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Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

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This study involves the in-vitro and in-vivo anti-TB potency and in-vivo safety of Transitmycin (TR) (PubChem CID:90659753)- identified to be a novel secondary metabolite derived from Streptomyces sp (R2). TR was tested in-vitro against drug resistant TB clinical isolates (n = 49). 94% of DR-TB strains (n = 49) were inhibited by TR at 10µg ml-1. In-vivo safety and efficacy studies showed that 0.005mg kg-1 of TR is toxic to mice, rats and guinea pigs, while 0.001mg kg-1 is safe, infection load did not reduce. TR is a potent DNA intercalator and also targets RecA and methionine aminopeptidases of Mycobacterium. Analogue 47 of TR was designed using in-silico based molecule detoxification approaches and SAR analysis. The multiple targeting nature of the TR brightens the chances of the analogues of TR to be a potent TB therapeutic molecule even though the parental compound is toxic. Analog 47 of TR is proposed to have non-DNA intercalating property and lesser in-vivo toxicity with high functional potency. This study attempts to develop a novel anti-TB molecule from microbial sources. Though the parental compound is toxic, its analogs are designed to be safe through in-silico approaches. However, further laboratory validations on this claim need to be carried out before labelling it as a promising anti-TB molecule.

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With the electric power grid experiencing a rapid shift to the smart grid paradigm over a deregulated energy market, Internet of Things (IoT)-based solutions are gaining prominence, and innovative peer-to-peer (P2P) energy trading at a micro level is being deployed. Such advancement, however, leaves traditional security models vulnerable and paves the path for blockchain, a distributed ledger technology (DLT), with its decentralized, open, and transparency characteristics as a viable alternative. However, due to deregulation in energy trading markets, most of the prototype resilience regarding cybersecurity attack, performance and scalability of transaction broadcasting, and its direct impact on overall performances and attacks are required to be supported, which becomes a performance bottleneck with existing blockchain solutions such as Hyperledger, Ethereum, and so on. In this paper, we design a novel permissioned Corda framework for P2P energy trading peers that not only mitigates a new class of cyberattacks, i.e., delay trading (or discard), but also disseminates the transactions in a optimized propagation time, resulting in a fair transaction distribution. Sharing transactions in a permissioned R3 Corda blockchain framework is handled by the Advanced Message Queuing Protocol (AMQP) and transport layer security (TLS). The unique contribution of this paper lies in the use of an optimized CPU and JVM heap memory scenario analysis with P2P metric in addition to a far more realistic multihosted testbed for the performance analysis. The average latencies measured are 22 ms and 51 ms for sending and receiving messages. We compare the throughput by varying different types of flow such as energy request, request + pay, transfer, multiple notary, sender, receiver, and single notary. In the proposed framework, request is an energy asset that is based on payment state and contract in the P2P energy trading module, so in request flow, only one node with no notary appears on the vault of the node.Energy request + pay flow interaction deals with two nodes, such as producer and consumer, to deal with request and transfer of asset ownership with the help of a notary. Request + repeated pay flow request, on node A and repeatedly transfers a fraction of energy asset state to another node, B, through a notary.

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BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

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BACKGROUND: Comparative data on percutaneous catheter drainage (PCD) vs EUS-guided drainage (EUS-D) for management of symptomatic walled-off-necrosis (WON), specially infected WON with/without organ failure(OF) is limited. METHODS: Patients with symptomatic WON were divided into two groups of PCD and EUS-D, depending on the modality of drainage. Resolution of OF, adverse events, and other outcome measures were recorded. The two modalities were compared among infected WON sub-cohort and also degree of solid component (SC). RESULTS: 218 patients (175 males; 80.3%) were included who underwent either PCD (n = 102) or EUS-D (n = 116). Clinical success was significantly higher in the EUS-D group (92.1% vs 64.6%; p < 0.0001) and even for infected WON (n = 128) (p = 0.004), with higher (p = 0.007) and faster (p < 0.0001) OF resolution. Other outcome measures including mortality were significantly higher in the PCD group. Among subgroups, PCD with >40% SC had the worst clinical success/OF resolution rates, while EUS-D with <40% SC had the best outcomes. CONCLUSION: EUS-D should be preferred over PCD in the management of WON, infected or otherwise, for higher clinical success, and higher/faster resolution of OF. PCD should be avoided in WON with>40% SC.

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Objective: By increasing the risk of isolation, fear, stigma, abuse, and economic fallout, COVID-19 has led to an increase in the risk of psychiatric disorders, chronic trauma, and stress. These factors eventually increase suicidality and suicidal behavior. This study intends to evaluate the reasons for suicide attempts due to the COVID-19 pandemic in the south Indian population.Design: Cross-sectional studySetting: The study was conducted in R. L. Jalappa Hospital and Research Centre, Kolar.Participants: This study was conducted on 91 patients admitted to the general medicine department for a suicide attempt because of the COVID 19 pandemic.Methods: A single examiner conducted a structured interview with a pretested questionnaire with each participant. Participants were asked to indicate the primary reason or motivation for their suicide attempt. Patients answered a set of questions regarding personal and family concerns (marginalization, fear and uncertainty, domestic abuse, loneliness, grief over loss of loved one) and work-related concerns (economic fallout, high-risk environment, shortage of personnel and personal protective equipment [PPE]). We employed mean and standard deviation to descriptively analyze quantitative variables. Categorical variables were expressed in terms of frequency and proportion. For non-normally-distributed quantitative parameters, medians and interquartile range (IQR) were compared across study groups using the Kruskal-Wallis test (> 2 groups). Data was analyzed using coGuide software, V.1.03.Results: The mean age of participants was 29.47±11.06 years, the majority (43.63%) of which were aged between 21 to 40 years of age. The majority (72.53%) of participants reported personal and family concerns as reasons/motivation for suicide, whereas only 17.58% reported work-related concerns. There was a statistically significant difference across reason or motivation for suicide with age (in years) and gender (P value < 0.001).Conclusion: The study concluded that more than half of the patients indicated personal and family concerns as the major reason for suicide attempts during the pandemic. It is vital to emphasize the mental health well-being of the population and take proactive steps to minimize its detrimental effects during the COVID-19 pandemic.

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With the advent of the technique of sub-mucosal tunnelling, peroral endoscopic myotomy (POEM) has been used for the treatment of esophageal diverticulum, which otherwise is a recurring problem with conventional flexible endoscopic treatment due to incompleteness of septotomy. This study reports our experience of the use of diverticular POEM (D-POEM) technique in the management of large esophageal diverticulum. This is a retrospective study of prospectively maintained database including all consecutive patients with symptomatic esophageal diverticulum presenting at a tertiary care academic center. D-POEM was performed using the technique of submucosal tunnelling and septotomy. Besides baseline parameters, technical success, clinical success, size of diverticula, procedure time, complications and symptom recurrence on follow up were noted. A total of five patients (4 males; median age 72) were included with an average Charlson comorbidity index of 3.2 ± 0.8. Of them, three had Zenker's while two had epiphrenic diverticulum. The median symptom duration was 12 months with a mean diverticulum size of 68.8 ± 1.9 mm. The mean procedure time was 64.80 ± 12.6 min. with a mean septotomy/myotomy length of 79.44 ± 12.2 mm. Minor adverse events were noted intra-procedure in two cases. Clinical success achieved in all cases with a significant mean dysphagia score reduction from 2.20 to 0.20 post procedure (p = 0.011). On a median follow up of 280 days (range 98-330), none had recurrence of symptoms. Our data highlighted that complete septotomy by D-POEM technique can be achieved for the management of large esophageal diverticulum and is safe and effective.

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INTRODUCTION: The purpose of this work was to evaluate the arteries supplying the pancreaticoduodenal (PD) complex. MATERIALS AND METHODS: The study was conducted on 15 fresh enbloc pancreatic specimens by latex injection method which enabled the visualization of the peripancreatic arteries and their minute branches. RESULTS: The gastroduodenal (GDA), anterior superior pancreaticoduodenal (ASPD), and anterior inferior pancreaticoduodenal (AIPD) artery was found in all the cases, whereas the posterior superior pancreaticoduodenal (PSPD) and posterior inferior pancreaticoduodenal (PIPD) artery was present in 93.34% cases. The ASPD artery originated from GDA in all the cases. Two types of variations were observed in the origin of PSPD artery and four types each in the origin of AIPD and PIPD artery. Anatomical and numerical variations were observed in both anterior and posterior arches, posterior arch being absent in 20% cases. CONCLUSIONS: In the present study, an attempt was made to systematically describe the individual arterial configurations of the PD complex. The information provided here has important implications for preoperative planning of technically challenging surgeries and interventions around the pancreatic head.

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ObjectivesConvalescent plasma (CP) as a passive source of neutralizing antibodies and immunomodulators is a century-old therapeutic option used for the management of viral diseases. We investigated its effectiveness for the treatment of COVID-19. DesignOpen-label, parallel-arm, phase II, multicentre, randomized controlled trial. SettingThirty-nine public and private hospitals across India. ParticipantsHospitalized, moderately ill confirmed COVID-19 patients (PaO2/FiO2: 200-300 or respiratory rate > 24/min and SpO2 [≤] 93% on room air). InterventionParticipants were randomized to either control (best standard of care (BSC)) or intervention (CP + BSC) arm. Two doses of 200 mL CP was transfused 24 hours apart in the intervention arm. Main Outcome MeasureComposite of progression to severe disease (PaO2/FiO2< 100) or all-cause mortality at 28 days post-enrolment. ResultsBetween 22nd April to 14th July 2020, 464 participants were enrolled; 235 and 229 in intervention and control arm, respectively. Composite primary outcome was achieved in 44 (18.7%) participants in the intervention arm and 41 (17.9%) in the control arm [aOR: 1.09; 95% CI: 0.67, 1.77]. Mortality was documented in 34 (13.6%) and 31 (14.6%) participants in intervention and control arm, respectively [aOR) 1.06 95% CI: -0.61 to 1.83]. InterpretationCP was not associated with reduction in mortality or progression to severe COVID-19. This trial has high generalizability and approximates real-life setting of CP therapy in settings with limited laboratory capacity. A priori measurement of neutralizing antibody titres in donors and participants may further clarify the role of CP in management of COVID-19. Trial registrationThe trial was registered with Clinical Trial Registry of India (CTRI); CTRI/2020/04/024775.

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The World Health Organization (WHO) has developed specific guidelines for critical concentrations (CCs) of antibiotics used for tuberculosis (TB) treatment, which is universally followed for drug susceptibility testing (DST) of clinical specimens. However, the CC of drugs can differ significantly among the mycobacterial species based on the population, geographic location, and the prevalence of the infecting strain in a particular area. The association between CC and the minimal inhibitory concentration (MIC) of anti-TB drugs is poorly understood. In this study, we assessed the MICs of anti-TB drugs, including isoniazid (INH), rifampicin (RMP), moxifloxacin (MXF), ethambutol (ETH), and p-aminosalicylic acid (PAS) on drug-sensitive Mtb isolates from pulmonary TB patients in South India. The MIC assays performed using solid- and liquid-growth media showed changes in the CC of a few of the tested antibiotics compared with the WHO-recommended levels. Our observation suggests that the WHO guidelines could potentially lead to overdiagnosis of drug-resistant cases, which can result in inappropriate therapeutic decisions. To evaluate the correlation between drug-resistance and CC, we performed the whole-genome sequencing for 16 mycobacterial isolates, including two wild-type and 14 resistant isolates. Our results showed that two of the isolates belonged to the W-Beijing lineage, while the rest were of the East-African-Indian type. We identified a total of 74 mutations, including five novel mutations, which are known to be associated with resistance to anti-TB drugs in these isolates. In our previous study, we determined the serum levels of INH and RMP among the same patients recruited in the current study and estimated the MICs of the corresponding infected isolates in these cases. Using these data and the CCs for INH and RMP from the present study, we performed pharmacodynamics (PD) evaluation. The results show that the PD of RMP was subtherapeutic. Together, these observations emphasize the need for optimizing the drug dosage based on the PD of large-scale studies conducted in different geographical settings.

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BACKGROUND: To describe the hepatic arterial anatomy in detail, tracing the individual hepatic arteries from their origin, extrahepatic course, branching to their segmental territorial supply as applicable to the vascular mapping for hepatic endovascular procedures. METHODS: The study was conducted on 100 formalin fixed adult cadaveric livers. The hepatic arterial anatomy was dissected from the origin of hepatic arteries up to their segmental branching. RESULTS: The origin of hepatic arteries was standard in 72% and aberrant in 28% livers. In livers with standard origin, extrahepatic branching of the main hepatic artery was close to the hepatic hilum in 48% and was in the lower part of the hepatoduodenal ligament in 24% livers. The pattern of extrahepatic branching in each type was three and five respectively. Aberrant arterial anatomy was broadly categorized into three groups. The mapping of segmental arterial vascularization of individual hepatic arteries in each type was also done. CONCLUSIONS: In the present study, an attempt was made to systematically describe the complex hepatic arterial anatomy in a clinically applicable fashion. High variability was seen in the hepatic arterial anatomy at each level, a lot of which could not be included in the current classification systems. The information provided is an important prerequisite for performing accurate intra-arterial hepatic interventions.

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Scrub typhus is associated with outbreaks of acute encephalitis syndrome in Uttar Pradesh, India. A case-control study indicated that children residing, playing, or visiting fields; living with firewood stored indoors; handling cattle fodder; and practicing open defecation were at increased risk for scrub typhus. Communication messages should focus on changing these behaviors.

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Background & objectives: Large variability in anti-tuberculosis (TB) drug concentrations between patients is known to exist. However, limited information is available on intrapatient drug levels during the course of anti-TB treatment (ATT). This study was conducted to evaluate intrapatient variability in plasma rifampicin (RMP) and isoniazid (INH) concentrations during ATT at start of the treatment, at the end of intensive phase (IP) of ATT and at the end of ATT in adult TB patients being treated in the Revised National TB Control Programme (RNTCP). Methods: Adult TB patients (n=485), receiving thrice-weekly ATT in the RNTCP, were studied. Two-hour post-dosing concentrations of RMP and INH were determined at month 1, end of IP and end of ATT, after directly observed drug administration. Drug concentrations were estimated by high-performance liquid chromatography. Results: The median (inter-quartile range) RMP concentrations during the first month, at end of IP and end of ATT were 2.1 (0.4-5.0), 2.4 (0.6-5.5) and 2.2 (0.5-5.3) µg/ml, respectively. The corresponding INH concentrations were 7.1 (4.2-9.9), 7.2 (3.9-10.9) and 6.7 (3.9-9.5) µg/ml. None of the differences in drug concentrations obtained at different time points during ATT were significant. RMP and INH concentrations at different time points were significantly correlated. Age and body mass index caused significant variability in drug concentrations. Interpretation & conclusions: Plasma RMP and INH estimations in adult TB patients at two hours after drug administration remained unaltered during ATT. Clinicians can consider testing drug concentrations at any time point during ATT. These findings may assume significance in the context of therapeutic drug monitoring of anti-TB drug concentrations.

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This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable ). Model-based simulation of optimized (Punfavorable ≤ 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines.

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Nevirapine, a component of antiretroviral therapy (ART) in resource-limited settings, known for auto-induction of metabolism, is initiated at half therapeutic dose until day 14 ('lead-in period'), and subsequently escalated to full dose. However, studies have shown that this dosing strategy based on adult studies may not be appropriate in children, given that younger children have higher drug clearance rates. In this prospective cohort study, we studied trough plasma nevirapine levels by high performance liquid chromatography (HPLC) at days 7, 14 (lead-in period) and 28 (full dose period) after ART initiation amongst HIV-1 infected children initiating nevirapine-based ART in southern India. Among the 20 children (50% male, median age 9 years) included in the study, sub-therapeutic trough plasma nevirapine concentration (<4µg/ml) was seen in 65% (13/20) of children during the lead-in period within two weeks of ART initiation and among 10% of children at 4 weeks during full-dose nevirapine. Adherence was documented as ≥95% in all children by both caregiver self-report and pill count. Median nevirapine concentrations achieved at week 1 was 4.8 µg/ml, significantly lower than 8 µg/ml, the concentration achieved at week 4 (p = 0.034). Virological failure at one year of ART was observed in six children, and was not associated with median nevirapine concentration achieved during week 1, 2 or 4. We conclude that the dose escalation strategy currently practiced among young children living with HIV-1 resulted in significant subtherapeutic nevirapine concentration (≤4µg/ml) during the lead-in period. We call for a closer look at pediatric-focused dosing strategies for nevirapine initiation in young children. Further studies to establish age-appropriate threshold nevirapine concentration are warranted in young children to corroborate the role of therapeutic drug monitoring in predicting virological outcome.

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PURPOSE: The aim of the study was to compare plasma concentrations of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between tuberculosis (TB) patients with and without diabetes mellitus (DM). METHODS: Two-hour post-dosing concentrations of RMP, INH and PZA were determined in adult TB patients that were studied with (n = 452) and without DM (n = 1460), treated with a thrice-weekly regimen in India. Drug concentrations were estimated by HPLC. RESULTS: The median (IQR) INH [6.6 (3.9-10.0) and 7.8 (4.6-11.3)] and PZA [31.0 (22.3-38.0) and 34.1 (24.6-42.7)] microgram per milliliter concentrations were significantly lower in diabetic than non-diabetic TB patients (p < 0.001 for both drugs). Blood glucose was negatively correlated with plasma INH (r = -0.09, p < 0.001) and PZA (r = -0.092, p < 0.001). Multiple linear regression analysis showed RMP, INH and PZA concentrations were influenced by age and drug doses, INH and PZA by DM, RMP by alcohol use and PZA by gender and category of ATT. DM reduced INH and PZA concentrations by 0.8 and 3.0 µg/ml, respectively. CONCLUSIONS: TB patients with DM had lower INH and PZA concentrations. Negative correlation between blood glucose and drug concentrations suggests delayed absorption/faster elimination of INH and PZA in the presence of elevated glucose.

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OBJECTIVES: To compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) between HIV-infected and HIV-uninfected children with tuberculosis (TB) and correlate it with TB treatment outcome. METHODS: HIV-uninfected (n = 84) and HIV-infected (n = 77) children with TB receiving standard thrice weekly treatment were recruited from 6 hospitals in India. Semi-intensive pharmacokinetic sampling was performed during intensive phase of TB treatment after directly observed administration of drugs. Drug concentrations were measured by high performance liquid chromatography. INH acetylator status was determined, and nutritional assessment was done. Children were followed-up and treatment outcomes noted. RESULTS: Children with HIV and TB had significantly lower RMP peak concentration (Cmax) (2.6 vs. 5.1 µg/mL; P < 0.001) and exposure [area under the time-concentration curve (AUC0-8); 10.4 vs. 23.4 µg/mL h; P < 0.001] than those with TB. Among HIV-infected children, a significantly higher proportion had stunting (77% vs. 29%; P < 0.001) and underweight (73% vs. 38%; P < 0.001) compared with children with TB. Combining both groups, RMP Cmax (P = 0.001; adjusted odds ratio = 1.437; 95% confidence interval: 1.157-1.784) and PZA Cmax (P = 0.027; adjusted odds ratio = 1.041; 95% confidence interval: 1.005-1.079) significantly influenced treatment outcome. CONCLUSIONS: HIV infection was associated with lower Cmax of RMP and INH and AUC0-8 of RMP. Over 90% of children in both groups had subtherapeutic RMP Cmax. Cmax of RMP and PZA significantly influenced TB treatment outcome in children with TB. The findings have important clinical implications and suggest the need to increase anti-TB drug doses in children with HIV and TB.

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The objective of this report was to study the pharmacokinetics of rifampin (RMP), isoniazid (INH), and pyrazinamide (PZA) in HIV-infected children with tuberculosis (TB) treated with a thrice-weekly anti-TB regimen in the government program in India. Seventy-seven HIV-infected children with TB aged 1 to 15 years from six hospitals in India were recruited. During the intensive phase of TB treatment with directly observed administration of the drugs, a complete pharmacokinetic study was performed. Drug concentrations were measured by high-performance liquid chromatography. A multivariable regression analysis was done to explore the factors impacting drug levels and treatment outcomes. The proportions of children with subnormal peak concentrations (Cmax) of RMP, INH, and PZA were 97%, 28%, and 33%, respectively. Children less than 5 years old had a lower median Cmax and lower exposure (area under the time-concentration curve from 0 to 8 h [AUC0-8]) of INH (Cmax, 2.5 versus 5.1 µg/ml, respectively [P=0.016]; AUC0-8, 11.1 versus 22.0 µg/ml·h, respectively [P=0.047[) and PZA (Cmax, 34.1 versus 42.3 µg/ml, respectively [P=0.055]; AUC0-8, 177.9 versus 221.7 µg/ml·h, respectively [P=0.05]) than those more than 5 years old. In children with unfavorable versus favorable outcomes, the median Cmax of RMP (1.0 versus 2.8 µg/ml, respectively; P=0.002) and PZA (31.9 versus 44.4 µg/ml, respectively; P=0.045) were significantly lower. Among all factors studied, the PZA Cmax influenced TB treatment outcome (P=0.011; adjusted odds ratio, 1.094; 95% confidence interval, 1.021 to 1.173). A high proportion of children with HIV and TB had a subnormal RMP Cmax. The PZA Cmax significantly influenced treatment outcome. These findings have important clinical implications and emphasize that drug doses in HIV-infected children with TB have to be optimized.

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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.

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