RESUMO
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.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/metabolismo , Infecções por HIV/genética , Humanos , Testes Farmacogenômicos , Resultado do TratamentoRESUMO
Virologic failure of antiretroviral therapy (ART) may be explained by single nucleotide polymorphisms (SNPs) in drug absorption and metabolism genes. Here, we characterized the associations between polymorphisms in cytochrome P450 enzymes' genes CYP2B6 and CYP3A4/A5, nuclear receptor genes NR1I2/3, and initial ART efficacy among 203 HIV-positive individuals from Rio de Janeiro. Association between SNPs and virologic control was evaluated after 6 and 12 months of follow-up using Cox regression models. The SNP rs2307424 (NR1I3) was associated with increased virologic response after 12 months of treatment, while rs1523127 (NR1I2), rs3003596, and rs2502815 (NR1I3) were associated with decreased response. Increased virologic response after 12 months (adjHR = 1.54; p = 0.02) was also observed among carriers of the NR1I3 haplotype rs2502815G-rs3003596A-rs2307424A versus the reference haplotype G-A-G. Our results suggest that NR1I2 and NR1I3 variants are associated with virologic responses to ART among Brazilians.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Receptor Constitutivo de Androstano/genética , Sistema Enzimático do Citocromo P-450/genética , Infecções por HIV/genética , Infecções por HIV/virologia , Soropositividade para HIV/tratamento farmacológico , Soropositividade para HIV/genética , Receptor de Pregnano X/genética , Adulto , Terapia Antirretroviral de Alta Atividade , Brasil , Estudos de Coortes , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Feminino , Infecções por HIV/tratamento farmacológico , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de N-Metil-D-Aspartato , Resultado do TratamentoRESUMO
ACE2 and TMPRSS2 are key players on SARS-CoV-2 entry into host cells. However, it is still unclear whether expression levels of these factors could reflect disease severity. Here, a case-control study was conducted with 213 SARS-CoV-2 positive individuals where cases were defined as COVID-19 patients with respiratory distress requiring oxygen support (N = 38) and controls were those with mild to moderate symptoms of the disease who did not need oxygen therapy along the entire clinical course (N = 175). ACE2 and TMPRSS2 mRNA levels were evaluated in nasopharyngeal swab samples by RT-qPCR and logistic regression analyzes were applied to estimate associations with respiratory outcomes. ACE2 and TMPRSS2 levels positively correlated with age, which was also strongly associated with respiratory distress. Increased nasopharyngeal ACE2 levels showed a protective effect against this outcome (adjOR = 0.30; 95% CI 0.09-0.91), while TMPRSS2/ACE2 ratio was associated with risk (adjOR = 4.28; 95% CI 1.36-13.48). On stepwise regression, TMPRSS2/ACE2 ratio outperformed ACE2 to model COVID-19 severity. When nasopharyngeal swabs were compared to bronchoalveolar lavages in an independent cohort of COVID-19 patients under mechanical ventilation, similar expression levels of these genes were observed. These data suggest nasopharyngeal TMPRSS2/ACE2 as a promising candidate for further prediction models on COVID-19.
