Marc Weiner

Three months of rifapentine and isoniazid for latent tuberculosis infection

BACKGROUND Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion. METHODS We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%. RESULTS In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001). CONCLUSIONS The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.).

Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial.

BACKGROUND Rifapentine has a long half-life in serum, which suggests a possible treatment once a week for tuberculosis. We aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week. METHODS We did a randomised, multicentre, open-label trial in the USA and Canada of HIV-negative people with drug-susceptible pulmonary tuberculosis who had completed 2 months of a 6-month treatment regimen. We randomly allocated patients directly observed treatment with either 600 mg rifapentine plus 900 mg isoniazid once a week or 600 mg rifampicin plus 900 mg isoniazid twice a week. Primary outcome was failure/relapse. Analysis was by intention to treat. FINDINGS 1004 patients were enrolled (502 per treatment group). 928 successfully completed treatment, and 803 completed the 2-year 4-month study. Crude rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin twice a week (relative risk 1.64, 95% CI 1.04-2.58, p=0.04). By proportional hazards regression, five characteristics were independently associated with increased risk of failure/relapse: sputum culture positive at 2 months (hazard ratio 2.8, 95% CI 1.7-4.6); cavitation on chest radiography (3.0, 1.6-5.9); being underweight (3.0, 1.8-4.9); bilateral pulmonary involvement (1.8, 1.0-3.1); and being a non-Hispanic white person (1.8, 1.1-3.0). Adjustment for imbalances in 2-month culture and cavitation diminished the association of treatment group with outcome (1.34; 0.83-2.18; p=0.23). Of participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the twice a week group (relative risk 1.15; 95% CI 0.38-3.50; p=0.81). Rates of adverse events and death were similar in the two treatment groups. INTERPRETATION Rifapentine once a week is safe and effective for treatment of pulmonary tuberculosis in HIV-negative people without cavitation on chest radiography. Clinical, radiographic, and microbiological data help to identify patients with tuberculosis who are at increased risk of failure or relapse when treated with either regimen.

Effects of Rifampin and Multidrug Resistance Gene Polymorphism on Concentrations of Moxifloxacin

ABSTRACT Treatment regimens combining moxifloxacin and rifampin for drug-susceptible tuberculosis are being studied intensively. However, rifampin induces enzymes that transport and metabolize moxifloxacin. We evaluated the effect of rifampin and the human multidrug resistance gene (MDR1) C3435T polymorphisms (P-glycoprotein) on moxifloxacin pharmacokinetic parameters. This was a single-center, sequential design study with 16 volunteers in which sampling was performed after four daily oral doses of moxifloxacin (400 mg) and again after 10 days of combined rifampin (600 mg) and moxifloxacin. After daily coadministration of rifampin, the area under the concentration-time curve from 0 to 24 h (AUC0-24) for moxifloxacin decreased 27%. Average bioequivalence between moxifloxacin coadministered with rifampin and moxifloxacin alone was not demonstrated: the ratio of geometric means (RGM) of the moxifloxacin AUC0-24 was 73.3 (90% confidence intervals [CI], 64.3, 83.5) (total P value, 0.87 for two one-sided t tests). Peak moxifloxacin concentrations, however, were equivalent: the RGM of the maximum concentration of the drug in serum was 93.6 (90% CI, 80.2, 109.3) (total P value, 0.049). Concentrations of the sulfate conjugate metabolite of moxifloxacin were increased twofold following rifampin coadministration (AUC0-24, 1.29 versus 2.79 μg·h/ml). Concomitant rifampin administration resulted in a 27% decrease in the mean moxifloxacin AUC0-24 and a marked increase in the AUC0-24 of the microbiologically inactive M1 metabolite. Additional studies are required to understand the clinical significance of the moxifloxacin-rifampin interaction.

Effects of tuberculosis, race, and human gene SLCO1B1 polymorphisms on rifampin concentrations.

ABSTRACT Rifampin has concentration-dependent activity against Mycobacterium tuberculosis. However, marked intersubject variation of rifampin concentrations occurs. In this study, we evaluated rifampin pharmacokinetics in relation to tuberculosis, geographic region, race, and single nucleotide polymorphisms of the human transporter genes SLCO1B1, SLCO1B3, and MDR1. Seventy-two adults with pulmonary tuberculosis from Africa, North America, and Spain were evaluated during multidrug intensive-phase therapy, and their results were compared to those from 16 healthy controls from North America. Rifampin pharmacokinetic values were similar between tuberculosis patients and controls (geometric mean [GM] area under the concentration-time curve from 0 to 24 h [AUC0-24] of 40.2 versus 40.9 μg·h/ml; P = 0.9). However, in multivariable analyses, the rifampin AUC0-24 was significantly affected by rifampin dosage (in mg/kg of body weight), polymorphisms in the SLCO1B1 gene, and the presence of tuberculosis by geographic region. The adjusted rifampin AUC0-24 was lowest in patients with tuberculosis from Africa compared to that in non-African patients or control subjects. The adjusted rifampin AUC0-24 was also 36% lower among participants with SLCO1B1 genotype c.463CA than that among participants with SLCO1B1 genotype c.463CC (adjusted GM, 29.8 versus 46.7 μg·h/ml; P = 0.001). Polymorphisms in the SLCO1B1 gene associated with lower rifampin exposure were more frequent among black subjects. In conclusion, marked intersubject variation of the rifampin AUC0-24 values was observed, but the mean values of the AUC0-24 did not significantly vary between patients with tuberculosis and healthy controls. Lower rifampin exposure was associated with the polymorphism of the SLCO1B1 c.463C>A gene. When adjusted for the patient mg/kg dosage and transporter gene polymorphisms, rifampin exposure was lower in patients with tuberculosis, which suggests that additional absorption or metabolic processes affect rifampin exposure with tuberculosis disease.

Elucidating Novel Serum Biomarkers Associated with Pulmonary Tuberculosis Treatment

In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention’s Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy.

Aspergillus antigen detection in bronchoalveolar lavage fluid from patients with invasive aspergillosis and aspergillomas

Improved diagnostic techniques have been needed for pulmonary aspergillosis, a common opportunistic fungal infection with a high mortality rate. Radioimmunoassay was used in this study to detect Aspergillus antigen in bronchoalveolar lavage fluid. In four patients with invasive aspergillosis or aspergillomas, Aspergillus antigen was detected in bronchoalveolar lavage fluid. In two patients, results of fungal cultures were negative or delayed. The specificity of antigen detection in bronchoalveolar lavage fluid was 91 percent in 35 control patients with a variety of pulmonary disorders. The technique or radioimmunoassay detection of microbial antigen in bronchoalveolar lavage fluid appears promising for the diagnosis of aspergillosis.

Antigenemia Detected by Radioimmunoassay in Systemic Aspergillosis

Because of difficulties in antemortem diagnosis of systemic aspergillosis, a radioimmunoassay to an Aspergillus fumigatus carbohydrate was developed and evaluated in patients with mycotic or bacterial infections. Antigenemia was detected in sera obtained antemortem from four of seven patients with systemic aspergillosis and in pleural fluid from an Aspergillus empyema but not in control sera or pleural fluid from 43 patients or 27 normal donors. When characterized with reference to onset of disease, antigenemia was an early sign of infection. This study shows the usefulness of the Aspergillus antigen radioimmunoassay for early, specific immunodiagnosis of systemic aspergillosis.

Treatment for Preventing Tuberculosis in Children and Adolescents: A Randomized Clinical Trial of a 3-Month, 12-Dose Regimen of a Combination of Rifapentine and Isoniazid

IMPORTANCE Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited. OBJECTIVES To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children. DESIGN, SETTING, AND PARTICIPANTS A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection. INTERVENTIONS Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months. MAIN OUTCOMES AND MEASURES We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%. RESULTS Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion. CONCLUSIONS AND RELEVANCE Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00023452.

Fluoroquinolone Susceptibility among Mycobacterium tuberculosis Isolates from the United States and Canada

BACKGROUND There is increasing interest in the possible role of new fluoroquinolone antibiotics for treatment of tuberculosis, but widespread use of fluoroquinolones for treatment of other bacterial infections may select for resistant strains of Mycobacterium tuberculosis. METHODS We evaluated fluoroquinolone susceptibility using the proportion method (critical ciprofloxacin concentration for susceptibility testing, 2.0 mu g/mL) in isolates obtained from patients enrolled in Tuberculosis Trial Consortium clinical trials during the period of 1995-2001 and in a referral sample of isolates sent to the Centers for Disease Control and Prevention (Atlanta, GA) during the period of 1996-2000 for additional testing, often because of drug resistance. RESULTS Of the 1373 isolates from the clinical trials, 1324 (96%) were susceptible to isoniazid and rifampin; 2 (0.15%) of these isolates were also resistant to ciprofloxacin. Of the 1852 isolates from the referral sample, 603 (32.6%) were resistant to isoniazid and rifampin (i.e., multidrug resistant), 849 (45.7%) were resistant to >or=1 first-line drug but were not resistant to both isoniazid and rifampin, and 400 (21.6%) were susceptible to all first-line agents. Ciprofloxacin resistance was found in 33 (1.8%) of the referral-sample isolates. Most ciprofloxacin-resistant isolates (25 [75.8%]) were resistant to isoniazid and rifampin. CONCLUSIONS Despite widespread use of fluoroquinolones for treatment of common bacterial infections, resistance among clinical isolates of M. tuberculosis in the United States and Canada remains rare, occurring primarily among multidrug-resistant strains.

Antigen Detection in the Diagnosis of Invasive Aspergillosis: Utility in Controlled, Blinded Trials

Two blinded, controlled trials were done to evaluate the usefulness of fungal antigen detection for the diagnosis of invasive aspergillosis. Detection of Aspergillus fumigatus carbohydrate by radioimmunoassay was compared with antibody detection by an enzyme-linked immunosorbent assay and with diagnostic microbiologic and histopathologic procedures. In the first trial, antigenemia was detected in 4 of 6 leukemic patients with invasive pulmonary aspergillosis, but not in 8 acute leukemic controls or in 24 normal controls. Fungal antigenemia persisted for 8 to 75 days in 4 patients and seroconversion occurred at the onset of pulmonary infiltrates in 3. Antibody to A. fumigatus was detected in 2 of the 6 patients with aspergillosis, but also in 2 leukemic controls and 6 normal controls. Aspergillus species were identified in four of seven bronchoscopies done in 5 patients with invasive pulmonary aspergillosis. Prospective nasal cultures grew Aspergillus species in 4 of the 6 patients with invasive aspergillosis, but in only 1 patient was this information available before a histologic diagnosis was made. In a second trial, antigenemia was detected in 2 patients with invasive aspergillosis, and in 1 with possible invasive aspergillosis, but not in 9 controls. This study indicates that the radioimmunoassay for A. fumigatus antigen is a highly specific and moderately sensitive serodiagnostic test for invasive pulmonary aspergillosis. Prospective nasal cultures grew Aspergillus species in 4 of the 6 patients with invasive aspergillosis, but in only 1 patient was this information available before a histologic diagnosis was made. In a second trial, antigenemia was detected in 2 patients with invasive aspergillosis, and in 1 with possible invasive aspergillosis, but not in 9 controls. This study indicates that the radioimmunoassay for A. fumigatus antigen is a highly specific and moderately sensitive serodiagnostic test for invasive pulmonary aspergillosis.