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Aim: This study evaluated associations between CYP3A4*22 and variants in other pharmacogenes (CYP3A5, SULT2A1, ABCB1, ABCG2, ERCC1) and the risk for palbociclib-associated toxicities. Materials & methods: Two hundred cancer patients who received standard-of-care palbociclib were genotyped and associations with toxicity were evaluated retrospectively. Results: No significant associations were found for CYP3A4*22, CYP3A5*3, ABCB1_rs1045642, ABCG2_rs2231142, ERCC1_rs3212986 and ERCC1_rs11615. Homozygous variant carriers of SULT2A1_rs182420 had higher incidence of dose modifications due to palbociclib toxicity (odds ratio [OR]: 4.334, 95% CI: 1.057-17.767, p = 0.042). ABCG2_rs2231137 variant carriers had borderline higher incidence of grade 3-4 neutropenia (OR: 4.14, 95% CI: 0.99-17.37, p = 0.052). Conclusion: Once validated, SULT2A1 and ABCG2 variants may be useful to individualize palbociclib dosing to minimize toxicities and improve treatment outcomes.
[Box: see text].
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The spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders with an autosomal dominant inheritance. Symptoms include poor coordination and balance, peripheral neuropathy, impaired vision, incontinence, respiratory insufficiency, dysphagia, and dysarthria. Although many patients with SCA have respiratory-related complications, the exact mechanism and extent of this pathology remain unclear. This review aims to provide an update on the recent clinical and preclinical scientific findings on neuropathology causing respiratory insufficiency in SCA.
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Transtornos de Deglutição , Neurologia , Insuficiência Respiratória , Ataxias Espinocerebelares , Humanos , Ataxias Espinocerebelares/complicações , Ataxias Espinocerebelares/genética , DisartriaRESUMO
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a deficiency in dystrophin - a structural protein which stabilises muscle during contraction. Dystrophin deficiency adversely affects the respiratory system leading to sleep-disordered breathing, hypoventilation, and weakness of the expiratory and inspiratory musculature, which culminate in severe respiratory dysfunction. Muscle degeneration-associated respiratory impairment in neuromuscular disease is a result of disruptions at multiple sites of the respiratory control network, including sensory and motor pathways. As a result of this pathology, respiratory failure is a leading cause of premature death in DMD patients. Currently available treatments for DMD respiratory insufficiency attenuate respiratory symptoms without completely reversing the underlying pathophysiology. This underscores the need to develop curative therapies to improve quality of life and longevity of DMD patients. This review summarises research findings on the pathophysiology of respiratory insufficiencies in DMD disease in humans and animal models, the clinical interventions available to ameliorate symptoms, and gene-based therapeutic strategies uncovered by preclinical animal studies.
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Distrofia Muscular de Duchenne , Doenças Neuromusculares , Animais , Modelos Animais de Doenças , Distrofina/metabolismo , Humanos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/terapia , Doenças Neuromusculares/complicações , Qualidade de Vida , RespiraçãoRESUMO
Many anticancer drugs cause adverse drug reactions (ADRs) that negatively impact safety and reduce quality of life. The typical narrow therapeutic range and exposure-response relationships described for anticancer drugs make precision dosing critical to ensure safe and effective drug exposure. Germline mutations in pharmacogenes contribute to inter-patient variability in pharmacokinetics and pharmacodynamics of anticancer drugs. Patients carrying reduced-activity or loss-of-function alleles are at increased risk for ADRs. Pretreatment genotyping offers a proactive approach to identify these high-risk patients, administer an individualized dose, and minimize the risk of ADRs. In the field of oncology, the most well-studied gene-drug pairs for which pharmacogenetic dosing recommendations have been published to improve safety are DPYD-fluoropyrimidines, TPMT/NUDT15-thiopurines, and UGT1A1-irinotecan. Despite the presence of these guidelines, the scientific evidence showing the benefits of pharmacogenetic testing (e.g., improved safety and cost-effectiveness) and the development of efficient multi-gene genotyping panels, routine pretreatment testing for these gene-drug pairs has not been implemented widely in the clinic. Important considerations required for widespread clinical implementation include pharmacogenetic education of physicians, availability or allocation of institutional resources to build an efficient clinical infrastructure, international standardization of guidelines, uniform adoption of guidelines by regulatory agencies leading to genotyping requirements in drug labels, and development of cohesive reimbursement policies for pretreatment genotyping. Without clinical implementation, the potential of pharmacogenetics to improve patient safety remains unfulfilled.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Farmacogenética , Testes Farmacogenômicos , Qualidade de VidaRESUMO
In the last decade, reliable scientific evidence has emerged to support the concept that undetectable viral loads prevent human immunodeficiency virus (HIV). Undetectable equals untransmissible (U = U) is a simple message that everyone can understand. The success of this concept depends on strict adherence to antiretroviral therapy (ART) and the attainment of suppressed viral loads (VLs). To achieve U = U in sub-Saharan Africa (SSA), poor adherence to ART, persistent low-level viremia, and the emergence of drug-resistant mutants are challenges that cannot be overlooked. Short of a cure for HIV, U = U can substantially reduce the burden and change the landscape of HIV epidemiology on the continent. From a public health perspective, the U = U concept will reduce stigmatization in persons living with HIV (PLWHIV) in SSA and strengthen public opinion to accept that HIV infection is not a death sentence. This will also promote ART adherence because PLWHIV will aim to achieve U = U within the shortest possible time. This article highlights challenges and barriers to achieving U = U and suggests how to promote the concept to make it beneficial and applicable in SSA. This concept, if expertly packaged by policy-makers, clinicians, health service providers, and HIV control programs, will help to stem the tide of the epidemic in SSA.
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Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , Carga Viral/efeitos dos fármacos , Adulto , África Subsaariana/epidemiologia , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/psicologia , Infecções por HIV/virologia , Humanos , Masculino , Adesão à MedicaçãoRESUMO
BACKGROUND: Maternal cytomegalovirus (CMV) infection and/or reactivation in pregnancy is associated with a myriad of adverse infant outcomes. However, the role of host genetic polymorphisms in modulating maternal CMV status is inconclusive. This study investigated the possible association of single nucleotide polymorphisms in toll-like receptor (TLR) and cytokine genes with maternal plasma CMV DNA status in black Zimbabweans. METHODS: In a cross-sectional study, 110 women in late gestation who included 36 CMV infected cases and 74 CMV uninfected, age and HIV status matched controls were enrolled. Twenty single nucleotide polymorphisms in 10 genes which code for proteins involved in immunity against CMV were genotyped using Iplex GOLD SNP genotyping protocol on the Agena MassARRAY® system. Statistical analyses were performed using Stata SE and the 'Genetics' and 'SNPassoc' packages of the statistical package R. RESULTS: The TLR7 rs179008A > T (p < 0.001) polymorphism was associated while the TLR9 rs352139T > C (p = 0.049) polymorphism was on the borderline for association with CMV positive (CMV+) status. In contrast, the interleukin (IL)-6 rs10499563T > C (p < 0.001) and TLR2 rs1816702C > T (p = 0.001) polymorphisms were associated with CMV negative (CMV-) status. Furthermore, allele frequencies of SNPs in TLR2, TLR4, TLR9, TLR7, IL-6, IL-10, IL-28B, IL-1A and interferon AR1 (IFNAR1) genes are being reported here for the first time in a Zimbabwean population. The allele frequencies in the Zimbabwean population are generally comparable to other African populations but different when compared to European and Asian populations. CONCLUSIONS: Toll-like receptor and interleukin genetic polymorphisms influence CMV status in late gestation among black Zimbabweans. This is attributable to possible modulation of immune responses to CMV reactivation in a population previously exposed to CMV infection.
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Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Citomegalovirus , Variação Genética , Interleucina-6/genética , Complicações Infecciosas na Gravidez , Receptores Toll-Like/genética , Adolescente , Adulto , Alelos , Citomegalovirus/imunologia , Suscetibilidade a Doenças , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Gravidez , Receptor 2 Toll-Like/genética , Receptor 7 Toll-Like/genética , Receptor Toll-Like 9/genética , Adulto JovemRESUMO
This study aimed to investigate the seroprevalence of cytomegalovirus (CMV) infection and risk factors associated with CMV acquisition among pregnant women in Zimbabwe. In a cross-sectional study, pregnant women were recruited in late gestation, seeking antenatal care at council clinics in three high-density suburbs in Harare, Zimbabwe. Anti-CMV IgM and IgG antibodies were quantified in serum using an enzyme-linked immunosorbent assay. Antibody avidity tests were used to distinguish active infection from viral reactivation in anti-CMV IgM-positive cases. Five hundred and twenty four women were recruited: 278 HIV infected and 246 HIV uninfected. Current or active CMV infection defined as IgM positive+low avidity was detected in 4.6% (24/524), 95% confidence interval (CI): 3-6.9 in all women, 5.8% (16/278) in the HIV infected and 3.3% (8/246), 95% CI: 1.4-6.3 in the HIV uninfected. IgG seroprevalence was 99.6% (522/524), 95% CI: 98.6-99.9 in all women. Notably, the difference in the prevalence of active CMV infection between the HIV-infected and HIV-uninfected women was not statistically significant (p = 0.173). The study shows a low prevalence of primary or active CMV infection among the pregnant women, but the IgG seroprevalence suggests high previous CMV exposure. Importantly, CMV seroprevalence was not associated with the HIV status of the women, perhaps due to the ubiquitous exposure of the population to CMV.
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Infecções por Citomegalovirus/epidemiologia , Citomegalovirus/isolamento & purificação , Infecções por HIV/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Cuidado Pré-Natal/estatística & dados numéricos , Adulto , Anticorpos Antivirais/sangue , Coinfecção/sangue , Coinfecção/epidemiologia , Coinfecção/virologia , Estudos Transversais , Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/virologia , Feminino , Infecções por HIV/sangue , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Gravidez , Complicações Infecciosas na Gravidez/sangue , Complicações Infecciosas na Gravidez/virologia , Estudos Soroepidemiológicos , Adulto Jovem , Zimbábue/epidemiologiaRESUMO
Past studies on the relationship between Killer cell Immunoglobulin-like Receptor (KIR) and Human Leukocyte Antigen (HLA) genetic variation and chronic immune activation (CIA) in HIV infection are not uniformly consistent. Moreover, interferon-γ-induced protein 10 (IP-10) is a soluble biomarker of immune activation, with high plasma concentrations predicting accelerated disease progression in HIV infection. Thus, we investigated the association of KIR and HLA-C genetic polymorphisms with plasma IP-10 concentration in 183 treatment-naive chronically HIV-infected adults of Bantu origin from Zimbabwe. KIR genetic variation was determined using allele-specific primer PCR while HLA-C typing was characterized by sequencing. Plasma IP-10 was quantified using enzyme-linked immunosorbent assay. The KIR2DL3 gene was significantly associated with CIA as observed from IP-10 concentrations among KIR2DL3 carriers (265.20 pg/mL, IQR: 179.99-385.19) compared with KIR2DL3 noncarriers (183.56 pg/mL; IQR: 110.98-230.81; p = 0.001) and among KIR2DL3+HLA-C2 carriers (226.23 pg/mL, IQR: 187.96-394.73) compared with KIR2DL3+HLA-C2 noncarriers (212.86 pg/mL, IQR: 160.15-344.99; p = 0.017), respectively. Similarly, IP-10 concentrations were significantly higher (p = 0.030) in the KIR3DS1 carriers (313.86 pg/mL, IQR: 230.05-469.20) compared with KIR3DS1 noncarriers (246.01 pg/mL, IQR: 169.58-373.32). Thus, KIR and HLA-C could be playing important roles in HIV-associated immune activation. The elevation of IP-10 in KIR2DL3 and KIR2DL3+C2 could potentially be explained by increased IFN-γ secretion from activated NK cell activation due to the absence of KIR2DL3's cognate C1 ligand. To the best of our knowledge, this is the first study on a potential link between KIR and HLA-C genetic determinants and plasma IP-10 concentration in this population sample. Future studies are called for in other world populations for biomarkers of disease progression and mechanisms of IP-10 variability in HIV infection.
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Antirretrovirais/uso terapêutico , Quimiocina CXCL10/sangue , Antígenos HLA-C/genética , Polimorfismo Genético/genética , Receptores KIR/genética , Adulto , Alelos , Biomarcadores/sangue , Feminino , Predisposição Genética para Doença , Genótipo , Infecções por HIV , Humanos , Células Matadoras Naturais/metabolismo , Masculino , ZimbábueRESUMO
INTRODUCTION: Vertical transmission of Cytomegalovirus (CMV), resulting in congenital CMV (cCMV) infection could have disabling and potentially fatal effects on the foetus or neonate. Although primary infection probably has a higher risk of leading to cCMV, in highly seropositive populations, a significant risk of vertical transmission is thought to be due to CMV reactivation and or reinfection during pregnancy. In this narrative review, we summarise the prevalence of CMV infection and associated risk factors among pregnant African women, in a setting where primary CMV infection usually occurs during infancy. METHODOLOGY: A systematic search of literature published between January 2000 and January 2019, retrieved on five bibliographic databases was performed. Search for relevant articles was performed using the following keywords: cytomegalovirus, CMV, infection, antenatal infections, pregnancy, pregnant women, gravidity, developing countries and Africa, with appropriate qualifiers such as OR, AND. RESULTS: Systematic searching retrieved 11 relevant original research papers. Prevalence of anti-CMV IgG and IgM antibodies ranged from 60-100% and 0-15.5%, respectively. Prevalence of CMV DNA ranged from 0-29%, depending on the specimen used. However, there was no geographic trend for CMV seroprevalence or CMV DNA prevalence across the African continent. Overall, a substantial percentage of women of reproductive-age were CMV seronegative and at risk of primary infection. Associations of sociodemographic factors with CMV infection were inconsistent across all reviewed studies. CONCLUSIONS: The limited data and inconsistency of findings from the few studies carried out in Africa calls for prospective studies comparing prevalence and outcomes of cCMV in infants born to women with both primary and reactivated CMV in Africa.
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Infecções por Citomegalovirus/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , África/epidemiologia , Citomegalovirus , Feminino , Humanos , Gravidez , Prevalência , Fatores de RiscoRESUMO
BACKGROUND: The inherent risk of developing tuberculosis (TB) in HIV- infected individuals is further enhanced by hypovitaminosis D. Interventions that offset HIV-associated immune deterioration potentially arrest disease progression and incidence of opportunistic infections including TB. Despite conflicting reports on association between vitamin D deficiency (VDD) and risk of TB, vitamin D (VD) supplementation remains a promising intervention. METHODS: We conducted a comparative cross-sectional study on 145 HIV+/pulmonary TB+ (PTB) and 139 HIV+/PTB- hospitalised patients to investigate association of vitamin D status and risk of PTB. Stratified random sampling was used to select archived serum specimens from participants enrolled in a randomised controlled trial (RCT) conducted to investigate the impact of using a point-of-care urine lipoarabinomannan strip test for TB diagnosis. PTB status was confirmed using sputum smear microscopy, culture or GeneXpert MTB/RIF. Serum 25-hydroxyvitamin D [25(OH) D] concentrations were assayed by competitive chemiluminescent immunoassay prior to commencement of anti-TB treatment. Effect of VD status on duration of hospital stay and patient outcomes on follow up at 8 weeks were also investigated. Median serum 25(OH) D concentrations were compared using Mann-Whitney test and covariates of serum VD status were assessed using logistic regression analysis. RESULTS: Overall VDD prevalence in the cohort was 40.9% (95% CI: 35.1-46.8). Median serum 25(OH)D concentrations were significantly higher in HIV+/PTB+ group (25.3 ng/ml, IQR:18.0-33.7) compared to the HIV+/PTB- group (20.4 ng/ml, IQR:14.6-26.9), p = 0.0003. Patients with serum 25(OH) D concentration ≥ 30 ng/ml were 1.9 times more likely to be PTB+ compared to those with serum 25(OH) D concentrations < 30 ng/ml (odds ratio (OR) 1.91; 95% CI 1.1-3.2). PTB-related death was associated with higher odds of having 25(OH) D levels≥30 ng/ml. Age, gender, CD4+ count, combination antiretroviral therapy (cART) status, efavirenz based cART regimen and length of hospital stay were not associated with vitamin D status. CONCLUSIONS: The finding of an association between higher serum 25(OH) D concentrations and active PTB and TB-related mortality among hospitalised HIV-infected patients in the present study is at variance with the commonly reported association of hypovitaminosis and susceptibility to TB. Our findings though, are in concordance with a small pool of reports from other settings.
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Antirretrovirais/uso terapêutico , Infecções por HIV , Tuberculose Pulmonar , Deficiência de Vitamina D , Vitamina D/análogos & derivados , Vitamina D/uso terapêutico , Adulto , Estudos Transversais , Progressão da Doença , Feminino , Infecções por HIV/sangue , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/terapia , Humanos , Incidência , Tempo de Internação/estatística & dados numéricos , Lipopolissacarídeos/análise , Lipopolissacarídeos/urina , Masculino , Infecções Oportunistas/complicações , Fatores de Risco , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/epidemiologia , Urinálise/métodos , Vitamina D/sangue , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/epidemiologia , Vitaminas/uso terapêutico , Zimbábue/epidemiologiaRESUMO
INTRODUCTION: Polymorphisms in killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) gene families are implicated in differential outcomes of HIV infection. However, research findings on the influence of KIR and HLA-C polymorphism on HIV disease progression remain inconclusive. We thus investigated the association of KIR and HLA-C gene polymorphisms with plasma HIV load (VL) and CD4+ T lymphocyte (CD4) count in 183 chronically HIV-infected, combination antiretroviral therapy (cART) naïve Zimbabweans of Bantu origin. METHODOLOGY: The presence or absence of 15 KIR genes were determined using sequence specific primer polymerase chain reaction while HLA-C typing was performed using chain termination DNA sequencing. Plasma VL was determined using the Cavidi Exavir viral load version 3 assay while CD4+ T lymphocytes were enumerated using flow cytometry. VLs and CD4 counts were compared between gene/genotype carriers and non-carriers using Mann-Whitney ranksum test. RESULTS: HLA-C*18:01 allele carriers had a significantly lower median log10 VL (2.87copies/mL [IQR;2.3-3.2]) than the non-C*18:01 carriers (3.33copies/mL [IQR; 2.74-3.9]), p = 0.018. Further, median log10 VL was significantly lower in KIR2DL2+C1 carriers (2.745 [IQR; 2.590-2.745]) than non-KIR2DL2+C1 carriers (3.4 [IQR; 2.746-3.412]), p = 0.041. Comparison of CD4 + T lymphocyte counts between C*08:02 allele carriers and non-C*08:02 carriers showed a significantly higher median CD4 count in C*08:02 carriers (548cells/µL [IQR;410-684]) than in non-carriers (428cells/µL [IQR;388-537]), p = 0.034. CONCLUSION: We conclude that the HLA-C*18:01 and KIR2DL2+C1 genetic variants are associated with low VL while the C*08:02 is associated with high CD4+ T lymphocyte count among cART naïve Zimbabwean adults with chronic HIV infection.
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Infecções por HIV/genética , Infecções por HIV/virologia , Antígenos HLA-C/genética , Receptores KIR2DL2/genética , Adulto , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD4-Positivos/virologia , Estudos Transversais , Frequência do Gene , Infecções por HIV/tratamento farmacológico , Humanos , Polimorfismo Genético , Carga Viral , ZimbábueRESUMO
BACKGROUND: Antiretroviral therapy (ART) to suppress HIV replication has reduced morbidity and mortality yet effectiveness of current HIV drugs is threatened by HIV drug resistance (HIVDR) mutations. OBJECTIVE: To determine HIVDR mutations using proviral DNA from specimens of patients presenting to an HIV treatment clinic. METHODS: DNA from 103 patients, 86 treatment-experienced, 17 treatment-naïve, were genotyped for the HIV-1C reverse transcriptase gene (RT; codons 21-304) using Sanger sequencing and sequences analyzed using Sequencher software. Resistance mutations were interpreted using Stanford HIVDR reference database. RESULTS: Median age was 39 (IQR, 33-46) years and 80% of patients were female. Six-percent (n=6) had at least one HIVDR mutation, comprising NRTI-associated mutations, (M184V, T69D, T69N and V75I); NNRTI-associated mutations (G190A, K103N, V106M, Y181C) and thymidine analogue associated mutations (D67N, K70R, K219Q, L210W, M41L, T215Y). Of the six participants, with at least one HIVDR mutation, all were treatment experienced, five were on tenofovir, lamivudine and nevirapine and one was on tenofovir, lamivudine and atazanavir. There was no difference in median CD4 count and viral loads when patients were compared by presence of HIVDR mutations. CONCLUSION: We demonstrated the use of proviral DNA in HIVDR testing in adult patients and present that all the patients with various kinds of HIVDR mutations were treatment experienced, pointing to the role of drug regimens in driving viral mutations. Thus, the use of proviral DNA has potential to help provide surveillance on risk of HIVDR in HIV-infected individuals who are on treatment, which may assist in corrective treatment.
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BACKGROUND: Chronic immune activation is a feature of HIV infection associated with accelerated HIV disease progression. There is conflicting data on the association of biomarkers of immune activation with traditional markers of HIV disease progression; CD4 counts and viral load (VL). OBJECTIVE: The study aimed to determine the association of biomarkers of immune activation; interferon (IFN)-γ-induced protein 10 (IP-10) and soluble cluster of differentiation 14 (sCD14) in chronic HIV infection with traditional markers of HIV disease progression. METHODS: We collected demographic data, enumerated CD4 counts and quantified VL in 183 antiretroviral therapy (ART)-naive adults with chronic HIV infection. Plasma concentrations of IP-10 and sCD14 were quantified in the ART-naive adults with chronic HIV infection and 75 HIV-uninfected controls. RESULTS: IP-10 concentrations were significantly higher in the HIV-infected group (median; 257.40pg/ml, IQR; 174.08-376.32) than in the HIV-uninfected (median; 86.19pg/ml, IQR; 67.70-116.39) (P<0.001). Similarly, sCD14 concentrations were significantly higher in the HIV-infected (median; 1.45µg/ml, IQR; 1.02-2.16) group than in the controls (median; 0.89µ/ml, IQR; 0.74-1.18) (P<0.001). High log10 IP-10 concentrations were positively correlated with high log10 viral loads (Spearman's correlation coefficient [R]=0.21, P=0.003) and inversely correlated with low CD4 counts (R= -0.19, P=0.011). In contrast, log10 sCD14 was not significantly associated with either log10 viral loads (R=0.03, P=0.707) nor CD4 count (R=-0.04, P=0.568). CONCLUSION: We conclude that plasma sCD14 and IP-10 were elevated in the HIV-infected patients compared to HIV-uninfected individuals possibly due to on-going immune activation. In addition, plasma high concentrations of IP-10 but not sCD14 concentrations are associated with high VL and low CD4 count.
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Killer cell immunoglobulin-like receptors (KIRs) mediate natural killer cell function through interaction with their cognate human leukocyte antigen ligands. Thus, KIR gene variants have been implicated in resistance or susceptibility to viral infections. However, research on the role of these variants remains contradictory and inconclusive. In the present study, we investigated KIR gene content diversity and its association with human immunodeficiency virus (HIV) infection in an adult Black Zimbabwean population. Presence or absence of 15 KIR genes was determined in 189 HIV-infected adults and 97 HIV-uninfected blood donors using sequence specific primer polymerase chain reaction. Frequencies of KIR genes, genotypes, and haplotypes were compared between the cases and controls to identify putative associations between KIR gene variants and HIV status. We report in this study the frequencies of 15 KIR genes and 43 KIR genotypes (40 known and 3 novel) among Zimbabweans. Importantly, the frequency of the inhibitory KIR2DL2 gene was significantly higher in the uninfected group (62%) compared to the HIV-infected group (47%) (OR = 0.55, 95% CI: 0.33-0.90, p = 0.019). KIR2DL2/2DL2 homozygosity was also significantly higher in the uninfected group (35%) compared to HIV-infected group (53%) (OR = 0.33, 95% CI: 0.16-0.72, p = 0.005) under a recessive model. We conclude that the KIR2DL2 gene may be involved in protection against HIV infection. It may be possible that inhibitory KIR genes may have an important role to play in HIV acquisition among populations of African origin in whom the activating KIR genes are less frequent compared to among Caucasians.
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Predisposição Genética para Doença/genética , Infecções por HIV/genética , Adulto , Feminino , Frequência do Gene/genética , Genótipo , Haplótipos/genética , Humanos , Masculino , Receptores KIR/genética , ZimbábueRESUMO
The extremely high prevalence of HIV/AIDS in sub-Saharan Africa and limitations of current antiretroviral medicines demand new tools to optimize therapy such as pharmacogenomics for person-to-person variations. African populations exhibit greater genetic diversity than other world populations, thus making it difficult to extrapolate findings from one population to another. Nevirapine, an antiretroviral medicine, displays large plasma concentration variability which adversely impacts therapeutic virological response. This study, therefore, aimed to identify sources of variability in nevirapine pharmacokinetics and pharmacodynamics, focusing on genetic variation in CYP2B6 and CYP1A2. Using a cross-sectional study design, 118 HIV-infected adult Zimbabwean patients on nevirapine-containing highly active antiretroviral therapy (HAART) were characterized for three key functional single nucleotide polymorphisms (SNPs), CYP2B6 c.516G>T (rs3745274), CYP2B6 c.983T>C (rs28399499), and CYP1A2 g.-163C>A (rs762551). We investigated whether genotypes at these loci were associated with nevirapine plasma concentration, a therapeutic biomarker, and CD4 cell count, a biomarker of disease progression. CYP2B6 and CYP1A2 were chosen as the candidate genes based on reports in literature, as well as their prominence in the metabolism of efavirenz, a drug in the same class with nevirapine. Nevirapine plasma concentration was determined using LC-MS/MS. The mean nevirapine concentration for CYP2B6 c.516T/T genotype differed significantly from that of 516G/G (p < 0.001) and 516G/T (p < 0.01) genotypes, respectively. There were also significant differences in mean nevirapine concentration between CYP2B6 c.983T > C genotypes (p = 0.04). Importantly, the CYP1A2 g.-163C>A SNP was significantly associated with the pharmacodynamics endpoint, the CD4 cell count (p = 0.012). Variant allele frequencies for the three SNPs observed in this Zimbabwean group were similar to other African population groups but different to observations among Caucasian and Asian populations. We conclude that CYP2B6 c.516G>T and CYP2B6 c.983T>C could be important sources of nevirapine pharmacokinetic variability that could be considered for dosage optimization, while CYP1A2 g.-163C>A seems to be associated with HIV disease progression. These inter- and intra-population pharmacokinetic and pharmacodynamics differences suggest that a single prescribed dosage may not be appropriate for the treatment of disease. Further research into a personalized nevirapine regimen is required.