Rolling out Efavirenz for HIV Precision Medicine in Africa: Are We Ready for Pharmacovigilance and Tackling Neuropsychiatric Adverse Effects?

Abstract

The introduction of antiretroviral therapy (ART) led to huge reductions in human immunodeficiency virus (HIV)-related deaths, turning HIV-infection into a chronic condition. Attention is now turning to quality of life for patients on lifelong ART treatment, reflecting on the safety of antiretroviral drugs. In sub-Saharan Africa, efavirenz (EFV) forms the preferred first-line ART but adverse drug events have also been reported. We express our concern on EFV-based regimens being part of mass rollout programs without full attention to toxicities. EFV is associated with various neuropsychiatric adverse events (AEs). If EFV use is not monitored, a huge burden of neuropsychiatric AEs and elevated risk of drug resistance due to nonadherence are likely to follow. A monumental EFV-based ART regimen rollout program, through the UNAIDS 90-90-90 and option B plus programs/approaches, is planned, which will more than double the number of patients on EFV-containing ART. According to this ambitious treatment target, by 2020, 90% of all people living with HIV will know their HIV status; 90% of all people with diagnosed HIV infection will receive sustained ART; and 90% of all people receiving ART will have viral suppression. On the other hand, HIV patients of African origin are predisposed to developing EFV-induced neuropsychiatric AEs due to specific CYP2B6 genetic variants causing impaired metabolism of EFV. It is our considered opinion that the potential quantitative and qualitative burden of EFV-induced neuropsychiatric AEs, which can vary from person-to-person and between populations, deserve special attention and action during the ART rollout program. We here make a case for Africa in particular where we project the burden of neuropsychiatric AEs to be greatest. We advocate for surveillance of neuropsychiatric AEs due to EFV therapy, incorporation of pharmacogenetics testing for CYP2B6 to assist in EFV dosing, and measurement of plasma EFV concentration, as a three-pronged rational therapeutic drug monitoring strategy to guide EFV treatment toward precision medicine.

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

“…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 ]. This has important consequences for the African continent as it may dramatically increase the burden of psychiatric illness in HIV-infected patients [ 217 , 218 ].…”

“…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 ]. This has important consequences for the African continent as it may dramatically increase the burden of psychiatric illness in HIV-infected patients [ 217 , 218 ]. In those individuals, compared to 15–20% of Caucasian and Asian populations [ 213 , 219 ], CYP2B6 enzyme activity is reduced, impairing the metabolism of Efavirenz and increasing plasma levels of the drug [ 215 , 217 , 220 ].…”

“…This has important consequences for the African continent as it may dramatically increase the burden of psychiatric illness in HIV-infected patients [ 217 , 218 ]. In those individuals, compared to 15–20% of Caucasian and Asian populations [ 213 , 219 ], CYP2B6 enzyme activity is reduced, impairing the metabolism of Efavirenz and increasing plasma levels of the drug [ 215 , 217 , 220 ]. Furthermore, the effect of the CYP2B6 G516T polymorphism on neurocognitive performance was evaluated in non-HIV-infected individuals who were administered Efavirenz [ 221 ].…”

Pharmacogenetics of ugt genes in North African populations

“…In prior work, we showed that besides polymorphisms in CYP450 , those in SULT and UGT also give rise to different serum levels of some drug metabolites than detected in wild-type carriers of the genes [ 1 ]. To date, most pharmacogenetic studies have examined Asian and Caucasian populations and although the pharmacogenetics of CYP450 genes has been explored in sub-Saharan countries, scarce data exist for African genetic variations in SULT and UGT [ 2 , 3 ].…”

Development to Enable Precision Medicine in Africa

“…Genetic variants in CYP2B6, which have been found at higher frequency in several African populations, affect the metabolism of EFV, thus predisposing these populations to the adverse effects. This argues for pharmacogenetics testing of CYP2B6 to improve the precision of EFV dosing [9].…”