Cytochrome 2B6 polymorphism and efavirenz‐induced central nervous system symptoms : a substudy of the ANRS ALIZE trial

Tiedeu

et al. 2019

TACG

PurposeThe metabolism of antiretroviral drugs is subject to individual variations of the CYP 2B6 gene. The objective of this study was to evaluate the prevalence of CYP 2B6 516 G>T and 983 T>C polymorphisms and investigate their association with the development of adverse drug reactions (ADRs) in people living with HIV/AIDS in Cameroon.Patients and methodsA total number of 122 patients, attending the Yaoundé Central Hospital HIV Day Clinic, consented to take part in this study. Blood specimens were collected and DNA was extracted using the Chelex method. Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) was performed for the detection of CYP 2B6 Single-Nucleotide Polymorphisms (SNPs). Genotype frequencies were compared between groups with or without ADRs. Logistic regression analysis was performed to assess association between genotype and adverse effects of antiretroviral therapy (ART).ResultsThree types of metabolizers were identified: extensive, intermediate and slow. For the 516G>T polymorphism, prevalences of 8.2% GG, 65.6% GT and 26.2% TT were obtained. For the 983T>C polymorphism, 89.3% TT, 4.1% CT and 6.6% CC prevalences were obtained. Those homozygous for the wild-type allele (516GG) were less likely to develop ADR with a statistically significant difference (OR=0.885, P=0.029). For the CYP2B6 T983C SNP, homozygous mutants (CC) may present a higher risk (threefold) of developing adverse reactions (OR=2.677, P=0.164).ConclusionThese findings demonstrate that ADRs among HIV/AIDS patients under ART may be associated with the genetic variability of the metabolizing enzyme CYP 2B6. Genotyping for this gene may guide the better administration of Efavirenz and Nevirapine to Cameroonian patients.

Section: Discussioncontrasting

confidence: 39%

Section: Introductionmentioning

confidence: 99%

<p>Adverse Drug Reactions Associated with CYP 2B6 Polymorphisms in HIV/AIDS-Treated Patients in Yaoundé, Cameroon</p>

Tiedeu

et al. 2019

TACG

Expert Opinion on Drug Metabolism & Toxicology

“…Similarly, 516G>T plays a significant role in EFV concentrations, especially in children older than 10 years [74]. Moreover, higher EFV plasma levels and CNS-related complications are observed in patients deficient in CYP2B6 516T allele [75]. 516G>T variant is most common in the South Asian population, while least frequently observed in East Asians [69].…”

Section: Polymorphism Of Cyp Enzymes Affecting Pharmacodynamics Of Cymentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of cytochrome P450 inhibitors for HIV treatment

Gong

Haque

Chowdhury

et al. 2019

Introduction-Drugs used in HIV treatment; all protease inhibitors, some non-nucleoside reverse transcriptase inhibitors, and pharmacoenhancers ritonavir and cobicistat can inhibit cytochrome P450 (CYP) enzymes. CYP inhibition can cause clinically significant drug-drug interactions (DDI), leading to increased drug exposure and potential toxicity. Areas covered-A complete understanding of pharmacodynamics and CYP-mediated DDI is crucial to prevent adverse side effects and to achieve optimal efficacy. We summarized the pharmacodynamics of all the CYP inhibitors used for HIV treatment, followed by a discussion of drug interactions between these CYP inhibitors and other drugs, and a discussion on the effect of CYP polymorphisms. We also discussed the potential advancements in improving the pharmacodynamics of these CYP inhibitors by using nanotechnology strategy.

“…Efavirenz is oxidized mainly by hepatic cytochrome P450, family 2, sub-family B, polypeptide 6 (CYP2B6) isozyme. The CYP2B6 gene is highly polymorphic [ 215 ] and the CYP2B6 c.516 G>T variant appears to strongly predict the pharmacokinetics of Efavirenz [ 216 ]. That is, this 516G>T change, specifically in HIV-infected individuals of African-ethnicity, genetically predisposes these patients (“slow Efavirenz metabolizers”) to develop adverse CNS reactions with a frequency of 34–50% [ 215 , 217 ].…”

Section: Drug Metabolism/transporter Genesmentioning

confidence: 99%

Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics

Olivier

Cacabelos

Naidoo

2018

IJMS

Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND. Differences in host (human) genetics determine, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. This review describes findings from studies investigating the role of human host genetics in the pathogenesis of HAND, including potential risk factors for developing HAND. The similarities and differences between HAND and Alzheimer’s disease are also discussed. While some specific variations in host genes regulating immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, a few specific gene variants appear to affect the risk for developing HAND and aid our understanding of HAND pathogenesis.