Lymphocyte Count Derived Polygenic Score and Interindividual Variability in CD4 T-cell Recovery in Response to Antiretroviral Therapy.

Access to safe and effective antiretroviral therapy (ART) is a cornerstone in the global response to the HIV pandemic. Among people living with HIV, there is considerable interindividual variability in absolute CD4 T-cell recovery following initiation of virally suppressive ART. The contribution of host genetics to this variability is not well understood. We explored the contribution of a polygenic score which was derived from large, publicly available summary statistics for absolute lymphocyte count from individuals in the general population (PGSlymph) due to a lack of publicly available summary statistics for CD4 T-cell count. We explored associations with baseline CD4 T-cell count prior to ART initiation (n=4959) and change from baseline to week 48 on ART (n=3274) among treatment-naïve participants in prospective, randomized ART studies of the AIDS Clinical Trials Group. We separately examined an African-ancestry-derived and a European-ancestry-derived PGSlymph, and evaluated their performance across all participants, and also in the African and European ancestral groups separately. Multivariate models that included PGSlymph, baseline plasma HIV-1 RNA, age, sex, and 15 principal components (PCs) of genetic similarity explained ∼26-27% of variability in baseline CD4 T-cell count, but PGSlymph accounted for <1% of this variability. Models that also included baseline CD4 T-cell count explained ∼7-9% of variability in CD4 T-cell count increase on ART, but PGSlymph accounted for <1% of this variability. In univariate analyses, PGSlymph was not significantly associated with baseline or change in CD4 T-cell count. Among individuals of African ancestry, the African PGSlymph term in the multivariate model was significantly associated with change in CD4 T-cell count while not significant in the univariate model. When applied to lymphocyte count in a general medical biobank population (Penn Medicine BioBank), PGSlymph explained ∼6-10% of variability in multivariate models (including age, sex, and PCs) but only ∼1% in univariate models. In summary, a lymphocyte count PGS derived from the general population was not consistently associated with CD4 T-cell recovery on ART. Nonetheless, adjusting for clinical covariates is quite important when estimating such polygenic effects.

Pharmacogenetics of tenofovir clearance among Southern Africans living with HIV.

BACKGROUND: Tenofovir is a component of preferred combination antiretroviral therapy (ART) regimens in Africa. Few pharmacogenetic studies have been conducted on tenofovir exposure in Africa, where genetic diversity is greatest. OBJECTIVE: We characterized the pharmacogenetics of plasma tenofovir clearance in Southern Africans receiving tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). METHODS: Adults randomized to TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262) were studied. Linear regression models stratified by study arm examined associations with unexplained variability in tenofovir clearance. We investigated genetic associations with polymorphisms selected a priori followed by genome-wide associations. RESULTS: A total of 268 participants (138 and 130 in the TAF and TDF arm, respectively) were evaluable for associations. Among polymorphisms previously associated with any drug-related phenotype, IFNL4 rs12979860 was associated with more rapid tenofovir clearance in both arms (TAF: P = 0.003; TDF: P = 0.003). Genome-wide, the lowest P values for tenofovir clearance in TAF and TDF arms were LINC01684 rs9305223 (P = 3.0 × 10-8) and intergenic rs142693425 (P = 1.4 × 10-8), respectively. CONCLUSION: Among Southern Africans randomized to TAF or TDF in ADVANCE, unexplained variability in tenofovir clearance was associated with a polymorphism in IFNL4, an immune-response gene. It is unclear how this gene would affect tenofovir disposition.

Leveraging Multi-Ancestry Polygenic Risk Scores for Body Mass Index to Predict Antiretroviral Therapy-Induced Weight Gain.

Widespread availability of antiretroviral therapies (ART) for HIV-1 have generated considerable interest in understanding the pharmacogenomics of ART. In some individuals, ART has been associated with excessive weight gain, which disproportionately affects women of African ancestry. The underlying biology of ART-associated weight gain is poorly understood, but some genetic markers which modify weight gain risk have been suggested, with more genetic factors likely remaining undiscovered. To overcome limitations in available sample sizes for genome-wide association studies (GWAS) in people with HIV, we explored whether a multi-ancestry polygenic risk score (PRS) derived from large, publicly available non-HIV GWAS for body mass index (BMI) can achieve high cross-ancestry performance for predicting baseline BMI in diverse, prospective ART clinical trials datasets, and whether that PRSBMI is also associated with change in BMI over 48 weeks on ART. We show that PRSBMI explained ∼5-7% of variability in baseline (pre-ART) BMI, with high performance in both European and African genetic ancestry groups, but that PRSBMI was not associated with change in BMI on ART. This study argues against a shared genetic predisposition for baseline (pre-ART) BMI and ART-associated weight gain.

Pharmacogenetics of Dolutegravir Plasma Exposure Among Southern Africans With Human Immunodeficiency Virus.

BACKGROUND: Dolutegravir is a component of preferred antiretroviral therapy (ART) regimens. We characterized the pharmacogenetics of dolutegravir exposure after ART initiation in the ADVANCE trial in South Africa. METHODS: Genome-wide genotyping followed by imputation was performed. We developed a population pharmacokinetic model for dolutegravir using nonlinear mixed-effects modeling. Linear regression models examined associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR). RESULTS: Genetic associations were evaluable in 284 individuals. Of 9 polymorphisms previously associated with dolutegravir pharmacokinetics, the lowest P value with AUCVAR was UGT1A1 rs887829 (P = 1.8 × 10-4), which was also associated with log10 bilirubin (P = 8.6 × 10-13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = .02), as were bilirubin concentrations (P = 7.7 × 10-8). In the population pharmacokinetic model, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively, compared with C/C. The lowest P value for AUCVAR genome-wide was CAMKMT rs343942 (P = 2.4 × 10-7). CONCLUSIONS: In South Africa, rs887829 and rs28899168 in the UGT1A locus were independently associated with dolutegravir AUCVAR. The novel rs28899168 association warrants replication. This study enhances understanding of dolutegravir pharmacogenetics in Africa.

Genetic Associations with Weight Gain among South Africans who Initiated Dolutegravir-Containing and Tenofovir-Containing Regimens.

BACKGROUND: Excessive weight gain affects some HIV-positive individuals prescribed dolutegravir-containing regimens. Mechanisms underlying such weight gain are unknown. SETTING: Data and DNA from antiretroviral therapy-naïve participants who were randomized to initiate dolutegravir with emtricitabine plus either tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) in the ADVANCE study (NCT03122262) were used to characterize associations between human genetic polymorphisms and magnitude of weight gain. METHODS: Associations with percent weight gain from baseline to week 48 were assessed using multivariable linear regression models. Primary analyses a priori considered 59 polymorphisms and 10 genes of potential relevance to dolutegravir, TAF, or TDF pharmacokinetics. We also explored genome-wide associations. RESULTS: Among the 314 (92%) of 340 dolutegravir recipients who were successfully genotyped, 160 (47%) and 154 (45%) were randomized to TAF/emtricitabine and TDF/emtricitabine, respectively. In target gene analyses, the lowest P-values for the dolutegravir and tenofovir groups were ABCG2 rs4148149 (P = 7.0 × 10-4) and ABCC10 rs67861980 (P = 1.0 × 10-2), respectively, which were not significant after correction for multiple testing. In genome-wide analyses, the lowest P-values were rs7590091 in TMEM163 (P = 3.7 × 10-8) for dolutegravir, rs17137701 in LOC105379130 (P = 6.4 × 10-8) for TAF, and rs76771105 in LOC105371716 (P = 9.7 × 10-8) for TDF. CONCLUSIONS: Among South African participants in a randomized clinical trial of dolutegravir plus either TAF/emtricitabine or TDF/emtricitabine, we identified several potential genetic associations with weight gain. Only TMEM163 rs7590091 withstood correction for multiple testing. These associations warrant replication in other cohorts.

Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor-Containing Regimens.

BACKGROUND: Unwanted weight gain affects some people living with human immunodeficiency virus (HIV) who are prescribed integrase strand transfer inhibitors (INSTIs). Mechanisms and risk factors are incompletely understood. METHODS: We utilized 2 cohorts to study pharmacogenetics of weight gain following switch from efavirenz- to INSTI-based regimens. In an observational cohort, we studied weight gain at 48 weeks following switch from efavirenz- to INSTI-based regimens among patients who had been virologically suppressed for at least 2 years at a clinic in the United States. Associations were characterized with CYP2B6 and UGT1A1 genotypes that affect efavirenz and INSTI metabolism, respectively. In a clinical trials cohort, we studied weight gain at 48 weeks among treatment-naive participants who were randomized to receive efavirenz-containing regimens in AIDS Clinical Trials Group studies A5095, A5142, and A5202 and did not receive INSTIs. RESULTS: In the observational cohort (n = 61), CYP2B6 slow metabolizers had greater weight gain after switch (P = .01). This was seen following switch to elvitegravir or raltegravir, but not dolutegravir. UGT1A1 genotype was not associated with weight gain. In the clinical trials cohort (n = 462), CYP2B6 slow metabolizers had lesser weight gain at week 48 among participants receiving efavirenz with tenofovir disoproxil fumarate (P = .001), but not those receiving efavirenz with abacavir (P = .65). Findings were consistent when stratified by race/ethnicity and by sex. CONCLUSIONS: Among patients who switched from efavirenz- to INSTI-based therapy, CYP2B6 genotype was associated with weight gain, possibly reflecting withdrawal of the inhibitory effect of higher efavirenz concentrations on weight gain. The difference by concomitant nucleoside analogue is unexplained.

Warfarin Dose and CYP2C Gene Cluster: An African Ancestral-Specific Variant Is a Strong Predictor of Dose in Black South African Patients.

Warfarin is a widely prescribed anticoagulant with a narrow therapeutic index. The rs12777823G>A single-nucleotide polymorphism (SNP) in the CYP2C gene cluster has been shown to influence optimal warfarin doses in African Americans. We report here effects of rs12777823G>A SNP on warfarin dose requirements in two South African population groups, black Africans (BA) and mixed ancestry (MA). A total of 425 participants on warfarin treatment were enrolled in the study. The age group of the studied population ranged between 44 and 66 years, with 69% females enrolled. Genetic characterization of the rs12777823G>A was done using the TaqMan SNP genotyping assay. To further compare effects of rs12777823G>A to those of other SNPs, VKORC1 g.-1639G>A and 4 SNPs in CYP2C9 gene (i.e., CYP2C9 c.430C>T, c.1075A>C, c.449G>A, and c.1003C>T) were analyzed. The rs12777823A variant allele frequencies were 0.28 and 0.25 in the BA and MA, respectively. The rs12777823A/A genotype was associated with significantly (p = 0.002) reduced mean warfarin dosage (27 ± 5.3 mg/week) compared with the G/G genotype (45 ± 16.1 mg/week) among BA, but not among the MA. The rs12777823G>A is located in a nongenomic region, suggesting that this SNP might be in linkage disequilibrium with another, likely causal SNP that is present in BA only. Given ongoing worldwide efforts to identify clinically relevant human genetic variation impacting on optimal warfarin dose selection, the African ancestry-specific genetic variant in the CYP2C cluster and others warrant further research and consideration in development of future warfarin dosing algorithms for precision medicine guidelines.

Harnessing Knowledge on Very Important Pharmacogenes CYP2C9 and CYP2C19 Variation for Precision Medicine in Resource-Limited Global Conflict Zones.

Pharmacogenomics harnesses the utility of a patient's genome (n = 1) in decisions on which therapeutic drugs and in what amounts should be administered. Often, patients with shared ancestry present with comparable genetic profiles that predict drug response. However, populations are not static, thus, often, population mobility through migration, especially enmasse as is seen for refugees, changes the pharmacogenetic profiles of resultant populations and therefore observed responses to commonly used therapeutic drugs. For example, in the aftermath of the Syrian civil war since 2011, millions have fled their homes to neighboring countries in the Middle East. The growing permanence of refugees and mass migrations is a call to shift our focus in the life sciences community from old models of pharmaceutical innovation. These seismic social changes demand faster decisions for "population-to-population bridging," whereby novel drugs developed in or for particular regions/countries can meet with rational regulatory decisions/approval in world regions impacted by migrant/refugee populations whose profiles are dynamic, such as in the Eastern Mediterranean region at present. Thus, it is important to characterize and report on the prevalence of pharmacogenes that affect commonly used medications and predict if population changes may call for attention to particular differences that may impact health of patients. Thus, we report here on four single-nucleotide polymorphism (SNP) variations in CYP2C9 and CYP2C19 genes among Mersin-Turkish healthy volunteers in the Mersin Province in the Eastern Mediterranean region that is currently hosting a vast number of migrant populations from Syria. Both CYP2C9 and CYP2C19 are very important pharmacogene molecular targets. We compare and report here on the observed SNP genetic variation in our sample with data on 12 world populations from dbSNP and discuss the feasibility of forecasting the pharmacokinetics of drugs utilized by migrant communities in Mersin and the Eastern Mediterranean region. This study can serve as a catalyst to invest in research in Syrian populations currently living in the Eastern Mediterranean. The findings have salience for rapid and rational regulatory decision-making for worldwide precision medicine and, specifically, "pharmacogenovigilance-guided bridging of pharmacokinetics" across world populations in the current era of planetary scale migration.