Antiretroviral therapy immunologic non-response in a Brazilian population: association study using pharmaco- and immunogenetic markers

Coelho, Antônio Victor Campos; Moura, Ronald; Guimarães, Rafael Lima; Brandão, Lucas André Cavalcanti; Crovella, Sérgio

doi:10.1016/j.bjid.2018.09.002

Cited by 3 publications

(4 citation statements)

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“…As described above, ASV is eliminated primarily via CYP3A4-mediated oxidative metabolism [10,11]. rs4646437 is representative of CYP3A4 SNPs, and numerous studies have reported its relationship with drug metabolism and adverse events in the treatment for various diseases: adverse events caused by efavirenz in human immunodeficiency virus [23] and sunitinib in metastatic renal cell carcinoma [24]; finasteride exposure in prostate cancer risk [25]; immune responses to antiretroviral therapy in human immunodeficiency virus [26]; voriconazole exposure in invasive fungal infections [27]; tacrolimus metabolism among Chinese transplant recipients [28,29]; and cyclosporine kinetics in Egyptian and White transplant recipients [30,31]. Reportedly, rs4646437 influences the protein expression and enzymatic activity of hepatic CYP3A4 in a sex-dependent manner; females have higher expression/activity compared to males.…”

Section: Discussionmentioning

confidence: 99%

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C

Kato

Shimada²,

Atsukawa

et al. 2019

PLoS ONE

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Aims Drug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy. Methods Subjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected. Results Among the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2–4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023). Conclusions CYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.

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Section: Discussionmentioning

confidence: 99%

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C

Kato

Shimada²,

Atsukawa

et al. 2019

PLoS ONE

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“…Variations at this gene were not associated with plasma concentrations or virological response to EFV among Haitians ( Leger et al , 2009 ; Haas et al , 2014 ). In Brazil, ABCB1 variations were not associated with intolerance or CNS adverse reactions to EFV ( Arruda et al , 2016 ; de Almeida et al , 2018 ) in cohorts from Southeast region, while 1236C>T was associated with decreased immunological response to this antiretroviral in patients from Northeast region ( Coelho et al , 2018 ).…”

Section: Metabolism Enzymes and Related Transcription Factorsmentioning

confidence: 98%

“…Additional studies have also investigated the role of polymorphisms in genes encoding cytokines and restriction factors and response to cART. In Brazil, variations at CCR5Δ32 (Rigato et al, 2008), IL2 (Coelho et al, 2018) et al, 2014). A large study, including 873 participants from United States and Puerto Rico, have also showed an association between polymorphisms in genes encoding TNF-α, TRAIL, Bcl-2, IL-15, IL-15Rα and IFN-α were associated CD4 lymphocyte counts after long-term cART.…”

Section: Other Associationsmentioning

confidence: 99%

“…Additional studies have also investigated the role of polymorphisms in genes encoding cytokines and restriction factors and response to cART. In Brazil, variations at CCR5Δ32 ( Rigato et al , 2008 ), IL2 ( Coelho et al , 2018 ) and IL18 ( Andrade-Santos et al , 2019 ) were associated to CD4+ T-cell recovery. Moreover, the IL10 −1082 AA genotype was associated with allergic reactions to efavirenz ( Rodrigues et al , 2014 ).…”

Section: Metabolism Enzymes and Related Transcription Factorsmentioning

confidence: 99%

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Pharmacogenetics of HIV therapy: State of the art in Latin American countries

et al. 2022

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The use of combined antiretroviral therapy (cART) has resulted in a remarkable reduction in morbidity and mortality of people living with HIV worldwide. Nevertheless, interindividual variations in drug response often impose a challenge to cART effectiveness. Although personalized therapeutic regimens may help overcome incidence of adverse reactions and therapeutic failure attributed to host factors, pharmacogenetic studies are often restricted to a few populations. Latin American countries accounted for 2.1 million people living with HIV and 1.4 million undergoing cART in 2020-21. The present review describes the state of art of HIV pharmacogenetics in this region and highlights that such analyses remain to be given the required relevance. A broad analysis of pharmacogenetic markers in Latin America could not only provide a better understanding of genetic structure of these populations, but might also be crucial to develop more informative dosing algorithms, applicable to non-European populations.

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HLA-B13, B35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil

et al. 2022

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IntroductionImmune reconstitution failure after HIV treatment is a multifactorial phenomenon that may also be associated with a single polymorphism of human leukocyte antigen (HLA); however, few reports include patients from the Brazilian Amazon. Our objective was to evaluate the association of the immunogenic profile of the “classical” HLA-I and HLA-II loci with treatment nonresponse in a regional cohort monitored over 24 months since HIV diagnosis.Materials and MethodsTreatment-free participants from reference centers in the state of Pará, Brazil, were enrolled. Infection screening was performed using enzyme immunoassays (Murex AG/AB Combination DiaSorin, UK) and confirmed by immunoblots (Bio-Manguinhos, FIOCRUZ). Plasma viral load was quantified by real-time PCR (ABBOTT, Chicago, Illinois, USA). CD4+/CD8+ T lymphocyte quantification was performed by immunophenotyping and flow cytometry (BD Biosciences, San Jose, CA, USA). Infection was monitored via test and logistics platforms (SISCEL and SICLOM). Therapeutic response failure was inferred based on CD4+ T lymphocyte quantification after 1 year of therapy. Loci A, B and DRB1 were genotyped using PCR-SSO (One Lambda Inc., Canoga Park, CA, USA). Statistical tests were applied using GENEPOP, GraphPad Prism 8.4.3 and BioEstat 5.3.ResultsOf the 270 patients monitored, 134 responded to treatment (CD4+ ≥ 500 cells/µL), and 136 did not respond to treatment (CD4+ < 500 cells/µL). The allele frequencies of the loci were similar to heterogeneous populations. The allelic profile of locus B was statistically associated with treatment nonresponse, and the B*13, B*35 and B*39 alleles had the greatest probabilistic influence. The B*13 allele had the highest risk of treatment nonresponse, and carriers of the allele had a detectable viral load and a CD4+ T lymphocyte count less than 400 cells/µL with up to 2 years of therapy. The B*13 allele was associated with a switch in treatment regimens, preferably to efavirenz (EFZ)-based regimens, and among those who switched regimens, half had a history of coinfection with tuberculosis.ConclusionsThe allelic variants of the B locus are more associated with non-response to therapy in people living with HIV (PLHIV) from a heterogeneous population in the Brazilian Amazon.

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Antiretroviral therapy immunologic non-response in a Brazilian population: association study using pharmaco- and immunogenetic markers

Cited by 3 publications

References 45 publications

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C

Pharmacogenetics of HIV therapy: State of the art in Latin American countries

HLA-B13, B35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil

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Antiretroviral therapy immunologic non-response in a Brazilian population: association study using pharmaco- and immunogenetic markers

Cited by 3 publications

References 45 publications

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C

Pharmacogenetics of HIV therapy: State of the art in Latin American countries

HLA-B*13, B*35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil

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Product

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HLA-B13, B35 and B*39 Alleles Are Closely Associated With the Lack of Response to ART in HIV Infection: A Cohort Study in a Population of Northern Brazil