CYP2B6 genotypes and early efavirenz-based HIV treatment outcomes in Botswana

Abstract

Objective(s) To determine the association between cytochrome p450 2B6 genotypes and efavirenz-based HIV treatment outcomes. Design Observational cohort study of HIV infected adults initiating efavirenz-based regimens in Botswana. Methods The primary endpoint was a composite of death or loss to care or HIV RNA>25 copies/ml at 6 months. CYP2B6 516G>T and 983T>C genotyping was done with Taqman Open Array platform. Adverse experiences were measured using the Subject Experience Questionnaire. Metabolism alleles were included in logistic regression models of the composite endpoint. Results 801 individuals included 406 (51%) males, median age 37 years, median baseline CD4 count 195 cells/mm3 and plasma HIV RNA 4·9 log10 copies/ml. 288 (36%) reached the endpoint including 34 (4%) deaths, 151 (19%) lost to care, 11 (1%) lost to the study, but alive and in care, and 92 (11%) with plasma HIV RNA>25 copies/ml. Metabolism variant alleles were common with 396 (49%) intermediate and 192 (24%) slow metabolizers. There were no statistically significant associations between metabolism and treatment endpoints. However, slower metabolism was associated with fewer adverse experiences. Conclusions Slow metabolism alleles were associated with lower efavirenz clearance but not any of the treatment endpoints. Slow efavirenz metabolism did not exacerbate CNS toxicity. These results should allay concern that slow efavirenz metabolism adversely impacts individuals in sub-Saharan African settings in which these alleles are common.

Heme oxygenase-1 promoter (GT) n polymorphism associates with HIV neurocognitive impairment

“…To confirm the apparent association between the trimodal HO-1 (GT) n allele length distribution, genotype prevalence distribution, and African ancestry, we genotyped a cohort (n = 428) of PLWH from previous observational studies of Africans in Botswana. 20,21 The allele distributions differed significantly from that observed in African Americans and European Americans genotyped in our CHARTER and NNTC cohorts (figure 5A). 16 Individuals in the Botswana cohort had the highest prevalence of long "L" alleles (38.4%) compared with African Americans (p < 0.01) and European Americans (32.4%, 4.7%, p < 0.01, respectively; figure 5, B and C).…”

“…43,44 Correction of this HO-1 deficiency prevents this neurotoxic effect in vitro. Thus, a state of reduced HO-1 expression within the HIVinfected brain could promote both neuroinflammation and Figure 5 Africans from Botswana have a higher prevalence of long HO-1 (GT) n alleles than African Americans and European Americans HO-1 (GT) n allele lengths were determined in African PLWH in Botswana (n = 428) who were previously enrolled in cohort studies, 20,21 and allele distributions were compared with those determined in individuals in our CHARTER and NNTC cohorts (592 European Americans and 446 African Americans). 16 neuronal injury through excitotoxic mechanisms, and therapeutic induction of HO-1 expression might therefore prevent or suppress these processes.…”

“…Among these 595 individuals, data from 528 total selfidentified African Americans and European Americans were analyzed to distinguish differences between these groups. HO-1 (GT) n allele genotyping was also performed on whole blood-derived DNA from a Botswana cohort of PLWH on antiretroviral therapy (ART), randomly selected irrespective of neurocognitive function, 20,21 and under separate IRB approval.…”

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz‐Containing Antiretroviral Therapy

“…For these patients, there is a “moderate” recommendation to consider initiating efavirenz with a decreased dose of 400 mg/day. CYP2B6 PMs are at greatest risk for higher dose‐adjusted trough concentrations compared with NMs and IMs, and greater overall plasma efavirenz exposure, which puts these patients up to a 4.8‐fold increased risk for adverse effects and treatment discontinuation . For these patients, there is a “moderate” recommendation to consider initiating efavirenz with a decreased dose of either 400 or 200 mg/day.…”

“…CYP2B6 PMs are at greatest risk for higher dose-adjusted trough concentrations compared with NMs and IMs, and greater overall plasma efavirenz exposure, which puts these patients up to a 4.8-fold increased risk for adverse effects and treatment discontinuation. [20][21][22][23][24][25][26][27][28][29][30][31] For these patients, there is a "moderate" recommendation to consider initiating efavirenz with a decreased dose of either 400 or 200 mg/day. This "moderate" rather than "strong" recommendation reflects the fact that most CYP2B6 PMs do not discontinue efavirenz 600 mg/day for adverse effects.…”