Pharmacogenetics of HIV therapy: challenges for tailoring treatment in genetically complex populations

Tweetable abstract Pharmacogenetic tests are a promising strategy to improve safety and effectiveness of HIV therapy. However, implementation can be challenging in populations with complex genetic structure.

Changing from mandatory to optional genotyping results in higher acceptance of pharmacist-guided warfarin dosing

Aim: We evaluated the clinical acceptance and feasibility of a pharmacist-guided personalized consult service following its transition from a mandatory (mPGx) to optional (oPGx) CYP2C9/ VKORC1/ CYP4F2 genotyping for warfarin. Methods: A total of 1105 patients were included. Clinical acceptance and feasibility outcomes were analyzed using bivariate and multivariable analyses. Results: After transitioning to optional genotyping, genotype testing was still ordered in a large segment of the eligible population (52.1%). Physician acceptance of pharmacist-recommended doses improved from 83.9% (mPGx) to 86.6% (oPGx; OR: 1.3; 95% CI: 1.1–1.5; p = 0.01) with a shorter median genotype result turnaround time (oPGX: 23.6 hr vs mPGX: 25.1 hr ; p < 0.01). Conclusion: Ordering of genotype testing and provider acceptance of dosing recommendations remained high after transitioning to optional genotyping.

Diagnosis and treatment monitoring in breast cancer: how liquid biopsy can support patient management

Imaging and tissue biopsies represent the current gold standard for breast cancer diagnosis and patient management. However, these practices are time-consuming, expensive and require invasive procedures. Moreover, tissue biopsies do not capture spatial and temporal tumor heterogeneity. Conversely, liquid biopsy, which includes circulating tumor cells, circulating free nucleic acids and extracellular vesicles, is minimally invasive, easy to perform and can be repeated during a patient's follow-up. Increasing evidence also suggests that liquid biopsy can be used to efficiently screen and diagnose tumors at an early stage, and to monitor changes in the tumor molecular profile. In the present review, clinical applications and prospects are discussed.

Association of NAT-2 gene polymorphisms toward lung cancer susceptibility and prognosis in North Indian patients treated with platinum-based chemotherapy

Aim: The present study has been carried out to evaluate the association of the N-acetyl transferase 2 ( NAT2) variants in North Indian lung cancer patients and healthy controls. Furthermore, we have also determined the effect of the polymorphic variants of the NAT2 gene on the clinical outcomes and overall survival among lung cancer (LC) subjects treated with platinum-based doublet chemotherapy. Methods: This case-control study comprised a total of 550 cases and 550 healthy controls. The genotyping was carried out using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and the statistical analysis was carried out using MedCalc. Results: There was a lack of any significant association for both 590G>A and 803A>G polymorphisms toward risk for LC, but 857G>A polymorphism exhibited a risk toward LC (p = 0.005). Whereas, variant alleles for the 481C>T polymorphism had a decreased risk for LC (p = 0.0003). Further, 857G>A polymorphism conferred a positive association between genotype and ADCC (p = 0.001) and 481C>T polymorphism had a decreased risk for SQCC (OR = 0.39, p = 0.0006) and SCLC (p = 0.001) subjects. The smokers carrying mutant genotype for the 481C>T polymorphism had a decreased risk toward LC (p < 0.0001) even in light (p = 0.002) as well as heavy smokers (p = 0.001). In case of females, 2.59-fold and 3.66-fold increased risk of LC development was observed in subjects with intermediate and slow acetylator for the 857G>A polymorphism. Whereas, in case of males this polymorphism depicts a reduced risk for LC. On the other hand, 803A>G depicted a 2.82-fold risk of LC in case of female subjects who were slow acetylators. Our study exhibits a significant difference in the overall haplotype distribution between cases and controls. In our study overall, (857G>A, 481C>T, 803A>G) was found to be best model, but was not significant using MDR. Considering the CART results 481C>T polymorphism came out to be the most significant factor in determining the LC risk. For the 803A>G polymorphism, a threefold odds of lymph node invasion were observed for mutant genotype, the recessive model exhibited an odd of 2.8. 590G>A appears to be a potential prognostic factor for OS of SCLC patients after irinotecan therapy as the survival time for such patients was better. Conclusion: These results suggest that NAT2 variant genotype for 590G>A and 803A>G was not found to modulate risk toward LC, but 857G>A polymorphism exhibited a risk toward LC and 481C>T polymorphism had a decreased risk for LC. NAT2 590G>A appears to be a potential prognostic factor for OS of SCLC patients after irinotecan therapy and 481C>T came out to be significant factor using CART.

Understanding the barriers and enablers of pharmacogenomic testing in primary care: a qualitative systematic review with meta-aggregation synthesis

Introduction: Pharmacogenomic testing can indicate which drugs may have limited therapeutic action or lead to adverse effects, hence guiding rational and safe prescribing. However, in the UK and other countries, there are still significant barriers to implementation of testing in primary care. Objective: This systematic review presents the barriers and enablers to the implementation of pharmacogenomics in primary care setting. Materials & methods: MEDLINE, EMBASE, PsycINFO and CINAHL databases were searched through to July 2020 for studies that reported primary qualitative data of primary care professionals and patient views. Following screening, data extraction and quality assessment, data synthesis was undertaken using meta-aggregation based on the theoretical domain’s framework (TDF). Confidence in the synthesized findings relating to credibility and dependability was established using CONQual. Eligible papers were categorized into six TDF domains – knowledge; social and professional roles; behavioral regulation; beliefs and consequences; environmental context and resources; and social influences. Results: From 1669 citations, eighteen eligible studies were identified across seven countries, with a sample size of 504 participants including both primary care professionals and patients. From the data, 15 synthesized statements, all with moderate CONQual rating emerged. These categories range from knowledge, awareness among Primary Care Physicians and patients, professional relationships, negative impact of PGx, belief that PGx can reduce adverse drug reactions, clinical evidence, cost–effectiveness, informatics, reporting issues and social issues. Conclusion: Through use of TDF, fifteen synthesized statements provide policymakers with valuable recommendations for the implementation of pharmacogenomics in primary care. In preparation, policymakers need to consider the introduction of effective educational strategies for both PCPs and patients to raise knowledge, awareness, and engagement. The actual introduction of PGx will require reorganization with decision support tools to aid use of PGx in primary care, with a clear delegation of roles and responsibilities between general professionals and pharmacists supplemented by a local pool of experts. Further policy makers need to address the cost effectiveness of pharmacogenomics and having appropriate infrastructure supporting testing and interpretation including informatic solutions for utilizing pharmacogenomic results.

Pharmacogenetic loci for rosuvastatin are associated with intima-media thickness change and coronary artery disease risk

Aim: Polymorphisms at LPA, LDLR, APOE, APOC1, MYLIP and ABCG2 are attractive targets for assessment of their impact on lipid-lowering therapy with rosuvastatin. The present study investigated whether polymorphisms at these genes are associated with the risk of coronary artery disease (CAD) development, and reduction of atherogenic lipids and carotid intima-media thickness (CIMT) in CAD patients, taking rosuvastatin. Materials & methods: 190 CAD patients and 1697 subjects were enrolled in pharmacogenetic and genetic association study, respectively. SNP genotyping was done using the MassARRAY-4 system. Results: MYLIP rs6924995, rs3757354, APOC1 rs445925, LDLR rs6511720, APOE rs7412, ABCG2 rs2199936, rs1481012 variants were significantly associated with CAD susceptibility (p = 0.016, 0.0003, <0.0001, <0.0001, 0.013, 0.016, 0.0035, respectively), as well as with CIMT regression (except ABCG2 variants; p = 0.05, 0.039, 0.039, 0.016, 0.0065), and changes in plasma lipids during rosuvastatin therapy. Conclusion: The studied polymorphisms possess pleiotropic effects on plasma lipids and CIMT, CAD susceptibility, and determine lipid-lowering response to rosuvastatin.

Polymorphisms of genes related to phase II metabolism and resistance to clopidogrel

Clopidogrel is an antiplatelet drug commonly used to prevent coagulation. This review aimed to investigate the effect of polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK and GLRX genes on clopidogrel during phase II metabolism through exploring previous studies. The results revealed that low glutathione plasma levels caused by several alleles related to these genes could affect the bioactivation process of the clopidogrel prodrug, making it unable to inhibit platelet aggregation perfectly and thus leading to severe consequences in patients with a high risk of blood coagulation. However, the study recommends platelet reactivity tests to predict clopidogrel efficacy rather than studying gene mutations, as most of these mutations are rare and other nongenetic factors could affect the drug’s efficacy.

The importance of including African populations in pharmacogenetics studies of warfarin response

Tweetable abstract Warfarin will remain in use for a long time to come, thus inclusion of African populations in pharmacogenomics is essential to be able to identify all possible biomarkers that are potential predictors for warfarin drug response.

The association between HLA-B*15:02 and phenytoin-induced severe cutaneous adverse reactions: a meta-analysis

Aim: Phenytoin (PHT) is a common anticonvulsant agent known for inducing severe cutaneous adverse reactions (SCARs). HLA-B*15:02 as a risk factor of PHT-induced SCARs was reported in numerous studies with inconsistent results. This meta-analysis aimed to establish pooling evidence of this association. Materials & methods: Pooled odds ratios (ORs) with 95% CIs were estimated using a random-effects model. Results: A total of 11 studies on 1389 patients, were included for the analyses. There was a significant association between HLA-B*15:02 and PHT-induced SCAR (pooled OR = 2.29, 95% CI: 1.25–4.19, p = 0.008). Furthermore, there was a significant association regarding Stevens–Johnson syndrome/toxic epidermal necrolysis (OR = 3.63, 95% CI: 2.15–6.13, p < 0.001) but no association regarding drug reaction with eosinophilia and systemic symptom. Conclusion: The results supported the recommendations of HLA-B*15:02 screening before treatment with PHT.