A Global Health Diagnostic for Personalized Medicine in Resource-Constrained World Settings: A Simple PCR-RFLP Method for Genotyping CYP2B6 g.15582C>T and Science and Policy Relevance for Optimal Use of Antiretroviral Drug Efavirenz

Abstract

The use of pharmacogenomics (PGx) knowledge in treatment of individual patients is becoming a common phenomenon in the developed world. However, poorly resourced countries have thus far been constrained for three main reasons. First, the cost of whole genome sequencing is still considerably high in comparison to other (non-genomics) diagnostics in the developing world where both science and social dynamics create a dynamic and fragile healthcare ecosystem. Second, studies correlating genomic differences with drug pharmacokinetics and pharmacodynamics have not been consistent, and more importantly, often not indexed to impact on societal end-points, beyond clinical practice. Third, ethics regulatory frames over PGx testing require improvements based on nested accountability systems and in ways that address the user community needs. Thus, CYP2B6 is a crucial enzyme in the metabolism of antiretroviral drugs, efavirenz and nevirapine. More than 40 genetic variants have been reported, but only a few contribute to differences in plasma EFV and NVP concentrations. The most widely reported CYP2B6 variants affecting plasma drug levels include c.516G > T, c.983T > C, and to a lesser extent, g.15582C > T, which should be considered in future PGx tests. While the first two variants are easily characterized, the g.15582C > T detection has been performed primarily by sequencing, which is costly, labor intensive, and requires access to barely available expertise in the developing world. We report here on a simple, practical PCR-RFLP method with vast potentials for use in resource-constrained world regions to detect the g.15582C > T variation among South African and Cameroonian persons. The effects of CYP2B6 g.15582C > T on plasma EFV concentration were further evaluated among HIV/AIDS patients. We report no differences in the frequency of the g.15582T variant between the South African (0.08) and Cameroonian (0.06) groups, which are significantly lower than reported in Asians (0.39) and Caucasians (0.31). The g.15582C/T and T/T genotypes were associated with significantly reduced EFV levels ( p = 0.006). This article additionally presents the policy relevance of the PGX global health diagnostics and therefore, collectively makes an original interdisciplinary contribution to the field of integrative biology and personalized medicine in developing world. Such studies are, in fact, broadly important because resource-constrained regions exist not only in developing world but also in major geographical parts of the G20 nations and the developed countries.

Analysis of cystic fibrosis–associated P67L CFTR illustrates barriers to personalized therapeutics for orphan diseases

“…Although third party reimbursement may require FDA approval for the diagnosed indication, an insufficient number of subjects for clinical trial evaluation impedes the conventional drug approval process. Such barriers have been highlighted previously from an ethical perspective (19–22), and specific examples also include access to anticancer and anti-infective treatments (20, 23, 24). …”

An Expanded Analysis of Pharmacogenetics Determinants of Efavirenz Response that Includes 3′-UTR Single Nucleotide Polymorphisms among Black South African HIV/AIDS Patients

“…Earlier studies have mostly investigated the role of exonic and promoter single nucleotide polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2B6 , and CYP3A on EFV plasma concentration (Wyen et al, 2008 ; Holzinger et al, 2012 ; Swart et al, 2012a , c , 2013 ; Cortes et al, 2013 ; Sarfo et al, 2013 ; Evans et al, 2015 ; Sinxadi et al, 2015 ). This study is a continuation emphasizing the role of genetic variation in the 3′-UTR of genes which products are either pharmacokinetic or pharmacodynamic targets of EFV.…”

Adverse Neuropsychiatric Events and Recreational Use of Efavirenz and Other HIV-1 Antiretroviral Drugs

“…Although the C15582T variant occurs frequently in most ethnic populations (32%-44%), it is much less common in Africans (8%) (1000 genomes release 17). The lower prevalence of the C15582T allele in Africans has been a consistent finding across studies (6%-9%) (Evans et al, 2015;Sinxadi et al, 2015). However, in African Americans the frequency of this SNP was reported to be much higher (35%) (Lamba et al, 2003).…”