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Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV.

ABSTRACT: Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. A cohort of 100 TB patients (58 men; median age, 35 [interquartile range {IQR}, 29 to 40] years, and median body mass index [BMI], 18.8 [17.3 to 19.9] kg/m(2)) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were determined after 1 week and 2 months of treatment. The effects of nutritional supplementation, HIV, time on treatment, body weight, and SLCO1B1 rs4149032 genotype were examined using a population pharmacokinetic model. The model adjusted for body size via allometric scaling, accounted for clearance autoinduction, and detected an increase in bioavailability (+14%) for the patients in the continuation phase. HIV coinfection in patients not receiving the supplementation was found to decrease bioavailability by 21.8%, with a median maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 to 24 h (AUC0-24) of 5.6 ?g/ml and 28.6 ?g · h/ml, respectively. HIV-coinfected patients on nutritional supplementation achieved higher Cmax and AUC0-24 values of 6.4 ?g/ml and 31.6 ?g · h/ml, respectively, and only 13.3% bioavailability reduction. No effect of the SLCO1B1 rs4149032 genotype was observed. In conclusion, nutritional supplementation during the first 2 months of TB treatment reduces the decrease in rifampin exposure observed in HIV-coinfected patients but does not affect exposure in HIV-uninfected patients. If confirmed in other studies, the use of defined nutritional supplementation in HIV-coinfected TB patients should be considered in TB control programs. (This study has the controlled trial registration number ISRCTN 16552219.).

SUBMITTER: Jeremiah K

PROVIDER: S-EPMC4068463 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV.

Jeremiah Kidola K Denti Paolo P Chigutsa Emmanuel E Faurholt-Jepsen Daniel D PrayGod George G Range Nyagosya N Castel Sandra S Wiesner Lubbe L Hagen Christian Munch CM Christiansen Michael M Changalucha John J McIlleron Helen H Friis Henrik H Andersen Aase Bengaard AB

Antimicrobial agents and chemotherapy 20140407 6

Nutritional supplementation to tuberculosis (TB) patients has been associated with increased weight and reduced mortality, but its effect on the pharmacokinetics of first-line anti-TB drugs is unknown. A cohort of 100 TB patients (58 men; median age, 35 [interquartile range {IQR}, 29 to 40] years, and median body mass index [BMI], 18.8 [17.3 to 19.9] kg/m(2)) were randomized to receive nutritional supplementation during the intensive phase of TB treatment. Rifampin plasma concentrations were det ...[more]

PMID: 24709267

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Project description:This is a substudy of the Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) Comparison of Nevirapine and Efavirenz for the Treatment of HIV-TB Co-infected Patients (ANRS 12146-CARINEMO) trial, which assessed the pharmacokinetics of rifampin or isoniazid with or without the coadministration of nonnucleoside reverse transcriptase inhibitor-based HIV antiretroviral therapy in HIV-tuberculosis-coinfected patients in Mozambique. Thirty-eight patients on antituberculosis therapy based on rifampin and isoniazid participated in the substudy (57.9% males; median age, 33 years; median weight, 51.9 kg; median CD4(+) T cell count, 104 cells/μl; median HIV-1 RNA load, 5.5 log copies/ml). The daily doses of rifampin and isoniazid were 10 and 5 mg/kg of body weight, respectively. Twenty-one patients received 200 mg of nevirapine twice a day (b.i.d.), and 17 patients received 600 mg of efavirenz once a day (q.d.) in combination with lamivudine and stavudine from day 1 until the end of the study. Blood samples were collected at regular time-dosing intervals after morning administration of a fixed-dose combination of rifampin and isoniazid. When rifampin was administered alone, the median maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve (AUC) at steady state were 6.59 mg/liter (range, 2.70 to 14.07 mg/liter) and 27.69 mg · h/liter (range, 11.41 to 109.75 mg · h/liter), respectively. Concentrations remained unchanged when rifampin was coadministered with nevirapine or efavirenz. When isoniazid was administered alone, the median isoniazid Cmax and AUC at steady state were 5.08 mg/liter (range, 1.26 to 11.51 mg/liter) and 20.92 mg · h/liter (range, 7.73 to 56.95 mg · h/liter), respectively. Concentrations remained unchanged when isoniazid was coadministered with nevirapine; however, a 29% decrease in the isoniazid AUC was observed when isoniazid was combined with efavirenz. The pharmacokinetic parameters of rifampin and isoniazid when coadministered with nevirapine or efavirenz were not altered to a clinically significant extent in these severely immunosuppressed HIV-infected patients. Patients experienced favorable clinical outcomes. (This study has been registered at ClinicalTrials.gov under registration no. NCT00495326.).

Project description:UnlabelledThe Brazilian Ministry of Health and the World Health Organization recommend dietary counseling for patients with malnutrition during tuberculosis treatment. Patients under tuberculosis therapy (infected and not infected with HIV) were followed-up to evaluate the effectiveness of dietary counseling.Objectivedescribe the nutritional status of patients with tuberculosis.Methodsan observational follow-up study over a 180-day period of tuberculosis therapy in adults was conducted. Subjects were assessed for body composition (using BMI, TSF and MUAC parameters), serum biomarkers and offered dietary counseling. The data obtained at each visit (D15, D30, D60, D90, D120, D150, and D180) were analyzed, showing trajectories over time and central tendencies each time.Resultsat baseline, the mean age was 41.1 (± 13.4) years; they were predominantly male, with income lower than a local minimum wage and at least six years of schooling. Patients showed predominantly pulmonary tuberculosis. At baseline, all patients suffered from malnutrition. The overall energy malnutrition prevalence was of 70.6%. Anemia at baseline was observed in both groups (63.2%), however, it was significantly more pronounced in the HIV+. At the end, energy malnutrition was reduced to 57.1% (42.9% of HIV- and 71.4% of the HIV+). Micronutrients malnutrition was evident in 71.4% of the HIV- patients and 85.7% of HIV+ patients at the end of tuberculosis therapy. Using BMI (≤ 18.5 kg/m2cutoff) as an index of malnutrition, it was detected in 23.9% of the HIV- and 27.3% of the HIV+ patients at baseline, with no evident improvement over time; using TSF (≤ 11.4mm as cutoff) or MUAC (≤ 28.5cm as cutoff), malnutrition was detected in 70.1% and 85.3% of all patients, respectively. Nevertheless, combining all biomarkers, at the end of follow-up, all patients suffered from malnutrition.ConclusionAlthough with a limited number of patients, the evidence does not support that dietary counseling is effective to recover from malnutrition in our population.

Project description:BackgroundThe current understanding of airborne tuberculosis (TB) transmission is based on classic 1950s studies in which guinea pigs were exposed to air from a tuberculosis ward. Recently we recreated this model in Lima, Perú, and in this paper we report the use of molecular fingerprinting to investigate patient infectiousness in the current era of HIV infection and multidrug-resistant (MDR) TB.Methods and findingsAll air from a mechanically ventilated negative-pressure HIV-TB ward was exhausted over guinea pigs housed in an airborne transmission study facility on the roof. Animals had monthly tuberculin skin tests, and positive reactors were removed for autopsy and organ culture for M. tuberculosis. Temporal exposure patterns, drug susceptibility testing, and DNA fingerprinting of patient and animal TB strains defined infectious TB patients. Relative patient infectiousness was calculated using the Wells-Riley model of airborne infection. Over 505 study days there were 118 ward admissions of 97 HIV-positive pulmonary TB patients. Of 292 exposed guinea pigs, 144 had evidence of TB disease; a further 30 were tuberculin skin test positive only. There was marked variability in patient infectiousness; only 8.5% of 118 ward admissions by TB patients were shown by DNA fingerprinting to have caused 98% of the 125 characterised cases of secondary animal TB. 90% of TB transmission occurred from inadequately treated MDR TB patients. Three highly infectious MDR TB patients produced 226, 52, and 40 airborne infectious units (quanta) per hour.ConclusionsA small number of inadequately treated MDR TB patients coinfected with HIV were responsible for almost all TB transmission, and some patients were highly infectious. This result highlights the importance of rapid TB drug-susceptibility testing to allow prompt initiation of effective treatment, and environmental control measures to reduce ongoing TB transmission in crowded health care settings. TB infection control must be prioritized in order to prevent health care facilities from disseminating the drug-resistant TB that they are attempting to treat.

Project description:Background:Recurrent tuberculosis (TB) following TB treatment completion in HIV-infected individuals remains a major public health burden. We assessed the role of various risk factors in mediating the development of recurrent TB and subsequent resistance to antiretroviral therapy and anti-TB drugs. Patients and methods:We analyzed secondary demographic, clinical, and laboratory data from medical records of five HIV-infected TB patients enrolled between 2009 and 2014 in a prospective observational study investigating TB recurrence. Paired clinical isolates of Myco-bacterium tuberculosis were typed by IS6110 restriction fragment length polymorphism analysis to determine the mechanism of TB recurrence. Plasma samples were genotyped to determine acquisition of HIV drug resistance mutations on antiretroviral treatment (ART). Results:All five patients were HIV-coinfected, with a previous history of TB infection and prior exposure to anti-TB treatment, and residual lung damage, and demonstrated poor treatment adherence - significant risk factors linked to the development of recurrent TB disease. Furthermore, three of the five patients had multiple episodes of drug-susceptible TB infection with subsequent drug-resistant TB infection. Genotyping of the initial and recurrent M. tuberculosis isolates demonstrated three cases of recurrent TB because of relapse and two because of reinfection. All five patients had no mutations at ART initiation; however, by the end of the study follow-up, all patients developed dual class resistance. Conclusion:This series demonstrates the complexity of recurrent TB in HIV coinfection. We highlight the challenges of managing coinfected patients and the increased propensity for the development of drug resistance. We report on the role of various risk factors mediating the development of resistance and subsequent clinical impact. This report underscores the need for structural clinical and adherence interventions for the management of complex treatment and dosing.

Project description:To date, tuberculosis (TB) remains the primary cause of mortality in human immunodeficiency virus (HIV) patients in Russia. Since the beginning of 2000, a sharp change in the HIV patients' structure, to the main known risk factors for HIV infection has taken place in Russia. The transmission of HIV through injectable drug use has begun to decline significantly, giving way to the prevalence of sexual HIV transmission today. These changes may require adjustments to organizational approaches to anti-TB care and the treatment of HIV-positive patients. Our study is aimed at identifying changes in TB-HIV coinfection patients' structures in 2019 compared to 2000. Based on the results obtained, our goal was to point out the parameters that need to be taken into account when developing approaches to improve the organization of TB control care for people with HIV infection. We have carried out a cross-sectional, retrospective, epidemiological study using government TB registry data from four regions in two federal districts of Russia in 2019. The case histories of 2265 patients from two regions with high HIV prevalence, which are part of the Siberian Federal District of Russia, and 89 patient histories from two regions of low HIV prevalence, which are part of the Central Federal District of Russia, were analyzed. We found that parenteral transmission (69.4%) remains the primary route of HIV transmission among the TB-HIV coinfected. The unemployed of working age without disability account for 80.2% of all coinfected people, while the formerly incarcerated account for 53.7% and the homeless account for 4.1%. Those with primary multidrug-resistant TB (MDR-TB) comprise 56.2% of HIV-TB patients. When comparing the incidence of coinfection with HIV among TB patients, statistically significant differences were obtained. Thus, the chances of coinfection increased by 4.33 times among people with active TB (95% CI: 2.31; 8.12), by 2.97 times among people with MDR-TB (95% CI: 1.66; 5.32), by 5.2 times in people with advanced processes in the lungs, including destruction, (95% CI: 2.78; 9.7), as well as by 10.3 times in the case of death within the first year after the TB diagnosis (95% CI: 2.99; 35.5). The absence of data for the presence of TB during preventive examination was accompanied by a decrease in the chances of detecting coinfection (OR 0.36; 95% CI: 0.2; 0.64). We have identified the probable causes of the high incidence of TB among HIV-infected: HIV-patient social maladaptation usually results in delayed medical care, leading to TB treatment regimen violations. Furthermore, self-administration of drugs triggers MDR-TB within this group. Healthcare providers should clearly explain to patients the critical importance of immediately seeking medical care when initial TB symptoms appear.

Project description:Macrophage dysfunction is associated with increased tuberculosis (TB) susceptibility in patients with human immunodeficiency virus (HIV) infection. However, the mechanisms underlying how HIV infection impairs macrophage function are unclear. Here, we found that levels of autoantibodies against red blood cells (RBCs) were significantly elevated in patients with HIV as determined by direct antiglobulin test (DAT). DAT positivity was significantly associated with TB incidence in both univariate and multivariate analyses (odds ratio [OR]?=?11.96 [confidence interval {CI}, 4.68 to 30.93] and 12.65 [3.33 to 52.75], respectively). Ex vivo analysis showed that autoantibodies against RBCs enhanced erythrophagocytosis and thus significantly impaired macrophage bactericidal function against intracellular Mycobacterium tuberculosis Mechanistically, autoantibody-mediated erythrophagocytosis increased heme oxygenase-1 (HO-1) expression, which inhibited M. tuberculosis-induced autophagy in macrophages. Silencing ATG5, a key component for autophagy, completely abrogated the effect of erythrophagocytosis on macrophage bactericidal activity against M. tuberculosis In conclusion, we have demonstrated that HIV infection increases autoantibody-mediated erythrophagocytosis. This process impairs macrophage bactericidal activity against M. tuberculosis by inhibiting HO-1-associated autophagy. These findings reveal a novel mechanism as to how HIV infection increases TB susceptibility.IMPORTANCE HIV infection significantly increases TB susceptibility due to CD4 T-cell loss and macrophage dysfunction. Although it is relatively clear that CD4 T-cell loss represents a direct effect of HIV infection, the mechanism underlying how HIV infection dampens macrophage function is unknown. Here, we show that HIV infection enhances autoantibody-mediated erythrophagocytosis, which dampens macrophage bactericidal activity against TB by inhibiting HO-1-associated autophagy. Our findings reveal a novel mechanism explaining how HIV infection increases susceptibility to TB. We propose that DAT could be a potential measure to identify HIV patients who are at high TB risk and who would be suitable for anti-TB chemotherapy preventive treatment.

Dataset Information

Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV.

Publications

Nutritional supplementation increases rifampin exposure among tuberculosis patients coinfected with HIV.

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