First-line Anti-tuberculosis Treatment Research Articles

Effect of Metformin on Plasma Exposure of Rifampicin, Isoniazid, and Pyrazinamide in Patients on Treatment for Pulmonary Tuberculosis.

To evaluate the effect of metformin on the plasma levels of rifampicin, isoniazid, and pyrazinamide in patients with drug-sensitive pulmonary tuberculosis being treated with first-line antituberculosis treatment (ATT) and to assess the influence of gene polymorphisms on the metabolic pathway of metformin and plasma levels of antitubercular drugs. Nondiabetic adults aged 18-60 years with pulmonary tuberculosis were randomized to either the standard ATT (ATT group) or ATT plus metformin (METRIF group) groups in a phase IIB clinical trial. An intensive pharmacokinetic study with blood collection at 0 hour (predosing), followed by 1, 2, 4, 6, 8, and 12 hours after dosing was conducted during the first month of treatment in a subset of 60 study participants after a minimum of 14 doses. Plasma concentrations of rifampicin, isoniazid, pyrazinamide, and metformin were measured by high-performance liquid chromatography using validated methods, and pharmacokinetic parameters and OCT1 and MATE1 gene polymorphisms were compared between the groups. Significant increases in the clearance of rifampicin, isoniazid, and pyrazinamide were observed in patients in the METRIF group (n = 29) compared with those in the ATT group (n = 31). The AA genotypes of the single-nucleotide polymorphism of rs2289669 ( MATE1 ) in the METRIF group showed a significantly decreased area under the concentration-time curve to the last observation point and increased clearance of rifampicin. Metformin altered rifampicin and isoniazid plasma concentrations in patients receiving antituberculosis treatment for pulmonary tuberculosis with little effect on sputum conversion at the end of treatment. Studies with larger sample sizes are needed to understand host drug-drug interactions.

Real-world impact of the fixed-dose combination on improving treatment outcomes of drug-susceptible tuberculosis: a comparative study using multiyear national tuberculosis patient data

BackgroundThe fixed-dose combination (FDC) for first-line antituberculosis (TB) treatment has long been a standard practice worldwide; however, there is limited evidence on whether the use of FDC improves long-term treatment...

Management of tuberculosis during pregnancy: first line anti-tuberculosis drug

Tuberculosis is a widespread, infectious disease caused by various strains of mycobacteria, commonly Mycobacterium tuberculosis. Tuberculosis not only responsible for an important proportion of the global burden of disease, but it is also an important contributor to maternal mortality, with the disease being among the three leading causes of death among women aged fifteen to forty five years. The main goals of tuberculosis treatment are to cure the patients, to prevent maternal and perinatal complications and to minimize the possibility of transmission of the bacillus to healthy individuals. First-line anti-tuberculosis treatment for medicine-sensitive tuberculosis can be highly effective; however, in absence of well-controlled studies in pregnant women, first-line tuberculosis medications have been listed as United States Food and Drug Administration pregnancy category C (ie, no adequate well-controlled human studies have been performed, but benefits may be acceptable despite potential risks) except ethambutol categorized as pregnancy category B. Rifampicin can be highly used by pregnant women; due to it is believed to be safe for pregnancy and no teratogenic effects has been observed. Neonates who born from mothers who have been taken rifampicin combination therapy may be developed an increased risk of haemorrhagic disorders in the new-born (postpartum hemorrhage); to avoid this postpartum hemorrhage supplemental vitamin K (10mg/day) should be given for the last four to eight weeks of pregnancy.

Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children

BackgroundTwo thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen.MethodsWe conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment.ResultsFrom July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, −0.4 percentage points; 95% confidence interval, −2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups).ConclusionsFour months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.)

Adverse Drug Reactions to a Daily Fixed-dose Combination Based Antituberculosis Treatment Regime in India’s National Tuberculosis Elimination Programme: A Prospective Cohort Study

Introduction: In India, the daily weight-based, Fixed Dose Combination (FDC) Antituberculosis Treatment (ATT) regime under the National Tuberculosis Elimination Programme (NTEP) was introduced, replacing the previous intermittent regime with the aim of improving compliance, decreasing Adverse Drug Reactions (ADRs) and thus ultimately translating to improved treatment outcomes. The ADRs are an important factor that can adversely impact the treatment compliance and outcomes of an ATT regime. There is currently a paucity of studies reflecting the development of ADRs in the Indian population to the new ATT regime. Aim: To study the ADRs of daily FDC-based first-line ATT regime under NTEP. Materials and Methods: A prospective cohort analysis was conducted in the Department of Respiratory Medicine at Indira Gandhi Government Medical College (tertiary care centre), Nagpur, Maharashtra, India, from January 2019 to September 2020. Total 750 People With Tuberculosis (PWTB) were enrolled in the study. They were administered a standardised daily FDC first-line ATT regime under NTEP comprising of initial two months of intensive phase with Isoniazid (INH or H), Rifampicin (R), Ethambutol (E), and Pyrazinamide (Z) followed by a continuation phase of four months with INH, rifampicin, and ethambutol (2EHRZ/4HRE). Clinical evaluation and/or laboratory investigations were used at baseline and when clinically indicated during therapy to identify treatmentrelated adverse events. Results: Among the 750 PWTB, 402 (53.60%) were females, and 348 (46.40%) were males. The mean age of PWTB was 36.46±15.6 years. The ADR to ATT was present in 271 (36.13%) PWTB, 217 (80.07%) were managed on an Outpatient Department (OPD) basis and 54 (19.93%) patients required hospitalisation. Causality assessment revealed that most ADRs were probable (81.18%), followed by possible (18.82%). Regarding the severity of ADRs, 87.08% were mild, 11.44% were moderate, 1.48% were severe, and none of the ADRs was life-threatening. In 67.9% of PWTB, gastrointestinal ADRs were seen, followed by joint pain (37.64%) and cutaneous drug reactions (16.60%). Female PWTB, People Living with Human Immunodeficiency Virus & Tuberculosis (PLHIV-TB), and PWTB with systemic co-morbidities, especially diabetes and systemic hypertension, were at a higher risk of developing ADRs. The risk of ADRs was unaltered with age distribution, body mass index distribution, type of diet, the type of tuberculosis, or the pill burden. Addiction to alcohol and tobacco did not significantly alter the risk of ADRs. Conclusion: The ADRs caused by daily FDC-based ATT are common, but most are mild and can be managed on an OPD basis. Gastrointestinal ADRs, arthralgia, and cutaneous drug reactions are the most common ADRs of the daily FDC-based ATT regime. Female PWTB, PLHIV-TB, and PWTB with systemic co-morbidities, especially diabetes and systemic hypertension, being at a high risk of developing ADRs, need to be actively screened for ADRs during treatment.

Variations of Serum Oxidative Stress Biomarkers under First-Line Antituberculosis Treatment: A Pilot Study.

Tuberculosis (TB) is one of the highest infectious burdens worldwide, and pathogenesis is yet incompletely elucidated. Bacilli dissemination is due to poor antioxidant defense mechanisms and intensified oxidative stress. There are few recent studies that analyzed and compared free radicals or antioxidant status before and after anti-TB treatment. Hence, the present study underlines the need to identify oxidative stress as it could be a useful tool in TB monitorisation. Thirty newly diagnosed patients with pulmonary TB were included after signing an informed consent. Blood was collected before receiving first-line anti-tubercular therapy (T0) and after 60 days (T2). Spectrophotometric methods were used to quantify oxidative parameters (TBARS—thiobarbituric acid reactive species); enzymatic antioxidants such as SOD (superoxide dismutase), CAT (catalase), GPx (glutathione peroxidase), and TAC (total antioxidant capacity); and non-enzymatic antioxidants such as GSH (reduced glutathione). A moderate positive correlation was found between GSH and TAC (r = 0.63, p-value = 0.046) and GSH and SOD (r = 0.64, p-value = 0.041) at T2. Increased values of GSH, CAT, and SOD were noted at T2 in comparison with T0, while GPx, TAC, and TBARS decreased at T2. A better monitorisation in TB could be based on oxidative stress and antioxidant status. Nevertheless, restoring redox host balance could reduce TB progression.

Longitudinal cerebrospinal fluid assessment in a patient with tuberculous meningitis—A case report

BackgroundDynamic assessment of cerebrospinal fluid (CSF) is essential for diagnosis, treatment, and prognosis of tuberculous meningitis, one of the most severe forms of central nervous system (CNS) infection.Case presentationA 45‐year‐old man sought care as he developed confusion, clonic convulsion, and coma. Longitudinal, comprehensive analyses of cytological, biochemical, and microbial changes in CSF specimen were assessed for this patient. On day 1 of hospitalization, modified Ziehl‐Neelsen staining of CSF identified positive acid‐fast bacilli, cytological analysis revealed neutrophilic‐predominant pleocytosis (neutrophils 77%), and adenosine deaminase (ADA) was substantially elevated. Therefore, tuberculous meningitis was diagnosed and first‐line standard anti‐tuberculosis treatment was initiated. Interestingly, after 7‐day treatment, the patient was greatly improved, and CSF disclosed a dominant percentage of lymphocytes (82%) as well as macrophages engulfing Mycobacterium tuberculosis. Later, the dose of dexamethasone was reduced, large number of neutrophils (57%) was present and protein level was immediately elevated in CSF specimen, indicating a possible relapse of tuberculous meningitis. Since the clinical condition of the patient was not worsening, the patient was stick to reduced dose of dexamethasone and standard anti‐tuberculosis agents. He was discharged from the hospital on day 34, with 1‐year continuation standard anti‐tuberculosis therapy, and was clinically resolved from tuberculous meningitis.ConclusionDetailed analyses of cellular composition, biochemical results, and microbial tests of CSF specimen provide the physician direct evidence of the immune surveillance status during tuberculous meningitis, which facilitates early diagnosis, optimal treatment, and improved prognosis.

Stability Study of Isoniazid and Rifampicin Oral Solutions Using Hydroxypropyl-Β-Cyclodextrin to Treat Tuberculosis in Paediatrics.

(1) Background: First-line antituberculosis treatment in paediatrics entails the administration of Isoniazid, Pyrazinamide, and Rifampicin. This study examines the possibility of developing a combined dose liquid formulation for oral use that would facilitate dose adjustment and adherence to treatment for younger children. (2) Methods: The active pharmaceutical ingredients stability under in vitro paediatric digestive pH conditions have been checked. The samples were studied as individual or fixed combined paediatric dosages to determine the pH of maximum stability. The use of hydroxypropyl-β-cyclodextrin to improve Rifampicin solubility and the use of ascorbic acid to increase the stability of the formulation have been studied. (3) Results: Maximum stability of combined doses was determined at pH 7.4, and maximum complexation at pH 8.0. Taking this into account, formulations presented the minimum dose of two active pharmaceutical ingredients dissolved. The addition of ascorbic acid at 0.1% w/v enables the detection of a higher remaining quantity of both drugs after three days of storage at 5 °C. (4) Conclusions: a formulation which combines the minimum paediatric dosages dissolved recommended by WHO for Isoniazid and Rifampicin has been developed. Future assays are needed to prolong the stability of the formulation with the aim of incorporating Pyrazinamide to the solution.

Rifampicin Induced Addisonian Crisis In a Patient With Suspected Adrenal Tuberculosis

A 49-year-old Indian gentleman attended A&E reporting a three-day history of fever, rigors and lower back pain. A CT KUB incidentally revealed a left adrenal mass and widespread abdominal lymphadenopathy. A subsequent CT NCAP showed lymphadenopathy above and below the hemidiaphragm with bilateral adrenal masses. A PET scan showed avidity in these locations. A right axillary lymph node biopsy revealed granulomatous lymphadenitis with focal necrosis. No microorganisms, including acid-fast bacilli were seen on staining. His Mantoux test was positive (34mm). Given his epidemiological risks factors, positive Mantoux test and evidence of necrotising granulomas on biopsy, tuberculosis was considered the most likely diagnosis, although lymphoma remained within the differential. He commenced standard first-line anti-tuberculosis treatment. One week later he re-presented reporting fever, dyspnoea, vomiting, generalised abdominal pain and increased skin pigmentation. He was tachycardic, hypotensive and hypoglycaemic (HR 129, BP 105/73, BM 3.8). Investigations showed a marked hyponatraemia, metabolic acidosis (Na+ 115, pH 7.24) and deranged liver function tests (ALT 510). ACTH was raised (869 ng/L) and a short Synacthen test showed no rise in serum cortisol. His tuberculosis medication was held and he was treated for Addisonian crisis with intravenous hydrocortisone and oral fludrocortisone. It is likely that commencing rifampicin induced metabolism of endogenous steroid, thus precipitating the crisis. Potentially, he was already compensating for low endogenous steroid production prior to initiation of rifampicin, caused by adrenal tuberculosis. He subsequently improved and was discharged with oral hydrocortisone and fludrocortisone. His tuberculosis medications with be restarted as an Outpatient.

Cash transfer scheme for people with tuberculosis treated by the National TB Programme in Western India: a mixed methods study

ObjectivesThis study aimed to assess the coverage and explore enablers and challenges in implementation of direct benefit transfer (DBT) cash incentive scheme for patients with tuberculosis (TB).DesignThis is a mixed...

Late diagnosis of multidrug-resistant tuberculosis in a child at Dr George Mukhari Academic Hospital, Ga-Rankuwa, South Africa: A case report.

IntroductionSouth Africa has one of the top ten tuberculosis burdens in the world, only lagging behind countries with significantly larger populations. Increased awareness of extrapulmonary tuberculosis, specifically spinal tuberculosis, is necessary, because of the HIV epidemic.Case presentationThis report describes the case of a 9-year-old male patient who was suspected of having multidrug-resistant (MDR) tuberculosis, based on failure to recover clinically and radiologically after 6 months on first-line anti-tuberculosis treatment. Pus samples were sent to an accredited academic laboratory for histopathology, microscopy, culture, line-probe assay (MTBDRplus assay) and phenotypic MGIT 960 drug susceptibility tests. Second-line MDR tuberculosis treatment was introduced. Clinical, radiological, physical processes and more laboratory tests were conducted to document whether or not there was improvement in the patient.Management and outcomeAfter laboratory diagnosis of MDR tuberculosis, the patient was started on MDR tuberculosis treatment. The patient started improving remarkably after the introduction of anti-tuberculosis treatment and rehabilitation, although he also required surgery to stabilise the spine. Neurological improvement was observed in the patient and he fully recovered.DiscussionAlthough the diagnosis of spinal MDR tuberculosis may not be achieved easily by culture, the well-known gold standard method of tuberculosis diagnosis, it is of great importance to rapidly initiate an effective anti-tuberculosis treatment of drug-resistant strains to reduce the deformity of the spine.

Incidence of adverse reactions caused by first-line anti-tuberculosis drugs and treatment outcome of pulmonary tuberculosis patients in Morocco.

The treatment of tuberculosis is associated with a high incidence of adverse reactions with different degrees of severity. The aim of this study was to determine the incidence of adverse reactions caused by first-line anti-tuberculosis drugs and to evaluate the treatment outcome of TB patients in a large region of Morocco. It is a multi-centric observational cohort study conducted from January 01, 2014 to January 01, 2016. A questionnaire was established for data collection from clinical charts of TB patients. The study was carried out in all the 18 centers located in the Rabat-Salé-Kénitra region of Morocco where tuberculosis is treated. Adverse reactions are evaluated from the start of TB treatment until its end by a specialist clinician. The treatment outcomes are evaluated, and the definitions and classifications of these outcomes are defined according to World Health Organization guidelines. Among a total number of 2532 patients treated for TB, the average age is 37.3 ± 16.4years, 10.0% of patients produced adverse reactions.7.4% of adverse reactions are gastrointestinal, 3.7% are cutaneous, 2.0% are hepatic, 1.14% are articular, 1.07% are immunoallergic, 0.7% are neuropsychiatric, and 0.1% are ocular. The treatment outcome of TB patients is 79.1% rate for successful treatment and 15.6% for unsuccessful treatment. Adverse reactions caused by anti-TB drugs are frequent among patients with TB. These ADRs must be followed up by a closer monitoring during anti-TB treatment period. Treatment success outcome in our study is slightly lower than the success rate target of WHO of at least 85%.

Non-response to first-line anti-tuberculosis treatment and MDR-TB in India: the role of implementation research

Non-response to first-line anti-tuberculosis treatment and MDR-TB in India: the role of implementation research

Sputum smear-positive, Xpert® MTB/RIF-negative results: magnitude and treatment outcomes of patients in Myanmar.

Setting: Myanmar's National Tuberculosis Programme (NTP) uses the Xpert® MTB/RIF assay to diagnose rifampicin (RMP) resistance in sputum smear-positive (Sm+) pulmonary tuberculosis (TB) patients. The Xpert test may occasionally yield negative results (Xpert-) for Mycobacterium tuberculosis complex, indicating a false-positive sputum smear result, false-negative Xpert result or infection with non-tuberculous mycobacteria (NTM). Patients with NTM may respond poorly to first-line anti-tuberculosis treatment. Objective: To assess the burden of Sm+, Xpert- results at the national level and treatment outcomes of Sm+, Xpert- patients in Yangon Region. Design: A cohort study involving a retrospective record review of routinely collected NTP data. Result: In 2015 and 2016, 4% of the 25 359 Sm+ patients who underwent Xpert testing nationally were Sm+, Xpert-. Similarly, in the Yangon Region, 5% of the 5301 Sm+ patients were also Xpert- and were treated with first-line anti-tuberculosis regimens. Smear grade (scanty/1+) and age ⩾65 years were associated with Sm+, Xpert- results. The 88% treatment success rate for this group was similar to that of Sm+, Xpert+ patients without RMP resistance. Conclusion: Approximately 4-5% of Sm+ TB patients were Xpert-. There is an urgent need to formulate guidelines on how to reassess and manage these patients.

Non-response to first-line anti-tuberculosis treatment in Sikkim, India: a risk-factor analysis study

Setting: Sikkim, India, has the highest proportion of tuberculosis (TB) patients on first-line anti-tuberculosis regimens with the outcome 'failure' or 'shifted to regimen for multidrug-resistant TB (MDR-TB)'. Objective: To assess the factors associated with non-response to treatment, i.e., 'failure' or 'shifted to MDR-TB regimen'. Methods: We conducted a retrospective cohort study using Revised National Tuberculosis Control Programme data of all TB patients registered in 2015 for first-line TB treatment. In addition, we interviewed 42 patients who had not responded to treatment to ascertain their current status. Results: Of 1508 patients enrolled for treatment, about 9% were classified as non-response to treatment. Patient factors associated with non-response were urban setting (adjusted odds ratio [aOR] 2.39, 95%CI 1.22-4.67), ethnicity (being an Indian tribal, aOR 1.73, 95%CI 1.17-2.57, Indian [other] aOR 1.83, 95%CI 1.29-2.60 compared to patients of Nepali origin) and those on retreatment (aOR 2.40, 95%CI 1.99-2.91). Of the patients interviewed, 28 (67%) had received treatment for drug-resistant TB. Conclusion: In Sikkim, one in 11 patients had not responded to first-line anti-tuberculosis treatment. Host-pathogen genetics and socio-behavioural studies may be required to understand the reasons for the differences in non-response, particularly among ethnic groups.

Age-stratified tuberculosis treatment outcomes in Zimbabwe: are we paying attention to the most vulnerable?

Setting: A high tuberculosis (TB) incidence, resource-limited urban setting in Zimbabwe. Objectives: To compare treatment outcomes among people initiated on first-line anti-tuberculosis treatment in relation to age and other explanatory factors. Design: This was a retrospective record review of routine programme data. Results: Of 2209 patients included in the study, 133 (6%) were children (aged <10 years), 132 (6%) adolescents (10-19 years), 1782 (81%) adults (20-59 years) and 162 (7%) were aged ⩾60 years, defined as elderly. The highest proportion of smear-negative pulmonary TB cases was among the elderly (40%). Unfavourable outcomes, mainly deaths, increased proportionately with age, and were highest among the elderly (adjusted relative risk 3.8, 95%CI 1.3-10.7). Having previous TB, being human immunodeficiency virus positive and not on antiretroviral treatment or cotrimoxazole preventive therapy were associated with an increased risk of unfavourable outcomes. Conclusion: The elderly had the worst outcomes among all the age groups. This may be related to immunosuppressant comorbidities or other age-related diseases mis-classified as TB, as a significant proportion were smear-negative. Older persons need better adapted TB management and more sensitive diagnostic tools, such as Xpert® MTB/RIF.

Therapeutic drug monitoring in anti-tuberculosis treatment: a systematic review and meta-analysis.

Therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes, but there is little evidence to guide TDM in clinical practice. We performed a systematic review and meta-analysis to summarise existing literature on TDM in first-line drugs. We identified 41 studies that reported 2 h post-dose drug concentrations (C2h) for first-line drugs and 12 studies that reported clinical outcomes. We pooled data by study quality, design, region, dosing modality and patient characteristics. The pooled proportion of subjects with low isoniazid C2h was 0.43 (95%CI 0.32-0.55), 0.67 (95%CI 0.60-0.74) had low rifampicin C2h, 0.27 (95%CI 0.17-0.38) had low ethambutol C2h, and 0.12 (95%CI 0.07-0.19) had low pyrazinamide C2h. Patients with diabetes had a non-significant increase in the proportion of subjects with low C2h levels across all four drugs. Only three of 12 studies that examined clinical outcomes demonstrated an association between low C2h and unsuccessful treatment outcomes. Across a wide variety of studies, a high proportion of patients undergoing first-line anti-tuberculosis treatment had 2 h drug concentrations below the accepted normal threshold. These findings point to a discrepancy between accepted 2 h TDM thresholds and TB drug dosing recommendations.

A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis

Background/aimIsoniazid (INH) is an essential component of first-line anti-tuberculosis (TB) treatment. However, treatment with INH is complicated by polymorphisms in the expression of the enzyme system primarily responsible for its elimination, N-acetyltransferase 2 (NAT2), and its associated hepatotoxicity. The objective of this study was to develop an individualized INH dosing regimen using a pharmacogenetic-driven model and to apply this regimen in a pilot study.MethodsA total of 206 patients with TB who received anti-TB treatment were included in this prospective study. The 2-hour post-dose concentrations of INH were obtained, and their NAT2 genotype was determined using polymerase chain reaction and sequencing. A multivariate regression analysis that included the variables of age, sex, body weight, and NAT2 genotype was performed to determine the best model for estimating the INH dose that achieves a concentration of 3.0–6.0 mg/L. This dosing algorithm was then used for newly enrolled 53 patients.ResultsSerum concentrations of INH were significantly lower in the rapid-acetylators than in the slow-acetylators (2.55 mg/L vs 6.78 mg/L, median, P<0.001). A multivariate stepwise linear regression analysis revealed that NAT2 and body weight independently affected INH concentrations: INH concentration (mg/L) =13.821–0.1× (body weight, kg) −2.273× (number of high activity alleles of NAT2; 0, 1, 2). In 53 newly enrolled patients, the frequency at which they were within the therapeutic range of 3.0–6.0 mg/L was higher in the model-based treatment group compared to the standard treatment group (80.8% vs 59.3%).ConclusionThe use of individualized pharmacogenetic-guided INH dosage regimens that incorporate NAT2 genotype and body weight may help to ensure achievement of therapeutic concentrations of INH in the TB patients.

Improved survival in multidrug-resistant tuberculosis patients receiving integrated tuberculosis and antiretroviral treatment in the SAPiT Trial

The therapeutic effects of antiretroviral treatment (ART) in patients with multidrug-resistant tuberculosis (MDR-TB) and human immunodeficiency virus (HIV) infection have not been established. To assess therapeutic outcomes of integrating ART with treatment for MDR-TB. A subgroup of MDR-TB patients from a randomised controlled trial, the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) study, conducted in an out-patient clinic in Durban, South Africa, from 2008 to 2012. Clinical outcomes at 18 months were compared in patients randomised to receive ART within 12 weeks of initiating standard first-line anti-tuberculosis treatment with those who commenced ART after completing anti-tuberculosis treatment. Mycobacterium tuberculosis drug susceptibility results were available in 489 (76%) of 642 SAPiT patients: 23 had MDR-TB, 14 in the integrated treatment arm and 9 in the sequential treatment arm. At 18 months, the mortality rate was 11.9/100 person-years (py; 95%CI 1.4-42.8) in the combined integrated treatment arm and 56.0/100 py (95%CI 18.2-130.8) in the sequential treatment arm (hazard ratio adjusted for baseline CD4 count and whether MDR-TB treatment was initiated: 0.14; 95%CI 0.02-0.94, P = 0.04). Despite the small sample size, the 86% reduction in mortality due to early initiation of ART in MDR-TB patients was statistically significant.

Relationship between CES2 genetic variations and rifampicin metabolism

Rifampicin is known to be deacetylated in vivo, resulting in its metabolite 25-desacetyl rifampicin, but the enzyme metabolizing rifampicin and the association of this process with any genetic variation have not yet been elucidated. In this study, genetic variations of a surrogate enzyme, carboxylesterase 2 (CES2), and their association with the metabolism of this drug, were investigated. Plasma concentrations of rifampicin and 25-desacetyl rifampicin were measured in 35 patients with tuberculosis receiving a first-line antituberculosis treatment. Direct PCR-based sequencing of the CES2 gene, covering all 12 exons, the 5'-untranslated region (UTR), the 3'-UTR and intronic and promoter regions, was performed. A dual luciferase reporter assay was carried out to assess whether variations in the promoter region affected the transcription of this gene. Ten variations were detected, of which two were in the candidate promoter region, five in introns and three in the 3'-UTR. One of the variations in the 3'-UTR was a novel variation. Genotypes at three closely linked variations (c.-2263A > G, c.269-965A > G and c.1612 + 136G > A) and c.1872*302_304delGAA were associated with significantly different plasma rifampicin concentrations. The mean plasma rifampicin concentration significantly increased with the number of risk alleles at the three closely linked variations, while the plasma concentration decreased along with an increase in the number of risk alleles at c.1872*302_304delGAA. When HepG2 cells were transfected with a luciferase reporter construct bearing the c.-2263G allele, luciferase activities were consistently decreased (by 5%-10%) compared with those harbouring the c.-2263A sequence. Variations in CES2, especially c.-2263A > G in the promoter region, may alter rifampicin metabolism by affecting expression of the gene.