Rifapentine With and Without Moxifloxacin for Pulmonary Tuberculosis in People With Human Immunodeficiency Virus (S31/A5349).

BACKGROUND: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH). METHODS: PWH and CD4+ counts ≥100 cells/µL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz. RESULTS: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/µL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%). CONCLUSIONS: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/µL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe. CLINICAL TRIALS REGISTRATION: NCT02410772.

A Case of Peritoneal Tuberculosis Mimicking Ovarian Cancer in a Young Female.

Background: Tuberculosis causes significant morbidity and mortality globally. Peritoneal tuberculosis can have a similar presentation to ovarian cancer. Case: We present a case of a 42-year-old female referred to gynecology oncology with imaging findings of enlarged right ovary, omental caking, and elevated CA-125 (1289 U/mL). A diagnostic laparoscopy revealed diffuse studding of intraperitoneal surfaces. Histopathological examination of omental and abdominal wall biopsies showed granulomas, but stains and cultures for mycobacteria were negative. Antimicrobial treatment for tuberculosis was initiated. Within eight weeks, there was clear clinical and radiographic improvement, consistent with a diagnosis of peritoneal tuberculosis. Conclusion: This case highlights the importance of including peritoneal tuberculosis in the differential diagnosis when evaluating for ovarian cancer in women with epidemiologic risk factors for tuberculosis.

Chest Computed Tomography Features of Nontuberculous Mycobacterial Pulmonary Disease Versus Asymptomatic Colonization: A Cross-sectional Cohort Study.

BACKGROUND: Asymptomatic colonization by nontuberculous mycobacteria (NTM) found in sputum isolates are commonly encountered and clinicians lack a biomarker for prognosticating the risk of transition asymptomatic colonization to active clinical disease. Chest computed tomography (CT) imaging is commonly obtained in this patient population and may serve a role for this purpose. METHODS: We conducted a single-center, cross-sectional study of patients followed in the NTM clinic at our center between August 2019 and August 2020. All patients had a history of NTM isolated from their airways and were cohorted as either nontuberculous mycobacteria-pulmonary disease (NTM-PD) if they met ATS/IDSA guidelines for treatment or as nontuberculous mycobacteria-colonized (NTM-C) if they did not meet ATS/IDSA criteria for NTM treatment. Patients with a chest CT were included in the analysis and CT scans were assessed for features including bronchiectasis, nodules, and cavities. Bronchiectasis severity was calculated using the modified Reiff scoring system. Univariate analyses were conducted to compare patients with NTM-C and NTM-PD. RESULTS: Eighty-four patients were included in the analysis and 27 were classified as NTM-C and 57 as NTM-PD. NTM-PD patients had a greater median number of lung lobes affected by bronchiectatic airways (6 [1] NTM-PD vs. 5 [3] NTM-C P=0.005) and a greater frequency of cystic bronchiectasis (17.5% NTM-PD vs. 0% NTM-PD, P=0.016). Bronchiectasis severity was higher for NTM-PD patients (7 [9] NTM-PD vs. 5 [1.5] NTM-C, P<0.001). CONCLUSIONS: Patients with NTM-PD have greater bronchiectatic airway involvement and the forms of bronchiectasis present are more severe compared with NTM-C patients. In addition, cavitation of lung parenchyma was a radiographic feature solely associated with NTM-PD. Features identified on chest CT may be useful as a prognostic biomarker for the risk of transition from NTM-C to NTM-PD.

Decreased plasma rifapentine concentrations associated with AADAC single nucleotide polymorphism in adults with tuberculosis.

BACKGROUND: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered. OBJECTIVES: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated. METHODS: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575. RESULTS: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10). CONCLUSIONS: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups.

Predictive value of TNF-α, IFN-γ, and IL-10 for tuberculosis among recently exposed contacts in the United States and Canada.

BACKGROUND: We examined cytokine immune response profiles among contacts to tuberculosis patients to identify immunologic and epidemiologic correlates of tuberculosis. METHODS: We prospectively enrolled 1272 contacts of culture-confirmed pulmonary tuberculosis patients at 9 United States and Canadian sites. Epidemiologic characteristics were recorded. Blood was collected and stimulated with Mycobacterium tuberculosis culture filtrate protein, and tumor necrosis factor (TNF-α), interferon gamma (IFN-γ), and interleukin 10 (IL-10) concentrations were determined using immunoassays. RESULTS: Of 1272 contacts, 41 (3.2%) were diagnosed with tuberculosis before or < 30 days after blood collection (co-prevalent tuberculosis) and 19 (1.5%) during subsequent four-year follow-up (incident tuberculosis). Compared with contacts without tuberculosis, those with co-prevalent tuberculosis had higher median baseline TNF-α and IFN-γ concentrations (in pg/mL, TNF-α 129 versus 71, P < .01; IFN-γ 231 versus 27, P < .001), and those who subsequently developed incident tuberculosis had higher median baseline TNF-α concentrations (in pg/mL, 257 vs. 71, P < .05). In multivariate analysis, contact age < 15 years, US/Canadian birth, and IFN or TNF concentrations > the median were associated with co-prevalent tuberculosis (P < .01 for each); female sex (P = .03) and smoking (P < .01) were associated with incident tuberculosis. In algorithms combining young age, positive skin test results, and elevated CFPS TNF-α, IFN-γ, and IL-10 responses, the positive predictive values for co-prevalent and incident tuberculosis were 40 and 25%, respectively. CONCLUSIONS: Cytokine concentrations and epidemiologic factors at the time of contact investigation may predict co-prevalent and incident tuberculosis.

A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine.

Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures.

Negative Tuberculin Skin Test and Prediction of Reversion of QuantiFERON Interferon Gamma Release Assay in US Healthcare Workers.

QuantiFERON tuberculosis tests (QFT) reverted in (612) 77% of 1,094 low-risk healthcare workers (HCW) testing less than 1.16 IU/mL. Of HCW testing greater than 1.1 IU/mL, 33 (59%) of 56 with negative tuberculin skin tests (TST) reverted vs 8 (6%) of 125 with positive TSTs. Retesting low-risk QFT-positive and TST-negative HCW is prudent.

Diagnostic accuracy of a urine lipoarabinomannan enzyme-linked immunosorbent assay for screening ambulatory HIV-infected persons for tuberculosis.

OBJECTIVE: To assess the diagnostic accuracy of the urine lipoarabinomannan (LAM) test among ambulatory HIV-infected persons. DESIGN: Cross-sectional. METHODS: HIV-infected persons consecutively presenting to the HIV Clinic at Tembisa Main Clinic in Ekhuruleni, South Africa, were screened for symptoms of tuberculosis (TB) and asked to provide sputum and blood samples for smears for acid-fast bacilli and mycobacterial culture and a urine specimen for a LAM enzyme-linked immunosorbent assay. Fine needle aspirates were obtained from participants with enlarged lymph nodes and sent for histopathology. Nonpregnant participants underwent chest x-ray. RESULTS: : Four hundred twenty-two HIV-infected participants were enrolled with median age 37 years (interquartile range: 31-44 years), median CD4+ T-cell count 215 cells per microliter (interquartile range: 107-347 cells/µL), and 212 (50%) receiving antiretroviral therapy. Thirty (7%) had active TB: 18 with only pulmonary TB, 5 with only extrapulmonary TB, and 7 with both pulmonary TB and extrapulmonary TB. Twenty-seven percent [95% confidence interval (CI): 12% to 48%] of TB cases were sputum acid-fast bacilli positive. The sensitivity and specificity of the urine LAM compared with the gold standard of positive bacteriology or histopathology were 32% (95% CI: 16% to 52%) and 98% (95% CI: 96% to 99%), respectively. Urine LAM had higher sensitivity in TB cases with higher bacillary burdens, though these differences were not statistically significant. CONCLUSIONS: The sensitivity of urine LAM testing is inadequate to replace mycobacterial culture. In contrast to prior research on the urine LAM, this study was conducted among less sick, ambulatory HIV-infected patients presenting for routine care.

Geographic differences in time to culture conversion in liquid media: Tuberculosis Trials Consortium study 28. Culture conversion is delayed in Africa.

BACKGROUND: Tuberculosis Trials Consortium Study 28, was a double blind, randomized, placebo-controlled, phase 2 clinical trial examining smear positive pulmonary Mycobacterium tuberculosis. Over the course of intensive phase therapy, patients from African sites had substantially delayed and lower rates of culture conversion to negative in liquid media compared to non-African patients. We explored potential explanations of this finding. METHODS: In TBTC Study 28, protocol-correct patients (n = 328) provided spot sputum specimens for M. tuberculosis culture in liquid media, at baseline and weeks 2, 4, 6 and 8 of study therapy. We compared sputum culture conversion for African and non-African patients stratified by four baseline measures of disease severity: AFB smear quantification, extent of disease on chest radiograph, cavity size and the number of days to detection of M. tuberculosis in liquid media using the Kaplan-Meier product-limit method. We evaluated specimen processing and culture procedures used at 29 study laboratories serving 27 sites. RESULTS: African TB patients had more extensive disease at enrollment than non-African patients. However, African patients with the least disease by the 4 measures of disease severity had conversion rates on liquid media that were substantially lower than conversion rates in non-African patients with the greatest extent of disease. HIV infection, smoking and diabetes did not explain delayed conversion in Africa. Some inter-site variation in laboratory processing and culture procedures within accepted practice for clinical diagnostic laboratories was found. CONCLUSIONS: Compared with patients from non-African sites, African patients being treated for TB had delayed sputum culture conversion and lower sputum conversion rates in liquid media that were not explained by baseline severity of disease, HIV status, age, smoking, diabetes or race. Further investigation is warranted into whether modest variation in laboratory processes substantially influences the efficacy outcomes of phase 2 TB treatment trials or if other factors (e.g., nutrition, host response) are involved. TRIAL REGISTRATION: ClinicalTrials.gov NCT00144417.

Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies.

BACKGROUND: Interferon gamma receptor 1 (IFNgammaR1) deficiency is a primary immunodeficiency with allelic dominant and recessive mutations characterised clinically by severe infections with mycobacteria. We aimed to compare the clinical features of recessive and dominant IFNgammaR1 deficiencies. METHODS: We obtained data from a large cohort of patients worldwide. We assessed these people by medical histories, records, and genetic and immunological studies. Data were abstracted onto a standard form. FINDINGS: We identified 22 patients with recessive complete IFNgammaR1 deficiency and 38 with dominant partial deficiency. BCG and environmental mycobacteria were the most frequent pathogens. In recessive patients, 17 (77%) had environmental mycobacterial disease and all nine BCG-vaccinated patients had BCG disease. In dominant patients, 30 (79%) had environmental mycobacterial disease and 11 (73%) of 15 BCG-vaccinated patients had BCG disease. Compared with dominant patients, those with recessive deficiency were younger at onset of first environmental mycobacterial disease (mean 3.1 years [SD 2.5] vs 13.4 years [14.3], p=0.001), had more mycobacterial disease episodes (19 vs 8 per 100 person-years of observation, p=0.0001), had more severe mycobacterial disease (mean number of organs infected by Mycobacterium avium complex 4.1 [SD 0.8] vs 2.0 [1.1], p=0.004), had shorter mean disease-free intervals (1.6 years [SD 1.4] vs 7.2 years [7.6], p<0.0001), and lower Kaplan-Meier survival probability (p<0.0001). M avium complex osteomyelitis was more frequent in dominant than in recessive patients (22/28 [79%] vs 1/8 [13%], p=0.002), and this disorder without other organ involvement arose only in dominant patients (9/28 [32%]). Disease caused by rapidly growing mycobacteria was present in more recessive than dominant patients (7/22 [32%] vs 1/38 [3%], p=0.002). INTERPRETATION: Recessive complete and dominant partial IFNgammaR1 deficiencies have related clinical phenotypes, but are distinguishable by age at onset, dissemination, and clinical course of mycobacterial diseases. A strong correlation exists between IFNGR1 genotype, cellular responsiveness to interferon gamma, and clinical disease features.

Susceptibility to tuberculosis: clues from studies with inbred and outbred New Zealand White rabbits.

The rabbit model of tuberculosis (TB) is important because rabbits develop a disease that is similar to TB in humans, namely, granulomas with caseous necrosis, liquefaction, and cavities. We describe here a comparison of inbred and outbred New Zealand White rabbits infected by aerosol with either Mycobacterium tuberculosis Erdman or H37Rv strain. Five weeks after infection with either bacillary strain, the inbred rabbits had significantly larger pulmonary tubercles than did outbred rabbits (2.7 versus 1.4 mm in diameter; P < 0.01). After infection with H37Rv, the inbred rabbits had significantly more pulmonary tubercles than did the outbred rabbits (98 +/- 12 versus 33 +/- 13; P < 0.01), with more mycobacterial CFU per tubercle (809 +/- 210 versus 215 +/- 115; P = 0.027) (means +/- standard errors of the means). Compared with histologic examination of lung granulomas from outbred rabbits, histologic examination of those from inbred rabbits showed more caseous necrosis, more visible bacilli, and fewer mature epithelioid cells. The delayed-type hypersensitivity (DTH) responses to intradermal tuberculin were significantly lower, and peritoneal macrophages from uninfected inbred rabbits produced significantly less tumor necrosis factor alpha after lipopolysaccharide (LPS) stimulation in vitro than those from the outbred rabbits (2,413 +/- 1,154 versus 8,879 +/- 966 pg/ml). We conclude that these inbred rabbits were more susceptible to TB than their outbred counterparts and had an impaired ability to contain disease, resulting in more grossly visible tubercles that were larger than those observed in outbred rabbits. Preliminary evidence is presented for a cell-mediated immune defect with lower DTH responses and macrophages that have a decreased ability to respond to in vitro stimulation with LPS or M. tuberculosis infection.

Immunoglobulin A (IgA) and IgG immune responses against P-90 antigen for diagnosis of pulmonary tuberculosis and screening for Mycobacterium tuberculosis infection.

The purpose of the present study was to evaluate the usefulness of detection of serum immunoglobulin A (IgA) and IgG antibodies directed against the mycobacterial P-90 antigen for the diagnosis of active pulmonary tuberculosis (PTB) among symptomatic individuals and for the detection of Mycobacterium tuberculosis infections among close contacts of PTB patients. Two commercially available enzyme immunoassay (EIA) kits (IgA EIA-TB [EIA-IgA] and IgG EIA-TB [EIA-IgG]; Kreatech Diagnostics) were evaluated in a blinded fashion by using stored serum samples from 268 individuals, including 69 patients with PTB, 41 patients with diseases other than tuberculosis (TB), 12 subjects with healed PTB, 39 close contacts of PTB patients, and 107 healthy volunteers. For the EIA-IgA, the sensitivity was 74% and the specificity was 68% when a cutoff determined by a receiver operator characteristic curve was used. For the EIA-IgG, the sensitivity was 69% and the specificity was 64%. The EIA-IgA was positive for 54% of healthy close contacts of PTB patients but only 8% of healthy controls without contact with a PTB patient or a prior personal history of TB (P < 0.001). The relatively low sensitivities and specificities of these serologic tests make them poor tools for the diagnosis of PTB among patients with suspected PTB. However, the relatively high prevalence of positive EIA-IgA results among healthy close contacts of PTB patients warrants further evaluation of this test with close contacts and other populations at risk for recent M. tuberculosis exposure and development of disease.

Nocardia infection in chronic granulomatous disease.

To determine the clinical characteristics and outcome of Nocardia infection in patients with chronic granulomatous disease (CGD), we reviewed data on 28 episodes of Nocardia infection in 23 patients with CGD. All episodes involved pulmonary infection. The frequency of disseminated nocardiosis was 25% for the case series overall, but it was 56% among episodes in patients receiving neither interferon-gamma (IFN-gamma) nor sulfonamide prophylaxis. Patients receiving prophylaxis with IFN-gamma and/or a sulfonamide were significantly less likely to have disseminated nocardiosis than were patients not receiving these medications, and no patient receiving both medications developed disseminated nocardiosis. One-third of the patients had concomitant fungal infections, and 2 patients had concomitant Legionella infections. The majority of patients were successfully treated with a sulfonamide-containing regimen, even though some patients had developed Nocardia infection while receiving sulfonamide prophylaxis. Nocardia infections in patients with CGD are not usually fatal if treated properly, and prophylaxis with IFN-gamma and a sulfonamide may protect against dissemination.