Glucose Metabolism Disorders among People Living with HIV/AIDS on Efavirenz and Atazanavir/Ritonavir-Based Combination Antiretroviral Therapy: A Pharmacogenetic and Pharmacokinetic Evaluation
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Date
2023
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Addis Ababa University
Abstract
This dissertation reports the results of cross-sectional and case-control studies investigating the
prevalence and the link between pharmacogenetic and pharmacokinetic factors with glucose
metabolism disorders (GMDs) among patients on efavirenz (EFV) and ritonavir (RTV)-
boosted atazanavir (ATV/r)-based combination.
GMD status was identified based on fasting glucose, fasting insulin, and HOMA-IR values.
Cases were defined as the presence of any impaired fasting glucose, insulin resistance (IR), or
diabetes mellitus (DM) while controls were those without GMDs. The cross-sectional
prevalence study was conducted on EFV- (n=240) and ATV/r -based (n=111) combination
antiretroviral therapy (cART). The prevalence and predictors of GMDs were determined by
association and regression analysis. Samples from patients on long-term EFV (75 cases and
165 controls) and ATV/r-based cART (22 cases and 89 controls) were then genotyped for
CYP3A4*1B, CYP3A5 (*3 and *6), CYP2B6*6, UGT2B7*2, ABCB1 (c.3435C>T,
c.4036A>G), and SLCO1B1 (*1b, *5). The mid-dose (CP12) of EFV, ATV, and RTV plasma
concentrations (CP12) was determined using LC-MS/MS. The association of genotypes and
CP12 of EFV and ATV/r with the incidence of GMDs were then investigated.
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The prevalence of GMDs for all regimens was 27.6% (97/351) [95% CI 23.0-32.6%], with
31.1% (75/240) [95% CI 25.4-37.5%] for EFV-based and 19.8% (22/111) [95% CI 12.9-
28.5%)] for ATV/r-based cART group. All genotype frequencies followed the Hardy-
Weinberg Equilibrium (p>0.05) between cases and controls. In the EFV group, the CYP3A5*6
allele (p = 0.005) and CYP3A5*6 genotype (p = 0.01) were significantly associated with GMD
cases. Similarly, multivariate analysis indicated CYP3A haplotype as a significant predictor of
GMDs (p = 0.02) and IFG (p = 0.004), while CYP2B6*6 significantly predicted DM (p = 0.03)
in EFV-based cART group. Furthermore, EFV Log CP12 ≥ 3.7 (5000) ng/ml was an
independent predictor of GMDs.
In ATV-based cART-receiving participants, the C allele carriers of SLCO1B1*5 c.521 T>C
demonstrated a 2.9 times higher risk of GMDs [AOR=2.9; 95% CI 1.03-8.1, p=0.04] than the
wildtype allele carriers. Haplotypes containing any *6 and only *3 of CYP3A conferred 80.0%
(p=0.03) and 90.0% (p=0.01) protection, respectively, from GMDs than the wildtype
combination haplotypes. In contrast, a 90% protection from IR was recorded for both haplotype
combinations containing any *6 (p=0.03) and only *3 (p=0.01) types than the wild-type
haplotype combinations. According to the plasma concentration analysis, the mean (SEM)
logCP12 of ATV was 3.24 ng/ml (0.04) in controls and 3.52 ng/ml (0.06) in cases. But, the
logCP12 of both ATV and RTV failed to show significant association with the GMDs.
In conclusion, GMDs are highly prevalent among adults on EFV- than ATV/r-based cARTs.
CYP3A haplotype and CYP2B6*6 genotype positively predicted GMDs and DM, respectively,
among patients on long-term EFV-based cART. On the other hand, the CYP3A haplotypes
decreased and the SLCO1B*5 allele increased the risk of GMDs among PLWH on ATV/r-
based regimens. Higher EFV plasma concentration level independently predicted GMDs while
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the ATV plasma concentration did not. Our findings warrant further research with a larger
sample size
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Keywords
Antiretroviral therapy, efavirenz, atazanavir/ritonavir, glucose metabolic disorder, HIV, pharmacogenetic variation, CYP3A5, CYP3A4, CYP2B6, genotype, drug transporters, single nucleotide polymorphisms, plasma concentration, Ethiopia.