti, Brazil, and Mexico.
Both unadjusted and adjusted analyses were performed for tuberculosis, mortality,
and progression of HIV disease. The adjusted analyses used the baseline variables
in Table 1. Primary analyses were
performed on an intention-to-treat basis. All P values
Safety and efficacy data were reviewed periodically by an independent
data and safety monitoring board, who used the Lan-DeMets method as a guideline
for early stopping.16
Enrollment was conducted from September 1991 to May 1996, with 791 patients
assigned rifampin and pyrazinamide, and 792 assigned isoniazid with pyridoxine
hydrochloride (Figure 1). All patients
were followed up through October 1997. There were 1128 patients in the United
States (603 from the Northeast), 157 in Haiti, 117 in Brazil, and 181 in Mexico.
The baseline characteristics of the study groups were similar (Table 1). Of the patients, 51% were black, 35% Latino; 28% were
women; mean age was 37 years (range, 16-70 years). Overall, the median CD4
cell count at entry was 436 × 106/L (interquartile range,
274-621 × 106/L), and 7% of the patients had AIDS. A current,
positive purified protein derivative test was documented for 57% of the patients,
and a historic positive for the remainder.
In the rifampin and pyrazinamide group, 636 (80%) of 791 patients completed
treatment, and 544 (69%) of 792 patients in the isoniazid group completed
treatment (P<.001). Adverse events led to discontinuation
of the study drug in 10% of the patients in the rifampin and pyrazinamide
group and in 6% of the patients in the isoniazid group (P = .01).
At the end of the study, 10.1% of the rifampin and pyrazinamide patients
and 9.2% of the isoniazid patients were lost to follow-up for development
of tuberculosis. With censoring for tuberculosis, death, and loss to follow-up,
the mean duration of follow-up was 37.2 months in the rifampin and pyrazinamide
group and 36.8 months in the isoniazid group. Despite the smaller sample size,
there was little loss of statistical power because the person-years of follow-up
was close to that in the original design.
Table 2 shows the rates
of tuberculosis, death, and progression of HIV disease with the associated
unadjusted and adjusted RRs. Confirmed tuberculosis developed in 19 (2.4%)
of 791 patients in the rifampin and pyrazinamide group (16 of 563 in the United
States, 3 of 78 in Haiti, 0 of 91 in Mexico, and 0 of 59 in Brazil) and in
26 (3.3%) of 792 patients in the isoniazid group (23 of 565 in the United
States, 2 of 79 in Haiti, 1 of 58 in Brazil, and 0 of 90 in Mexico). The rates
of tuberculosis per 100 patient-years of follow-up were 0.8 and 1.1, respectively,
for the rifampin and pyrazinamide and isoniazid groups; RR, 0.72 (95% confidence
interval, 0.40-1.31; P = .28); the wide confidence
interval was due to few events. Figure 2
shows cumulative rates of confirmed tuberculosis. Table 1 lists subgroups examined; no significant differences existed
between the rifampin and pyrazinamide group and the isoniazid group.
In an analysis comparing the 636 persons who completed rifampin and
pyrazinamide with the 544 who completed isoniazid, the case rates of tuberculosis
were similar (0.6 vs 0.8; RR, 0.84 [95% confidence interval, 0.39-1.78]; P = .65). Completers had a lower rate of tuberculosis compared
with noncompleters for both rifampin plus pyrazinamide (0.6 vs 1.6; RR, 0.42; P = .08) and isoniazid (0.8 vs 2.1; RR, 0.36; P = .01).
Drug susceptibility testing was performed on all 19 isolates of M tuberculosis in the rifampin and pyrazinamide group and
in 24 of the 26 isolates in the isoniazid group (Table 3). Rifampin resistance was detected in 3 individuals treated
with rifampin and pyrazinamide, and in 1 treated with isoniazid. There were
no cases of rifampin monoresistance. In each treatment group, 3 individuals
had isolates resistant to isoniazid.
In the rifampin and pyrazinamide group, 139 (18%) of 791 patients died
compared with 159 (20%) of 792 patients in the isoniazid group (RR, 0.87; P = .23). In the rifampin and pyrazinamide group, 192 (24%)
of 791 died or had progression of HIV disease, compared with 224 (28%) of
792 patients in the isoniazid group (RR, 0.83; P
At least 1 reportable adverse event occurred in 97 patients receiving
rifampin and pyrazinamide vs 83 patients receiving isoniazid (Table 4; P = .27). One case of grade 4
hepatitis occurred in a patient receiving rifampin and pyrazinamide, while
there were 2 cases among isoniazid recipients. Not included in Table 4 were 90 cases of suspected hepatitis that did not result
in study drug discontinuation in the rifampin and pyrazinamide group, and
107 cases in the isoniazid group. Abnormal liver function test results, which
were grade 4 or that resulted in study drug discontinuation, occurred in 11
rifampin and pyrazinamide patients and in 26 isoniazid patients (P = .02). Patients taking rifampin and pyrazinamide experienced a small,
statistically significant increase in nausea, vomiting, and narcotic withdrawal.
Also, 52 patients in the rifampin and pyrazinamide group and 2 in the isoniazid
group had uric acid values of grade 3 or higher (713.8 µmol/L; P<.001).
This study found that a 2-month course of daily rifampin and pyrazinamide
is similar in safety and efficacy to a standard 12-month course of isoniazid
for preventing tuberculosis in individuals with HIV infection and a positive
tuberculin test result. Adherence to rifampin and pyrazinamide was superior
and rates of toxicity were low in both groups, although discontinuation was
slightly higher in the rifampin and pyrazinamide group. There was no evidence
that rifampin and pyrazinamide selected for resistant strains of M tuberculosis.
The prevention of tuberculosis in people with HIV infection has both
clinical and public health importance. Globally, tuberculosis is the principal
cause of death in up to one third of people dying who have HIV infection.17 Even in patients with HIV whose tuberculosis is effectively
treated, subsequent mortality is high, reflecting the impact that active tuberculosis
has on HIV replication and the natural history of HIV disease.18,19
Tuberculosis is the one opportunistic infection occurring in people with HIV
that readily infects people with whom they come in contact, potentially resulting
in institutional and community outbreaks of disease.20,21
Isoniazid has been shown to be effective in reducing the occurrence
of tuberculosis in tuberculin-positive HIV-infected persons.3- 6,22- 24
Based on these data, 9 to 12 months of isoniazid has been recommended for
patients who are both HIV- and tuberculin-positive.7,25,26
This longer duration is recommended because HIV infection is the most potent
risk factor for reactivation of latent tuberculosis,27
and because 12 months of isoniazid was proven to be more effective than 6
months in preventing tuberculosis in persons with fibrotic lung disease.28
Isoniazid preventive therapy is effective, but several limitations have
been identified. First, compliance with a 9- to 12-month course of therapy
is difficult because patients receive the medication, not for an active illness,
but for prevention of an illness. Only about half of those beginning preventive
therapy complete a 6-month regimen.29 A second
concern is isoniazid-related hepatitis, which is occasionally fatal.30 Third, isoniazid is also associated with peripheral
neuropathy,4,7 which is of concern
because of the increased occurrence of peripheral neuropathy in HIV-infected
persons. Finally, the effectiveness of isoniazid may decrease as isoniazid-resistant
strains of M tuberculosis become more common.10,11
These concerns with isoniazid preventive therapy have led to the study
of short-course, rifampin-based regimens. In a study of HIV-infected individuals
in Uganda, Whalen et al6 compared 3 daily regimens
to a placebo: 3 months of isoniazid and rifampin; 3 months of isoniazid and
rifampin and pyrazinamide; and 6 months of isoniazid. Both of the rifampin-based
regimens appeared effective in preventing tuberculosis. Two other groups31,32 have examined rifampin and pyrazinamide
regimens for the prevention of tuberculosis in purified protein derivative–positive,
HIV-infected persons. Both groups used rifampin and pyrazinamide twice weekly
for 2 months in a study in Haiti32 and for
3 months in Zambia.31 In the Haiti study, the
rifampin and pyrazinamide arm had a tuberculosis rate of 1.8 per 100 person-years;
in Zambia, the rate was 2.7. Both rates were slightly higher than those in
the respective arms that received 6 months of isoniazid. In contrast, in the
present study, patients received daily rifampin and pyrazinamide, resulting
in a tuberculosis rate of only 0.8, a rate lower than the comparative group,
which received isoniazid for the full recommended duration (12 months). Greater
confidence in the results of the present study is also secured by the study's
larger sample size and longer follow-up.
The 2-month rifampin and pyrazinamide regimen offers advantages over
the 12 months of isoniazid, despite the similar efficacy of the 2 regimens.
Because of the shorter duration, there was a higher completion rate; this
has practical implications in time savings for both patients and staff. Rates
of rifampin resistance are lower than isoniazid resistance in almost all areas
of the world10,11; therefore,
the rifampin-containing regimen is potentially of greater value where drug-resistant
isolates are a concern, although it will be important to continue to monitor
for rifampin resistance.
The use of preventive chemotherapy is a major component of the tuberculosis
control plan of the United States1 and is being
more widely applied in other regions of the world.33
Ten years ago, a shorter, safer, and more economical alternative to isoniazid
preventive therapy was deemed important in eliminating tuberculosis from the
United States.12 This study has demonstrated
that the 2-month regimen is similar in safety and efficacy to a 12-month regimen
in providing tuberculosis prevention in HIV-infected populations. Furthermore,
this study has shown that, for both of these regimens, completion of therapy
is key to achieving maximum reduction in tuberculosis risk. The results of
this trial provided the basis for the revised CDC guidelines that endorsed
the 2-month regimen of daily rifampin and pyrazinamide for the treatment of
latent tuberculosis in HIV-infected persons26
(twice-weekly rifampin and pyrazinamide was not recommended for this population).
The study data were also pivotal in providing the basis for the new recommendations
in development from the American Thoracic Society and CDC on use of this regimen
in persons without HIV infection (D. Cohn, MD, oral communication, January
2000). Preliminary information indicates that this new regimen is highly cost-effective
when given to persons with latent tuberculosis infection who are at high risk
of active disease.34 The challenge now is to
educate both physicians and patients about this new treatment and to determine
how it may be most effectively implemented.