Low Serum Concentrations of Rifampicin and Pyrazinamide Associated with Poor Treatment Outcomes in Children with Tuberculosis Related to HIV Status

Ramachandran, Geetha; Kumar, A. K. Hemanth; Thiruvengadam, Kannan; Bhavani, Perumal Kannabiran; Kumar, Santosh; Gangadevi, N. Poorana; Velayutham, Banurekha; Sudha, Vasudevan; Venkatesh, Srinivasan; Ravichandran, N.; Kalpana, S; Mathevan, G.; Sanjeeva, G N; Agarwal, Dipti; Swaminathan, Soumya

doi:10.1097/inf.0000000000001069

Cited by 35 publications

(40 citation statements)

References 17 publications

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“…Five studies only included an HIV-positive TB group, whereas a comparator HIV-negative TB group was lacking [34][35][36][37][38]; therefore these studies were excluded for further analysis. Twelve studies only included HIV-positive TB participants not receiving ART [22-24, 26, 32, 33, 39-44], in ten studies a proportion of HIV-positive participants were receiving ART [19,34,38,[45][46][47][48][49][50][51], and five studies did not provide information on ART use among HIV-positive TB patients [25,[35][36][37]52]. In 11 studies, a limited number of fewer than five blood samples were drawn for determination of drug concentrations [19,25,34,36,37,40,41,43,46,47,52].…”

Section: Resultsmentioning

confidence: 99%

A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs

et al. 2018

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Introduction Contrasting findings have been published regarding the effect of human immunodeficiency virus (HIV) on tuberculosis (TB) drug pharmacokinetics (PK). Objectives The aim of this systematic review was to investigate the effect of HIV infection on the PK of the first-line TB drugs (FLDs) rifampicin, isoniazid, pyrazinamide and ethambutol by assessing all published literature. Methods Searches were performed in MEDLINE (through PubMed) and EMBASE to find original studies evaluating the effect of HIV infection on the PK of FLDs. The included studies were assessed for bias and clinical relevance. PK data were extracted to provide insight into the difference of FLD PK between HIV-positive and HIV-negative TB patients. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and its protocol was registered at PROSPERO (registration number CRD42017067250). Results Overall, 27 studies were eligible for inclusion. The available studies provide a heterogeneous dataset from which consistent results could not be obtained. In both HIV-positive and HIV-negative TB groups, rifampicin (13 of 15) and ethambutol (4 of 8) peak concentration (C max) often did not achieve the minimum reference values. More than half of the studies (11 of 20) that included both HIV-positive and HIV-negative TB groups showed statistically significantly altered FLD area under the concentration-time curve and/or C max for at least one FLD. Conclusions HIV infection may be one of several factors that reduce FLD exposure. We could not make general recommendations with respect to the role of dosing. There is a need for consistent and homogeneous studies to be conducted.

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Section: Resultsmentioning

confidence: 99%

A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs

et al. 2018

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“…In contrast, a recent study that enrolled 66 children with TB (24 HIV coinfected) in India who were given previously recommended daily dosages of the drugs reported significantly lower ethambutol C max and AUC 0 -4 in the TB/HIV-coinfected children than in the children with TB alone, but rifampin, pyrazinamide, and isoniazid C max and AUC 0 -4 were similar between the two groups (29). Another Indian study that included 84 HIV-uninfected and 77 HIV-infected children given three-times-weekly dosages based on the old treatment guidelines found significantly lower rifampin C max and AUC 0 -8 in the HIV-infected children than in those with TB alone (32). The current study found significantly lower rifampin and ethambutol C max and AUC 0 -8 , as well as a lower pyrazinamide AUC 0 -8 , in the TB/HIVcoinfected children than in the children with TB alone.…”

Section: Discussionmentioning

confidence: 99%

“…While our study was not designed to investigate the relationship between pharmacokinetics and TB treatment outcome, the lower median plasma exposure and C max of rifampin and ethambutol in the HIV-coinfected patients is concerning and raises the question of whether inadequate drug pharmacokinetics is a contributor to the higher risk of an unfavorable treatment response. At least one group reported a relationship between lower rifampin and pyrazinamide C max and unfavorable TB treatment outcome (death, failure, and default) in HIV-infected children (19) and in a combined group of HIV-infected and uninfected children in India treated with a thrice-weekly regimen (32). Thus, strategies to improve TB treatment outcomes in children, especially with HIV coinfection, should include optimized dosages of rifampin, pyrazinamide, and ethambutol.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Antwi

Yang

Enimil

et al. 2017

Antimicrob Agents Chemother

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Although human immunodeficiency virus (HIV) coinfection is the most important risk factor for a poor antituberculosis (anti-TB) treatment response, its effect on the pharmacokinetics of the first-line drugs in children is understudied. This study examined the pharmacokinetics of the four first-line anti-TB drugs in children with TB with and without HIV coinfection. Ghanaian children with TB on isoniazid, rifampin, pyrazinamide, and ethambutol for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods and pharmacokinetic parameters calculated using noncompartmental analysis. The area under the concentration-time curve from 0 to 8 h (AUC 0 -8 ), maximum concentration (C max ), and apparent oral clearance divided by bioavailability (CL/F) for each drug were compared between children with and without HIV coinfection. Of 113 participants, 59 (52.2%) had HIV coinfection. The baseline characteristics were similar except that the coinfected patients were more likely to have lower weight-for-age and height-for-age Z scores (P Ͻ 0.05). Rifampin, pyrazinamide, and ethambutol median body weight-normalized CL/F values were significantly higher, whereas the plasma AUC 0 -8 values were lower, in the coinfected children than in those with TB alone. In the multivariate analysis, drug dose and HIV coinfection jointly influenced the apparent oral clearance and AUC 0 -8 for rifampin, pyrazinamide, and ethambutol. Isoniazid pharmacokinetics were not different by HIV coinfection status. HIV coinfection was associated with lower plasma exposure of three of the four first-line anti-TB drugs in children. Whether TB/HIV-coinfected children need higher dosages of rifampin, pyrazinamide, and ethambutol requires further investigation. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

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“…Few stud-ies have examined disease outcome with respect to low PZA and POA concentrations in the plasma. Three studies within the last eight years have shown an association between low serum concentrations of PZA and poor disease outcome [76][77][78] . For example, Chideya et al [76] reported that patients with inadequate PZA levels in serum (adjusted for HIV status and CD4 + T cell counts) were at three times greater risk for poor outcome compared to patients with normal concentrations of PZA.…”

Section: Pza and The Host Environmentmentioning

confidence: 99%

Impact of the host environment on the antitubercular action of pyrazinamide

Lamont

Baughn

2019

eBioMedicine

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a b s t r a c tPyrazinamide remains the only drug in the tuberculosis pharmacopeia to drastically shorten first-line therapy from nine to six months. Due to its unparalleled ability to sterilize non-replicating bacilli and reduce relapse rates, PZA is expected to be irreplaceable in future therapies against tuberculosis. While the molecular target of PZA is unclear, recent pharmacokinetic studies using small animal models and patient samples have highlighted the importance of host metabolism and immune responses in PZA efficacy. Delineating which host factors are important for PZA action will be integral to the design of next-generation therapies to shorten current TB drug regimens as well as to overcome treatment limitations in some patients. In this review, we discuss evidence for influence of the host environment on PZA activity, targets for PZA mechanism of action, recent studies in PZA pharmacokinetics, PZA antagonism and synergy with other first-line anti-TB drugs, and implications for future research.

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Low Serum Concentrations of Rifampicin and Pyrazinamide Associated with Poor Treatment Outcomes in Children with Tuberculosis Related to HIV Status

Cited by 35 publications

References 17 publications

A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs

A Systematic Review on the Effect of HIV Infection on the Pharmacokinetics of First-Line Tuberculosis Drugs

Pharmacokinetics of the First-Line Antituberculosis Drugs in Ghanaian Children with Tuberculosis with or without HIV Coinfection

Impact of the host environment on the antitubercular action of pyrazinamide

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