Comparative evaluation of intensified short course regimen and standard regimen for adults TB meningitis: a protocol for an open label, multi-center, parallel arms, randomized controlled superiority trial (INSHORT trial).

BACKGROUND: Despite several incremental improvements in the management of tuberculous meningitis (TBM), the mortality rates remain high. In spite of national and international guidelines, variation in the choice, dose, and duration of drugs exist between countries and clinicians. We propose to evaluate a shorter and more effective regimen containing agents with augmented intracerebral drug exposure and anti-inflammatory approaches to improve disability-free survival among patients with TBM. Our strategy incorporates the various developments in the field of TBM over the last two decades and only few trials have evaluated a composite of these strategies in the overall outcomes of TBM. METHODS: An open label, parallel arms, randomized controlled superiority trial will be conducted among 372 participants across 6 sites in India. Eligible participants will be randomly allocated in 1:1:1 ratio into one of the three arms. The intervention arm consists of 2 months of high-dose rifampicin (25 mg/kg), moxifloxacin (400 mg), pyrazinamide, isoniazid, aspirin (150 mg), and steroids followed by rifampicin, isoniazid, and pyrazinamide for 4 months. The second intervention arm includes all the drugs as per the first arm except aspirin and the patients in the control arm will receive treatment according to the National TB Elimination Program guidelines. All participants will be followed up for 1 year after the treatment.  DISCUSSION: Current WHO regimens have agents with poor central nervous system drug exposure and is too long. It does not reflect the accumulating evidence in the field. We propose a comprehensive clinical trial incorporating the emerging evidence accrued over the last two decades to shorten the duration and improve the treatment outcomes. This multi-centric trial may generate crucial evidence with policy and practice implications in the treatment of TBM. TRIAL REGISTRATION: Clinical Trial Registry India CTRI/2023/05/053314. Registered on 31 May 2023 ( https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODYzMzg=&Enc=&userName=CTRI/2023/05/053314 ). CLINICALTRIALS: gov NCT05917340. Registered on 6 August 2023 ( https://classic. CLINICALTRIALS: gov/ct2/show/NCT05917340 ). PROTOCOL VERSION: Version 1.3 dated 12 July 2023.

An integrative machine learning framework for classifying SEER breast cancer.

Breast cancer is the commonest type of cancer in women worldwide and the leading cause of mortality for females. The aim of this research is to classify the alive and death status of breast cancer patients using the Surveillance, Epidemiology, and End Results dataset. Due to its capacity to handle enormous data sets systematically, machine learning and deep learning has been widely employed in biomedical research to answer diverse classification difficulties. Pre-processing the data enables its visualization and analysis for use in making important decisions. This research presents a feasible machine learning-based approach for categorizing SEER breast cancer dataset. Moreover, a two-step feature selection method based on Variance Threshold and Principal Component Analysis was employed to select the features from the SEER breast cancer dataset. After selecting the features, the classification of the breast cancer dataset is carried out using Supervised and Ensemble learning techniques such as Ada Boosting, XG Boosting, Gradient Boosting, Naive Bayes and Decision Tree. Utilizing the train-test split and k-fold cross-validation approaches, the performance of various machine learning algorithms is examined. The accuracy of Decision Tree for both train-test split and cross validation achieved as 98%. In this study, it is observed that the Decision Tree algorithm outperforms other supervised and ensemble learning approaches for the SEER Breast Cancer dataset.

Randomised trial to evaluate the effectiveness and safety of varying doses of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary tuberculosis: study protocol.

INTRODUCTION: Drug-resistant tuberculosis (DR-TB) is a global public health problem. Patients suffer for months if undiagnosed or treated inadequately, transmitting DR-TB in the community before succumbing to the disease. Early diagnosis, prompt treatment initiation and completion play a significant role in treatment success. However, extended regimens with injectable result in poor treatment adherence and outcomes. Our objective is to evaluate the effectiveness, safety and tolerability of various doses and duration of linezolid (LZD) in combination with bedaquiline (BDQ) and pretomanid (Pa) after 26 weeks of treatment in adults with pre-extensively drug-resistant or treatment intolerant/non-responsive multidrug-resistant pulmonary TB. METHODS AND ANALYSIS: A multicentric, randomised pragmatic clinical trial in India will enrol participants in one of the three arms-control arm (arm 1): BDQ, Pa and LZD 600 mg daily for 26 weeks or intervention arms (arm 2): BDQ, Pa and LZD 600 mg for 9 weeks followed by 300 mg for 17 weeks or arm 3: BDQ, Pa and LZD 600 mg for 13 weeks followed by 300 mg for 13 weeks. The primary endpoint is the proportion of patients with favourable outcomes as sustained cure and treatment completion. The secondary endpoint is unfavourable outcomes, including deaths, treatment failure, toxicity/adverse events and lost to follow-up till 48 weeks post-treatment. ETHICS AND DISSEMINATION: The study has been approved by the ethics committees of participating institutes and the National Institute for Research in TB. The trial results will help establish evidence towards a safe and effective dose of LZD that can be used in a fully, all-oral short course regimen for highly DR-TB patients. The results of this study will be shared with the National TB Elimination Programme of the country and the WHO guidelines development group through publications and dissemination meetings. TRIAL REGISTRATION NUMBER: NCT05040126.

Heightened Microbial Translocation Is a Prognostic Biomarker of Recurrent Tuberculosis.

BACKGROUND: Microbial translocation is a known characteristic of pulmonary tuberculosis (PTB). Whether microbial translocation is also a biomarker of recurrence in PTB is not known. METHODS: We examined the presence of microbial translocation in a cohort of newly diagnosed, sputum smear, and culture positive individuals with drug-sensitive PTB. Participants were followed up for a year following the end of anti-tuberculosis treatment. They were classified as cases (in the event of recurrence, n = 30) and compared to age and gender matched controls (in the event of successful, recurrence free cure; n = 51). Plasma samples were used to measure the circulating microbial translocation markers. All the enrolled study participants were treatment naïve, HIV negative and with or without diabetes mellitus. RESULTS: Baseline levels of lipopolysaccharide (LPS) (P = .0002), sCD14 (P = .0191), and LPS-binding protein (LBP) (P < .0001) were significantly higher in recurrence than controls and were associated with increased risk for recurrence, whereas intestinal fatty acid binding protein (I-FABP) and Endocab showed no association. Receiver operating characteristic (ROC) curve analysis demonstrated the utility of these individual microbial markers in discriminating recurrence from cure with high sensitivity, specificity, and area under the curve (AUC). CONCLUSIONS: Recurrence following microbiological cure in PTB is characterized by heightened baseline microbial translocation. These markers can be used as a rapid prognostic tool for predicting recurrence in PTB.

Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine.

Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). The present work reports the design and synthesis of a hybrid of the precursors of rifampicin and clofazimine, which led to the discovery of a novel Rifaphenazine (RPZ) molecule with potent anti-TB activity. In addition, the efficacy of RPZ was evaluated in-vitro using the reference strain Mtb H37Rv. Herein, 2,3 diamino phenazine, a precursor of an anti-TB drug clofazimine, was tethered to the rifampicin core. This 2,3 diamino phenazine did not have an inherent anti-TB activity even at a concentration of up to 2 µg/mL, while rifampicin did not exhibit any activity against Mtb at a concentration of 0.1 µg/mL. However, the synthesized novel Rifaphenzine (RPZ) inhibited 78% of the Mtb colonies at a drug concentration of 0.1 µg/mL, while 93% of the bacterial colonies were killed at 0.5 µg/mL of the drug. Furthermore, the Minimum Inhibitory Concentration (MIC) value for RPZ was 1 µg/mL. Time-kill studies revealed that all bacterial colonies were killed within a period of 24 h. The synthesized novel molecule was characterized using high-resolution mass spectroscopy and NMR spectroscopy. Cytotoxicity studies (IC50) were performed on human monocytic cell line THP-1, and the determined IC50 value was 96 µg/mL, which is non-cytotoxic.

Effectiveness and safety of bedaquiline under conditional access program for treatment of drug-resistant tuberculosis in India: An interim analysis.

BACKGROUND: India accounts for a quarter of the world's multidrug-resistant tuberculosis (MDR-TB); with less than 50% having successful treatment outcomes. Bedaquiline (BDQ) was approved for use under conditional access program in India in 2015. OBJECTIVE: We evaluate the effectiveness, safety, and tolerability of a BDQ containing regimen used under field settings in India. METHOD: Interim analysis of a prospective cohort of MDR-TB patients on a BDQ containing regimen at six sites in the country. RESULTS: Six hundred and twenty MDR-TB patients [349 (56%) males; 554 (89%) between 18 and 50 years and 240 (39%) severely malnourished] were started on BDQ containing regimen between June 2016 and August 2017. There 354 (57%) patients had MDR-TB with additional drug resistance to fluoroquinolone (MDRFQ); 31 (5%) with additional resistance to second-line injectable (MDRSLI) and 101 (16%) extensively drug-resistant TB. After 6 months of treatment, culture conversion was achieved in 513 of 620 (83%) patients. The median time to culture conversion was 60 days. Higher body mass index was the only factor associated with faster culture conversion (HR 1.97; 95% CI 1.24-2.9). Around 100 patients (16.3%) experienced a ≥60-ms increase in QTc interval during the treatment. Seventy-three (12%) deaths were reported, the majority of them (56%) occurring within the first 6 months of treatment. CONCLUSIONS: BDQ with a background regimen has the potential to achieve higher and faster culture conversion rates with a lower toxicity profile among DR-TB patients. Use of BDQ with additional monitoring may be safe and effective even in the field settings.

HIV-infected patients retreated for tuberculosis with intermittent Category II regimen--treatment outcome at 24-month follow-up.

BACKGROUND: The management of tuberculosis re-treatment in HIV-infected individuals is complex. The clinical and radiological manifestations in this group and response to Category II treatment is not well described. METHODS: We performed a prospective cohort study of HIV-infected patients retreated for TB due to failure, relapse or default after treatment, at Tuberculosis Research Centre, Chennai, between February 2001 to September 2005. The Category II regimen followed in the TB programme in India (RNTCP) was administered (2 months of Streptomycin (S), Ethambutol (E), INH (H), Rifampicin (R), Pyrazinamide (Z)/1 month of EHRZ/5 months of HRE all given thrice weekly). Antiretroviral treatment was not routinely available at that time. RESULTS: Of the 42 patients enrolled, 35 (83%) were males. The mean age was 33.2 (SD-6.3) years. Cough was the commonest (67%) presenting symptom and opacities were the commonest (48%) radiographic occurrence. 31 patients were culture-positive at baseline, drug susceptibility results showed that 21 (68%) were fully susceptible to all first line drugs, four patients (13%) had MDR TB and four had resistance to INH alone. Among the 31 culture-positive patients, 15 patients (48.4%) completed treatment and were declared cured, of whom two subsequently relapsed. All four MDR patients died. Six patients who received ART, survived. CONCLUSION: Only 50% of HIV-infected, ART-naive patients who were retreated for tuberculosis using an intermittent Category II regimen had a favourable response to treatment. Early detection of MDRTB and concurrent antiretroviral therapy could contribute to improved outcomes.

Early changes in hepatic function among HIV-tuberculosis patients treated with nevirapine or efavirenz along with rifampin-based anti-tuberculosis therapy.

OBJECTIVES: To describe the longitudinal changes in hepatic function among HIV-infected tuberculosis (TB) patients receiving once-daily nevirapine (NVP)- or efavirenz (EFV)-based antiretroviral treatment (ART) along with rifampin-containing anti-TB treatment. METHODS: This was a nested study within a randomized clinical trial, taking place between May 2006 and June 2008 at the National Institute for Research in Tuberculosis, Chennai, India. Antiretroviral-naïve HIV-infected TB patients were initiated on an intermittent short-course regimen and randomized to receive didanosine and lamivudine with either NVP (400 mg) or EFV (600 mg) once-daily. Blood was analyzed for alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum alkaline phosphatase (SAP), and bilirubin at baseline, at ART initiation, fortnightly after ART initiation until 2 months, then monthly until 6 months and 6-monthly thereafter. RESULTS: Of the 168 patients included (79% men, median CD4 count 93 cells/mm3, median viral load 242,000 copies/ml), 104 were on EFV-based ART and 64 on NVP-based ART. There was a small but statistically significant elevation in ALT and SAP at 2 weeks and AST at 6 weeks after ART initiation. The proportion of patients with rate-limiting toxicity of liver enzymes was small. None had treatment terminated because of hepatotoxicity. CONCLUSION: Hepatotoxicity is not a major concern when HIV-infected TB patients, with normal baseline liver function initiate treatment for both infections simultaneously.

Lack of association between plasma levels of non-nucleoside reverse transcriptase inhibitors & virological outcomes during rifampicin co-administration in HIV-infected TB patients.

BACKGROUND & OBJECTIVES: Among patients with HIV-associated tuberculosis (TB), reduced plasma non-nucleoside reverse transcriptase inhibitors (NNRTI) concentrations during rifampicin (RMP) co-administration could lead to HIV treatment failure. This study was undertaken to examine the association between plasma nevirapine (NVP) and efavirenz (EFV) concentrations and virological outcomes in patients infected with HIV-1 and TB. METHODS: This was a nested study undertaken in a clinical trial of patients with HIV-1 and TB, randomized to two different once-daily antiretroviral treatment (ART) regimens along with anti-TB treatment (ATT). Trough concentrations of plasma NVP and EFV were estimated at months 1 (during ATT and ART) and 6 months (ART only) by HPLC. Plasma HIV-1 RNA level >400 copies/ml or death within 6 months of ART were considered as unfavourable outcomes. Genotyping of CYP2B6 516G>T polymorphism was performed. RESULTS: Twenty nine per cent of patients in NVP arm had an unfavourable outcome at 6 months compared to 9 per cent in EFV arm (P<0.08). The mean NVP and EFV levels estimated at 1 and 6 months did not significantly differ between favourable and unfavourable responders. Logistic regression analysis showed CYP2B6 516G>T polymorphism significantly associated with virologic outcome in patients receiving EFV-based regimen. INTERPRETATION & CONCLUSIONS: Trough plasma concentrations of NVP and EFV did not show any association with response to ART in patients on ATT and once-daily ART. CYP2B6 516G>T polymorphism was associated with virologic outcome among patients on EFV.

Luciferase reporter phage phAE85 for rapid detection of rifampicin resistance in clinical isolates of Mycobacterium tuberculosis

OBJECTIVE@#To evaluate luciferase reporter phage (LRP) phAE85 in rapid detection of rifampicin resistance in a region where TB is endemic.@*METHODS@#One hundred and ninety primary isolates on Lowenstein-Jensen medium were tested. Middlebrook 7H9 complete medium with and without rifampicin at 2 μg/mL was inoculated with standard inoculum from suspensions of the clinical isolate. After incubation for 72 h, LRP was added. Following 4 h of further incubation, light output from both control and test was measured as relative light units. Strains exhibiting a reduction of less than 50% relative light units in the drug containing vial compared to control were classified as resistant. Results were compared with the conventional minimum inhibitory concentration method (MIC) of drug susceptibility testing.@*RESULTS@#The two methods showed high level of agreement of 97% (CI 0.94, 0.99) and P value was 0.000 1. The sensitivity and specificity of LRP assay for detection of rifampicin resistance were 91% (CI 0.75, 0.98) and 99% (CI 0.95, 1.00) respectively. Time to detection of resistance by LRP assay was 3 d in comparison with 28 d by the minimum inhibitory concentration method.@*CONCLUSIONS@#LRP assay with phAE85 is 99% specific, 91% sensitive and is highly reproducible. Thus the assay offers a simple procedure for drug sensitivity testing, within the scope of semi-automation.

Assessment of panel slides prepared by phenol ammonium sulphate and NALC methods for proficiency testing.

BACKGROUND: Existing methods for the preparation of panel slides necessitate handling high-grade acid-fast bacilli positive sputum samples. OBJECTIVE: To compare panel slides prepared using the phenol ammonium sulphate sediment (PhAS) method with those prepared using the N-acetyl-L-cysteine (NALC) method in proficiency testing. METHODS: Pooled sputum specimens of known smear-positives and -negatives were divided into two parts: one part was used for preparing panel slides using the NALC method and the other using PhAS, a non-hazardous method. Respectively 413 and 384 smears of different grades were prepared in three batches using the PhAS and NALC methods. Smear grade and quality were recorded by 121 microscopists during proficiency testing in different states. Agreement between reference and reported results was analysed using the kappa test. RESULTS: The overall agreement was 96% for the PhAS method and 91% for the NALC method. There were 37 errors using the NALC method compared to 21 for the PhAS method (P < 0.223). Smear quality was equally good in both methods; however, the cell count was significantly higher in the PhAS than in the NALC method. CONCLUSION: The PhAS method, a non-hazardous procedure with good-quality smears, may be further explored for the preparation of panel slides.

The cost-effectiveness of tuberculosis preventive therapy for HIV-infected individuals in southern India: a trial-based analysis.

BACKGROUND: Regimens for isoniazid-based preventive therapy (IPT) for tuberculosis (TB) in HIV-infected individuals have not been widely adopted given concerns regarding efficacy, adherence and drug resistance. Further, the cost-effectiveness of IPT has not been studied in India. METHODS: We used an HIV/TB model to project TB incidence, life expectancy, cost and incremental cost-effectiveness of six months of isoniazid plus ethambutol (6EH), thirty-six months of isoniazid (36H) and no IPT for HIV-infected patients in India. Model input parameters included a median CD4 count of 324 cells/mm(3), and a rate ratio of developing TB of 0.35 for 6EH and 0.22 for 36H at three years as compared to no IPT. Results of 6EH and 36H were also compared to six months of isoniazid (6H), three months of isoniazid plus rifampin (3RH) and three months of isoniazid plus rifapentine (3RPTH). RESULTS: Projected TB incidence decreased in the 6EH and 36H regimens by 51% and 62% respectively at three-year follow-up compared to no IPT. Without IPT, projected life expectancy was 136.1 months at a lifetime per person cost of $5,630. 6EH increased life expectancy by 0.8 months at an additional per person cost of $100 (incremental cost-effectiveness ratio (ICER) of $1,490/year of life saved (YLS)). 36H further increased life expectancy by 0.2 months with an additional per person cost of $55 (ICER of $3,120/YLS). The projected clinical impact of 6EH was comparable to 6H and 3RH; however when compared to these other options, 6EH was no longer cost-effective given the high cost of ethambutol. Results were sensitive to baseline CD4 count and adherence. CONCLUSIONS: Three, six and thirty-six-month regimens of isoniazid-based therapy are effective in preventing TB. Three months of isoniazid plus rifampin and six-months of isoniazid are similarly cost-effective in India, and should be considered part of HIV care.

Quality indicators in a mycobacteriology laboratory supporting clinical trials for pulmonary tuberculosis.

BACKGROUND: Documentation of structured quality indicators for mycobacteriology laboratories supporting exclusively controlled clinical trials in pulmonary tuberculosis (PTB) is lacking. OBJECTIVE: To document laboratory indicators for a solid (Lowenstein-Jensen medium) culture system in a mycobacteriology laboratory for a period of 4years (2007-2010). METHODS: The sputum samples, collected from PTB suspects/patients enrolled in clinical trials, were subjected to fluorescence microscopy, culture and drug sensitivity testing (DST). Data was retrospectively collected from TB laboratory registers and computed using pre-formulated Microsoft Office Excel. Laboratory indicators were calculated and analyzed. RESULTS: The number of samples processed in a calendar year varied from 6261 to 10,710. Of the samples processed in a calendar year, specimen contamination (4.8-6.9%), culture positives (78.4-85.1%) among smear positives, smear positives (71.8-79.0%) among culture positive samples, smear negatives among culture negative samples (95.2-96.7%), and average time to report DST results (76-97days) varied as shown in parentheses. CONCLUSION: Values of quality indicators in mycobacteriology laboratories supporting exclusively clinical trials of PTB have to be defined and used for meaningful monitoring of laboratories.

Performance indicators of fluorescence microscopy for sputum samples in pulmonary tuberculosis.

To get insight into the sensitivity of fluorescence microscopy for diagnostic and follow-up sputum samples from pulmonary tuberculosis patients in clinical trials, the yield of smear positivity - among culture positive sputum samples - encountered in diagnostic and follow-up samples was retrospectively analyzed from the data available in a mycobacteriology laboratory in India. The sensitivity of fluorescence microscopy for diagnostic and follow-up samples respectively was found to be 94.3% and 60.7%. With these values as guidelines, the performance of fluorescence microscopy in the treatment of multi-drug resistant tuberculosis under DOTS plus program remains to be monitored and studied.

Survival analysis of women with breast cancer under adjuvant therapy in South India.

While there has been much research in identifying risk factors and prognostic factor for breast cancer for breast cancer survival, the research specific to South Indian population is limited: Most of the association studies between breast cancer and risk factor have been widely studied in developed countries. This study attempts to explore the survival experience of breast cancer patients treated under adjuvant and neo-adjuvant therapy. The data were obtained from a Government Cancer Hospital, Tamil Nadu, South India and included 522 women diagnosed and treated with adjuvant and neo-adjuvant therapy between January 2000 to December 2008 and follow up to May 2010. The survival experiences under two treatments are presented using Kaplan-Meier survival curves. The important prognostic variables for response to treatment survival were identified using Cox regression with and without time-dependent covariates. Of the 522 cases, 248(47.5%) were of stage 2 (A and B), 249 (47.7%) were of stage 3 (A and B). About 90% received neo-adjuvant therapy. About 94% of the patients had response to treatment. The Cox model showed that apart from the chemotherapy, number of children, child birth status and stage 3B and 4 turn out to be significant predictors for response to treatment survival. This is the first study to evaluate adjuvant therapy effects under hospital setup in South India. The results show that response to treatment survival is related poor in advanced stage patients under treatment.

Long term follow up of HIV-infected patients with tuberculosis treated with 6-month intermittent short course chemotherapy.

BACKGROUND: Tuberculosis occurs in 60%-70% of HIV-positive persons in India. The outcome of HIV-positive patients treated with 6-month intermittent short course antituberculosis regimens in India is not well described. METHODS: This was a prospective observational feasibility study of 71 patients with HIV and tuberculosis who were treated with category I regimen of the Revised National Tuberculosis Control Programme (ethambutol, isoniazid, rifampicin and pyrazinamide thrice weekly for the initial 2 months followed by rifampicin and isoniazid thrice weekly for the next 4 months). Sputum was examined by smear and culture for Mycobacterium tuberculosis every month up to 24 months. Chest X-ray, CD4 cell count and viral load were done prior to and at the end of treatment. None of the patients received antiretroviral therapy. RESULTS: We present here the treatment response of patients with sputum culture-positive pulmonary tuberculosis to category I regimen. By efficacy analysis, among 43 patients treated with category I regimen, sputum smear conversion was observed in 79% and culture conversion in 82% at the second month. A favourable response was seen in 72% of patients. The mean (SD) CD4% fell from 12.6 (5.9) to 8.9 (4.9) (p < 0.001) with no significant change in mean (SD) CD4 cell count (169 [126] to 174 [158]; ns) at the end of treatment. Viral load change from 1.8 x 10(5) at baseline to 1.3 x 10(5) at the end of treatment was not statistically significant. Thirty-one patients, who completed the full course of treatment, were declared cured and were followed up for 24 months. Twelve had recurrent tuberculosis (39%); 16 of 43 (37%) patients had died by the end of 24 months, two-thirds due to causes other than tuberculosis. CONCLUSION: Though the early bacteriological response to intermittent short course antituberculosis regimen was satisfactory, the overall outcome was adversely affected by the high mortality (during and after completion of treatment) and recurrence rate among HIV-infected patients with tuberculosis. Immune status deteriorated in spite of antituberculosis treatment, highlighting the need for antiretroviral treatment in addition to antituberculosis treatment to improve the long term outcome. The results of this pilot study need to be confirmed by larger studies.

Miliary tuberculosis in human immunodeficiency virus infected patients not on antiretroviral therapy: clinical profile and response to shortcourse chemotherapy.

BACKGROUND: An increase in tuberculosis (TB) incidence has been associated with human immunodeficiency virus (HIV). AIMS: To describe the clinical characteristics and treatment outcome of patients with HIV and miliary TB treated with short-course intermittent chemotherapy in the absence of access to highly active antiretroviral therapy (HAART). SETTINGS AND DESIGN: Prospective study of HIV infected adults referred to a TB clinic between July 1999 and July 2004. MATERIALS AND METHODS: On diagnosis of miliary TB, patients were treated with a standard regimen of two months of isoniazid, rifampicin, ethambutol and pyrazinamide followed by four months of isoniazid and rifampicin (2EHRZ 3 /4RH 3 ) thrice weekly and followed up for 24 months. Patients were reviewed clinically every month and two sputa were collected. Chest radiographs and blood investigations were done at two months, end of treatment and every six months thereafter. RESULTS: Of 498 patients with HIV and tuberculosis, 31 (6%) were diagnosed as miliary tuberculosis. At diagnosis, sputum smear was positive for acid-fast bacilli (AFB) in 14 patients (45%) and Mycobacterium tuberculosis was isolated in 21 (68%). The mean CD4 cell count was 129 +/- 125 cells/mm3 . Twenty-five patients were declared cured at the end of treatment (81%) while one (3%) died and five (16%) failed. The recurrence rate was 19.4/100 person-years and the median survival was 17 months (95% CI 14 to 20). None of the patients received antiretroviral therapy. CONCLUSIONS: Miliary TB tends to occur among HIV infected patients with severe immunosuppression. Though the initial response to short-course chemotherapy was encouraging, a high recurrence rate and mortality was observed indicating poor prognosis in HIV.

Anti-tuberculosis drug resistance in patients with HIV and tuberculosis in South India.

SETTING: Tuberculosis Research Centre clinics at Chennai and Madurai, Tamil Nadu, South India. OBJECTIVES: To investigate the prevalence and pattern of drug resistance among patients with HIV and pulmonary tuberculosis (PTB). DESIGN: Prospective cohort study of HIV-positive patients with PTB between January 2001 and May 2003. Sputum mycobacterial culture and drug susceptibility testing were performed. RESULTS: A total of 204 patients with positive sputum cultures for Mycobacterium tuberculosis were included; 167 of them were new cases, and 37 had a history of previous anti-tuberculosis treatment for > 1 month. Among the former, resistance to isoniazid (INH) was observed in 22 (13%) and MDR-TB in 7 (4.2%). Reported resistance rates in this geographic area among new cases ranged from 15% to 28% for INH and 2.8% to 3.4% for MDR (INH + rifampicin [RMP]). In contrast, among HIV-positive patients with a history of previous treatment, resistance was found to INH in 10 (27%) and to RMP in 7 (18.9%), while MDR-TB was seen in 5 (13.5%) patients. CONCLUSION: Among new TB patients, MDR-TB is marginally higher in HIV-positive patients than in the non-HIV-infected population in this region. Standard treatment guidelines should be followed. Higher rates of drug resistance are observed among previously treated patients.

Increased detection by restaining of acid-fast bacilli in sputum samples transported in cetylpyridinium chloride solution.

SETTING: Seventeen health facilities in a Tuberculosis Unit, and the Tuberculosis Research Centre (TRC), Chennai, India. AIM: Evaluation of restaining by the auramine-phenol method for detection of acid-fast bacilli (AFB) in direct smears of samples transported in cetylpyridinium chloride (CPC) solution. METHODS: Among patients attending the above health facilities, 730 samples were collected in CPC and transported to the TRC. Two direct smears were prepared from each sample, one stained by the usual auraminephenol method (primary staining) and the other stained again by the same method (restaining) for examination by fluorescence microscopy. All the samples were processed for culture of Mycobacterium tuberculosis. RESULTS: A significantly higher proportion (49.6%) of samples were positive by restaining compared to primary staining (32.5%, P < 0.0001). Of 362 samples positive by restaining, 38.7% were negative by primary staining. The yield of different grades of smears was significantly higher with restaining than with primary staining (P < 0.0001). More smear-negative culture-positive smears were observed with the primary than with the restaining method (178/400 [44.5%] vs. 78/ 400 [19.5%], P < 0.001). CONCLUSION: The rate of detection of AFB in direct smears made from sputum samples transported in CPC was higher on restaining than on primary staining.