Hepatic toxicity in South Indian patients during treatment of tuberculosis with short-course regimens containing isoniazid, rifampicin and pyrazinamide

Results are presented of the incidence of hepatitis, nearly always with jaundice, among 1686 patients in clinical trials of the treatment of spinal tuberculosis, of tuberculosis meningitis and of pulmonary tuberculosis with short-course regimens containing rifampicin, isoniazid, streptomycin and pyrazinamide. The incidence was high in patients treated with daily regimens of isoniazid and rifampicin: 16-39% in children with tuberculous meningitis, 10% in patients with spinal tuberculosis (non-surgical cases), and 2-8% in those with pulmonary tuberculosis. Hepatitis, in those receiving rifampicin occurred more often in slow than in rapid acetylators of isoniazid, the proportions amongst those whose acetylator phenotype had been determined being 11% of 317 slow acetylators and 1% of 244 rapid acetylators. In children with tuberculous meningitis, the risk of hepatitis with isoniazid 20 mg/kg (39%) was higher than that with 12 mg/kg (16%), and appreciably lower in patients given rifampicin twice-weekly (5%) rather than daily (21%). There was no indication that pyrazinamide contributed to the hepatic toxicity.     

Comparison between acetylator phenotype and genotype polymorphism of n-acetyltransferase-2 in tuberculosis patients

Background  

Isoniazid (INH) is one of the most important drugs of antitubercular treatment regime, and in some cases it causes hepatotoxicity. It is metabolized by hepatic N-acetyltransferase-2 (NAT2).     

Comparison between serum and urinary sulphadimidine acetylation as predictors of isoniazid acetylator status in patients with pulmonary tuberculosis

The acetylator status of 200 pulmonary tuberculosis patients was determined by sulphadimidine (SDM) acetylation in (1) urine and (2) serum. In both estimations, distribution of the patients with regard to the acetylation rates was found to be bimodal. Based on the percent frequency distribution of acetylated SDM, the antimode for urine and serum was 65% for the former and 45% for the latter. Patients acetylating above 65% or 45% of administered SDM were taken as rapid acetylators, while those acetylating less, were slow acetylators. The ratio of slow to rapid acetylators in urine and serum was 58 : 42 and 66 : 34 respectively. The renal clearance of acetylated fraction of SDM was considerably greater as compared to that of the unacetylated fraction. Agreement between the two methods as evaluated by the kappa statistic was 0.71. The determination of the acetylator status by the SDM acetylation test in the urine is simple to perform and has acceptable accuracy. It may be used as an acceptable substitute to serum for estimating the isoniazid inactivation status which is of considerable importance when patients are treated with daily/ intermittent/once-weekly drug regimens for tuberculosis.     

No demonstrable relationship between IgM and IgG antinuclear antibody levels and acetylator phenotype in patients with systemic lupus erythematosus

To ascertain the possible influence of acetylator phenotype on antinuclear antibodies in systemic lupus erythematosus (SLE), we assayed sera from 11 rapid acetylators and 10 slow acetylators for IgM and IgG antibodies to chromatin, histones, denatured DNA, and native DNA. Whereas the majority of SLE patients of both acetylator phenotypes had elevated levels of antibodies to all 4 antigens compared with normal controls, there was no difference in antibody activities between slow acetylator patients versus rapid acetylator patients for these antigens. We conclude that levels of antibody to chromatin, histones, and DNA in SLE patients are similar irrespective of acetylator phenotype, and that if a protective effect of slow acetylation on spontaneous development of antinuclear antibodies does occur, a prospective study of presymptomatic individuals at high risk for lupus may be required to reveal this effect.     

Improved adherence and less toxicity with rifampin vs isoniazid for treatment of latent tuberculosis: a retrospective study

BACKGROUND: Treatment of latent tuberculosis infection (LTBI) is an important aspect of tuberculosis control in the United States, but the effectiveness of this strategy is compromised by poor adherence to the recommended 9-month isoniazid regimen. In this study, we compared treatment completion and clinically recognized adverse drug reactions in patients prescribed 9 months of isoniazid therapy or 4 months of rifampin therapy for LTBI. METHODS: Retrospective chart review of patients who received LTBI treatment at a public health clinic. RESULTS: A total of 770 patients were prescribed 9 months of isoniazid therapy, and 1379 patients were prescribed 4 months of rifampin therapy. The percentages of patients who completed 80% or more of their prescribed treatment were 52.6% and 71.6% in the isoniazid and rifampin groups, respectively (P<.001). In multivariate logistic regression analysis, treatment regimen was independently associated with treatment completion (adjusted odds ratio for treatment completion, 2.88 for rifampin group vs isoniazid group; 95% confidence interval, 2.27-3.66). Clinically recognized adverse reactions resulting in permanent treatment discontinuation occurred in 4.6% and 1.9% of patients in the isoniazid and rifampin groups, respectively (P<.001). Clinically recognized hepatotoxicity was more common in the isoniazid group (1.8%) than in the rifampin group (0.08%, P<.001). CONCLUSIONS: Compared with a 9-month isoniazid regimen, a 4-month rifampin regimen was associated with a higher percentage of patients completing treatment and a lower percentage of patients with clinically recognized adverse reactions. Additional studies are warranted to determine efficacy and effectiveness of rifampin therapy for LTBI.     

Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa

Background  

Tuberculosis (TB) is the most common opportunistic infection in HIV-infected adults in developing countries. Isoniazid (INH) is recommended for treatment of latent TB infection, however non-adherence is common. The purpose of this study was to apply in-house prepared isoniazid (INH) urine test strips in a clinical setting, and identify predictors of positive test results in an adherence questionnaire in HIV-infected adults taking INH for prevention of TB.     

Effect of acetylator phenotype on efficacy and toxicity of sulphasalazine in rheumatoid arthritis.

A group of 54 patients with rheumatoid arthritis (31 fast, 23 slow acetylators) treated with sulphasalazine 3 g/day were studied retrospectively. At 24 weeks no difference in the efficacy of the drug could be shown between fast and slow acetylators. In a second prospective study 40 fast acetylators were allocated to 3 g/day and 20 slow acetylators to 1.5 g/day. At 24 weeks marked improvement was seen in the fast acetylators given high dose but not the slow acetylators given low dose. It was also noted in this study that the usual ratio of fast : slow acetylators was reversed, and there is some suggestion that fast acetylators may be predisposed to more severe rheumatoid arthritis. The toxicity pattern in a total of 149 patients (83 fast, 66 slow acetylators) was also studied. Significantly more slow acetylators stopped treatment because of nausea or vomiting, or both, but serious toxicity was not confined to either group. Acetylator phenotype therefore appears important in determining the incidence of nausea and/or vomiting associated with sulphasalazine therapy in patients with rheumatoid arthritis but has no effect on the occurrence of potentially serious toxicity or efficacy. Thus prior measurement of acetylator phenotype in patients with rheumatoid arthritis confers little practical benefit in their management.     

Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine

To understand why once-weekly isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly isoniazid/rifampin, we studied human immunodeficiency virus-seronegative patients with either failure (n = 4), relapse (n = 35), or cure (n = 94), recruited from a comparative treatment trial. In multivariate analyses that were adjusted for severity of disease, low plasma concentrations of isoniazid were associated with failure/relapse with once-weekly isoniazid/rifapentine (median isoniazid area under the concentration-time curve for 12 hours after the dose [AUC(0-12)] was 36 microg x hour/ml in failure/relapse versus 56 microg x hour/ml in control cases p = 0.005), but not with twice-weekly isoniazid/rifampin. Furthermore, two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid. Finally, isoniazid acetylator status determined by N-acetyltransferase type 2 genotype was associated with outcome with once-weekly isoniazid/rifapentine (p = 0.03) but not twice-weekly isoniazid/rifampin. No rifamycin pharmacokinetic parameter was consistently and significantly associated with outcome (p > 0.10). Because low isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration-time curve than isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine.     

Determination of risk factors for isoniazid monoresistance and multidrug-resistant tuberculosis in treatment failure patients

India has a high number of drug-resistant tuberculosis cases. Patient records were screened to determine risk factors possibly associated with monoresistance and multidrug-resistant tuberculosis (MDR-TB) in comparison with patients with susceptible TB. We retrospectively screened and selected 250 patient records from a tertiary care centre, in which detailed clinical histories were provided. Of the 250 patients, 10 had isoniazid monoresistant TB, 184 patients had MDR-TB, and 56 patients had TB susceptible to first-line drugs. Binary regression analysis revealed that previous treatment with a fluoroquinolone and an injectable other than streptomycin (odds ratio (OR) 3.889, 95% confidence interval (CI) 1.828-8.272) was associated with MDR-TB. Previous history of TB (OR 0.697, 95% CI 0.363-1.338) and the presence of cavities on radiographs (OR 0.371, 95% CI 0.160-0.862) did not show any association. None of these reported risk factors were associated with isoniazid monoresistance. In conclusion, a history of previous treatment with a fluoroquinolone and an injectable other than streptomycin was found to be a risk factor for MDR-TB.     

Association of HLA and other genetic markers in South Indian patients with pulmonary tuberculosis

Histocompatibility antigens (A, B & C loci) and 23 other single gene characters were studied in 204 pulmonary tuberculosis patients belonging to a single endogamous group in South India. None of the previously reported associations with HLA antigens was confirmed, nor any new one found. The blood O and Rh negative associations were also not confirmed, although a new association with the Jk blood group system appears possible. Of particular interest is the association with the phosphoglucomutase (PGM1) system, which parallels that found in a different population located some 1000 km away. Relative risks were calculated to measure the resistance of individuals with the PGM1*2+ allele.     

Complex treatment of patients with destructive pulmonary tuberculosis including intramuscular administration of isoniazid

The results of a complex treatment of 126 patients with destructive pulmonary tuberculosis have been studied. The chemotherapy regimen of 72 patients comprised intramuscular administration of a 10% isoniazid solution and 54 received isoniazid orally. Both groups of patients were identical in the clinical pattern of pulmonary tuberculosis and treatment conditions. Treatment effectiveness proved to be higher in Group I patients in whom the hospital stay was mainly 6 months. With oral isoniazid, it was longer and 24% of patients (versus 9.7% in Group I) required more prolonged therapy. Clinical manifestations, which were identical in both groups in the pre-treatment period, subsided earlier when isoniazid was administered intramuscularly. Hence, intramuscular administration of 10% isoniazid solution, as compared with its oral use, raises the effectiveness of chemotherapy and decreases the terms of a hospital treatment.     

异烟肼对利福平单耐/多耐药肺结核患者治疗效果的分析

分析异烟肼对患者的治疗效果,为有效治疗和预防控制利福平单耐/多耐药肺结核提供参考依据。     

Effectiveness of isoniazid inhalation in patients with endobronchial tuberculosis]

The clinical effectiveness of isoniazid (INH) inhalation was studied retrospectively in 34 patients with endobronchial tuberculosis. Diagnoses of endobronchial tuberculosis and assessments of bronchial stenosis were based on bronchoscopic examinations. We divided the patients into 2 groups: 13 who received systemic chemotherapy for lung tuberculosis only, and 21 who received systemic chemotherapy combined with INH inhalation (200 mg/day). No significant differences distinguished the groups with respect to duration of positive sputum culture or ESR normalization. However, a significant alleviation of bronchial stenosis and earlier reduction of respiratory symptoms were observed in the patients who received systemic chemotherapy with INH inhalation. We concluded that INH inhalation in addition to standard therapy for lung tuberculosis is effective in patients with endobronchial tuberculosis.