High efavirenz serum concentrations in TB/HIV-coinfected Ugandan adults with a CYP2B6 516 TT genotype on anti-TB treatment

Braun, Amrei von; Castelnuovo, Barbara; Ledergerber, Bruno; Cusato, Jessica; Buzibye, Allan; Kambugu, Andrew; Fehr, Jan; Calcagno, Andrea; Lamorde, Mohammed; Sekaggya-Wiltshire, Christine

doi:10.1093/jac/dky379

Cited by 7 publications

(5 citation statements)

References 11 publications

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“…Our findings are consistent with a study by Chirehwa et al, who reported a 54% increase in isoniazid acetylation clearance in patients on efavirenz (25), and another by Bhatt et al, who demonstrated a 29% decrease in isoniazid concentrations in patients on efavirenz (8). Efavirenz concentrations in this cohort of SOUTH study patients have previously been reported to be higher than in other populations (26), so the effect of efavirenz coadministration may even be amplified compared to previous reports. The mechanism for this decrease in concentrations is still unclear and needs to be evaluated; it could be due to the induction of drug-metabolizing enzymes or the effect on an efflux pump or uptake transporter.…”

Section: Discussionsupporting

confidence: 93%

Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

Sekaggya-Wiltshire

Chirehwa

Musaazi

et al. 2019

Antimicrob Agents Chemother

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Antituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations. HIVinfected Ugandan adults with pulmonary tuberculosis treated according to international weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2, and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation. Between May 2013 and November 2015, we enrolled 268 patients (148 males) with a median weight of 53.5 (interquartile range [IQR], 47.5 to 59.0) kg and a median age of 35 (IQR, 29 to 40) years. Population pharmacokinetic modeling was used to interpret the data and revealed that patients weighing Ͻ55 kg achieved lower concentrations than those in higher weight bands for all drugs in the regimen. The models predicted that this imbalance could be solved with a dose increment of one fixed-dose combination (FDC) tablet for the weight bands of 30 to 37 and 38 to 54 kg. Additionally, the concomitant use of efavirenz increased isoniazid clearance by 24.1%, while bioavailability and absorption of rifampin and isoniazid varied up to 30% in patients on different formulations. Current dosing guidelines lead to lower drug exposure in patients in the lower weight bands. Simply adding one FDC tablet to current weight band-based dosing would address these differences in exposure and possibly improve outcomes. Lower isoniazid exposures due to efavirenz deserve further attention, as does the quality of currently used drug formulations of anti-TB drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT01782950.)

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Section: Discussionsupporting

confidence: 93%

Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

Sekaggya-Wiltshire

Chirehwa

Musaazi

et al. 2019

Antimicrob Agents Chemother

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“…Increasing interest in CYP2B6 genetic polymorphism has been stimulated by revelations of a specific CYP2B6 genotype that significantly affects the metabolism of various drugs in common clinical use in terms of increasing drug efficacy and avoiding adverse drug reactions (Yuce-Artun et al, 2014). In recent years, the research on CYP2B6 gene polymorphism has focused on its pharmacokinetic and pharmacodynamic effects on the chemotherapy drug cyclophosphamide (Shu et al, 2017), the anesthetics ketamine (Wang, Neiner, & Kharasch, 2018), the central nervous system-active bupropion (Tomaz et al, 2015) and methadone (Ahmad, Valentovic, & Rankin, 2018), and the antiretroviral drug efavirenz (von Braun et al, 2018). In addition, the distribution of CYP2B6 genotypes have been studied in several different populations (Szalai, Hadzsiev, & Melegh, 2016;Yuce-Artun et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Association between CYP2B6 polymorphism and acute leukemia in a Han population of Northwest China

Zhang

et al. 2020

Molec Gen & Gen Med

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BackgroundThe aim of this study was to investigate potential associations between CYP2B6 c.516G>T polymorphism and the occurrence and prognosis of acute leukemias (AL) in the Han population of Northwest China.MethodsThe CYP2B6 gene polymorphism was analyzed by PCR‐RFLP and Sanger DNA sequencing in 126 patients with AL and 161 healthy controls.ResultsCompared with controls, there were significantly higher frequencies of GT and TT genotypes and T alleles in AL patients (p < .05), particularly in fusion gene‐positive AL patients. There was no significant difference in CYP2B6 polymorphic genotypes and T alleles between AL patients with complete remission after the first course of chemotherapy and controls (p > .05), while the frequencies in AL patients with partial remission and no remission were significantly higher. The CYP2B6 allele frequency in Han Chinese in Northwest China was significantly different to that reported in Han Chinese and other ethnic minorities in southern China, Uygur Chinese, Vietnamese, African, German, British, Spanish, Turkish, and Argentinian populations; however, there was no significant difference compared with allele frequencies reported in Tibetan and Mongolian Chinese, Japanese, Korean, and American populations.ConclusionOur findings show a strong correlation of the CYP2B6 c.516G>T polymorphism in the Han population of Northwest China with AL, especially fusion gene‐positive AL, and indicate a poor prognosis after the first course of chemotherapy. Our findings also implicate the T allele in AL susceptibility and indicate the existence of racial and geographical differences in allele frequencies of CYP2B6 c.516G>T polymorphism.

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“…Serum concentrations of RIF, INH, ethambutol, and pyrazinamide were measured at 1, 2, and 4 hours postdosing. EFV (600 mg) was measured at 12 ± 2 hours postdosing, but the results of genetic variants and EFV exposure have been reported separately . Patients with undetectable 2‐hour concentrations were excluded from the analysis.…”

Section: Methodsmentioning

confidence: 99%

“…EFV (600 mg) was measured at 12 ± 2 hours postdosing, but the results of genetic variants and EFV exposure have been reported separately. 39 Patients with undetectable 2-hour concentrations were excluded from the analysis. The pharmacokinetic analyses were performed with high-performance liquid chromatography, and AUCs were estimated using noncompartmental analysis.…”

Section: Methodsmentioning

confidence: 99%

The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

Calcagno

Cusato

Sekaggya-Wiltshire

et al. 2019

Clin Pharma and Therapeutics

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Unsatisfactory treatment outcomes have been reported in patients coinfected with HIV/tuberculosis (TB). The aim of this study was to assess the influence of single‐nucleotide polymorphisms (SNPs) in genes encoding for proteins involved in antitubercular drug disposition or effect. A pharmacogenetic study was conducted in Kampala, Uganda, where all analysis was performed. The impact of SNPs on antitubercular drug exposure, adverse events, and treatment outcomes was evaluated in patients coinfected with HIV/TB receiving treatments for both conditions. In 221 participants, N‐acetyltransferase 2 (NAT2; rs1799930), solute carrier organic anion transporter family member 1B1 (SLCO1B1; rs4149032), and pregnane X receptor (PXR; rs2472677) variants affected isoniazid exposure in multivariate analysis. Most patients were deemed cured (163; 73.8%), yet PXR 63396TT carriers had a higher probability of death (P = 0.007) and of worsening peripheral neuropathy (P = 0.018). In this exploratory study in Ugandan patients coinfected with HIV/TB, genetic variants in PXR, SLCO1B1, and NAT2 were moderately associated with isoniazid exposure, whereas PXR 63396TT carriers showed worse outcomes.

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High efavirenz serum concentrations in TB/HIV-coinfected Ugandan adults with a CYP2B6 516 TT genotype on anti-TB treatment

Cited by 7 publications

References 11 publications

Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

Association between CYP2B6 polymorphism and acute leukemia in a Han population of Northwest China

The Influence of Pharmacogenetic Variants in HIV/Tuberculosis Coinfected Patients in Uganda in the SOUTH Study

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