Association of HLA genotypes with Beta-lactam antibiotic hypersensitivity in children.

BACKGROUND: Beta-lactam (BL) antibiotics hypersensitivity is common in children. Clinical manifestation of BL hypersensitivity varies from mild to severe cutaneous adverse drug reactions (SCARs). OBJECTIVE: To determine the association of HLA genotype and BL hypersensitivity and the prevalence of true drug allergy in patients with history of BL hypersensitivity. METHODS: A case-control study was performed in 117 children with aged 1-18 years. Children with history of non-SCARs BL hypersensitivity were evaluated for true drug hypersensitivity including skin test and drug provocation test. Tolerant control patients were children who could tolerate BL for at least 7 days without hypersensitivity reaction. HLA genotype (HLA-A, HLA-B, HLA-C and HLA-DRB1) were performed in 24 cases and 93 tolerant controls using PCR-SSO (polymerase chain reaction - sequence specific oligonucleotide probes). RESULTS: There were association of HLA-C*04:06 (OR = 13.14, 95%CI: 1.3-137.71; p = 0.027), and HLA-C*08:01 (OR = 4.83, 95%CI: 1.93-16.70; p = 0.016) with BL hypersensitivity. HLA-B*48:01 was strongly associated with immediate reaction from BL hypersensitivity (OR = 37.4, 95%CI: 1.69-824.59; p = 0.016) while HLA-C*04:06, HLA-C*08:01 and HLA-DRB1*04:06 were associated with delayed reaction (p < 0.05). Among 71 cases who were newly evaluated for BL hypersensitivity, only 7 cases (9.8%) had true BL hypersensitivity. CONCLUSIONS: Less than 10% of children with suspected of BL hypersensitivity have true hypersensitivity. There might be a role of HLA-B, HLA-C and HLA-DRB1 genotype in predicting BL hypersensitivity in Thai children.

Association of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis with the HLA-B75 serotype or HLA-B*15:21 allele in Filipino patients.

A case-control study was conducted to investigate the association of HLA-A alleles, HLA-B alleles including HLA-B*15:02 and HLA-B75 serotype with carbamazepine-induced SJS/TEN in Filipino patients. A retrospective review of medical records was performed. Pertinent clinical data were collected. Eight (8) carbamazepine-induced SJS/TEN cases and 32 tolerant controls were recruited. Genomic DNA was extracted from the saliva samples and genotyping was performed by employing allele-specific polymerase chain reaction. Data were analyzed using the Fisher's exact test, Mann-Whitney U test, univariate logistic regression, and multivariate logistic regression. Single allele association analysis was done. The strength of association was expressed as odds ratio with 95% confidence interval. Positive predictive value, negative predictive value, sensitivity, and specificity were computed. Of all the alleles tested, the HLA-B75 serotype (p = 0.007, OR = 23.25, 95% CI = 2.33-232.21) and HLA-B*15:21 (p = 0.026, OR = 7.53, 95% CI = 1.27-44.79) were significantly associated with carbamazepine-induced SJS/TEN. The HLA-B75 serotype or HLA-B*15:21 allele may be used as a genetic risk assessment prior to prescription for prevention of carbamazepine-induced SJS/TEN in Filipino patients.

Genome-wide association study of neovascular age-related macular degeneration in the Thai population.

We performed a genome-wide association study on 377 cases of neovascular age-related macular degeneration (AMD) and 1074 controls to determine the association of previously reported genetic variants associated with neovascular AMD in the Thai population. All patients were of Thai ancestry. We confirmed the association of age-related maculopathy susceptibility 2 (ARMS2) rs10490924 (P=7.38 × 10-17), HTRA1 rs11200638 (P=5.47 × 10-17) and complement factor H gene (CFH) rs800292 (P=2.53 × 10-8) with neovascular AMD, all loci passing the genome-wide significance level (P<5.22 × 10-8). We also found association of the previously reported CFH rs10737680 (P=1.76 × 10-6) locus in the discovery sample. Two loci not previously reported to be associated with neovascular AMD were selected for replication in 222 cases and 623 controls. The loci included LINCO1317 rs6733379 and rs2384550 on chromosome 12. LINCO1317 rs6733379 (P=3.85 × 10-2) remained significantly associated with neovascular AMD after replication. In conclusion, we confirm that ARMS2, HTRA1 and CFH variants are associated with neovascular AMD in the Thai population. Findings from this study also suggest that variants contributing to the susceptibility of neovascular AMD in the Thai population are mostly similar to other Asians with additional local genetic risks that may specifically be identified in Thai population.

Pathogen lineage-based genome-wide association study identified CD53 as susceptible locus in tuberculosis.

Tuberculosis (TB) is known to be affected by host genetic factors. We reported a specific genetic risk factor through a genome-wide association study (GWAS) that focused on young age onset TB. In this study, we further focused on the heterogeneity of Mycobacterium tuberculosis (M. tb) lineages and assessed its possible interaction with age at onset on host genetic factors. We identified the pathogen lineage in 686 Thai TB cases and GWAS stratified by both infected pathogen lineage information and age at onset revealed a genome-wide significant association of one single-nucleotide polymorphism (SNP) on chromosome 1p13, which was specifically associated with non-Beijing lineage-infected old age onset cases (P=2.54E-08, OR=1.74 (95% CI=1.43-2.12)), when we compared them to the population-matched healthy controls. This SNP locates near the CD53 gene, which encodes a leukocyte surface glycoprotein. Interestingly, the expression of CD53 was also correlated with the patients' active TB status. This is the first report of a pathogen lineage-based genome-wide association study. The results suggested that host genetic risk in TB is depended upon the pathogen genetic background and demonstrate the importance of analyzing the interaction between host and pathogen genomes in TB.

Associations between HLA class I and cytochrome P450 2C9 genetic polymorphisms and phenytoin-related severe cutaneous adverse reactions in a Thai population.

BACKGROUND: Phenytoin is one of the most common causative drugs of several types of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS). Genetic polymorphisms of the human leukocyte antigens (HLA) and cytochromes P450 (CYP) have been proposed as key elements for the susceptibility to phenytoin-related SCAR in certain ethnicities. This study investigated the associations between the genetic polymorphisms of HLA class I and CYP2C9 and phenytoin-related SCAR in a Thai population. MATERIALS AND METHODS: Sixty phenytoin-related SCAR (i.e. 39 SJS/TEN and 21 DRESS) and 92 phenytoin-tolerant patients were enrolled in the study. The genotypes of HLA class I and CYP2C9 were determined. RESULTS: Six HLA alleles including HLA-A*33:03, HLA-B*38:02, HLA-B*51:01, HLA-B*56:02, HLA-B*58:01, and HLA-C*14:02 were significantly associated with phenytoin-related SJS/TEN, whereas only the HLA-B*51:01 was significantly associated with phenytoin-related DRESS. The odds ratios of phenytoin-related SJS/TEN in the patients who carried one of these alleles ranged from 4- to 10-fold. The frequencies of patients who carried the HLA-B*15:02 in the SJS/TEN (12.82%) or the DRESS (9.52%) groups were not significantly different from that of the controls (14.13%). The higher risk of phenytoin-related SJS/TEN was observed in the patients with CYP2C9*3 (odds ratio=4.30, 95% confidence interval=1.41-13.09, P<0.05). CONCLUSION: Neither SJS/TEN nor DRESS caused by phenytoin was significantly associated with the HLA-B*15:02. The CYP2C9*3 variant was significantly associated with phenytoin-related SJS/TEN, but not DRESS. Certain alleles of HLA, particularly HLA-B*56:02, were significantly associated with phenytoin-related SCAR in the study population.

Association of BAK1 single nucleotide polymorphism with a risk for dengue hemorrhagic fever.

BACKGROUND: Dengue hemorrhagic fever (DHF) is a severe life-threatening form of dengue infection. Low platelet count is one of the characteristic clinical manifestations in patients with severe dengue. However, little is known about genetic factors in the host that cause low platelet count in patients with dengue. METHODS: A previous genome-wide association study of hematological and biochemical traits identified single nucleotide polymorphisms (SNPs) associated with low platelet count in healthy subjects. To examine the possible association of these SNPs with DHF, 918 Thai patients with dengue [509 patients with DHF and 409 with dengue fever (DF)] were genotyped for five SNPs: rs5745568 in BAK1, rs6141 in THPO, rs6065 in GP1BA, rs739496 in SH2B3, and rs385893 in RCL1. In addition, rs4804803 in CD209, that has been reported to be associated with dengue infection, was also genotyped to examine if rs4804803 affects the association detected in this study. RESULTS: The allele frequencies of each SNP were compared between the DHF and DF groups. Among the five SNPs, the G allele of rs5745568 in BAK1 was significantly associated with a risk for DHF [P = 0.006 and crude odd ratio (95 % confidence interval) = 1.32 (1.09-1.60)]. The association of this allele with DHF was also significant in a logistic regression analysis adjusted for age, sex, hospital (i.e., geographic region), immune status (i.e., primary or secondary infection), and virus serotype [P = 0.016 and adjusted odd ratio (95 % confidence interval) = 1.29 (1.05-1.58)]. The result was not influenced by rs4804803 [P = 0.0167 and adjusted OR (95 % CI) = 1.29 (1.05-1.58)]. No other SNPs including rs4804803 showed significant association. CONCLUSIONS: The low-level constitutive production of platelets caused by the G allele of rs5745568 seems to increase the risk of bleeding in dengue infection. Our results suggest that BCL-2 homologous antagonist/killer (BAK) protein, encoded by BAK1, plays a crucial role in the pathogenesis of DHF.

Comparison of genetic variation in drug ADME-related genes in Thais with Caucasian, African and Asian HapMap populations.

The objectives of this study are to investigate allele frequencies of drug absorption, distribution, metabolism and elimination (ADME)-related genes in the Thai population and to compare these genes to HapMap populations including Caucasians (CEU), Africans (YRI) and Asians (CHB/JPT). Genetic variations of drug ADME-related genes in 190 Thais were investigated using drug metabolizing enzymes and transporters (DMET) plus genotyping system. We examined 1936 single nucleotide polymorphisms (SNPs) of 225 genes that have documented functional and clinical significances in phase I and phase II drug metabolism enzymes, drug transporters and other genes involved in ADME processes. Distributions of genotyping data from Thai were compared with other HapMap populations including Caucasian, African and Asian populations. The analysis demonstrated 43 SNPs with statistical significance comparing among five populations. However, only 26 SNPs showed statistical significance in pair-wise comparisons between Thai versus CEU and Thai versus CHB/JPT. These 26 SNPs belong to 13 groups of drug ADME-related genes which are CYP2A6, CYP3A5, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, VKORC1, COMT, NAT2, TPMT, UGT1A1 and SLCO1B1. These genes demonstrated clinical significances as previously observed in many studies. The results could explain clinical variability in pharmacokinetics and pharmacodynamics of drugs in Thais based on genetic variations in drug ADME-related gene emphasized in this article.

Association of HLA genotypes with phenobarbital hypersensitivity in children.

OBJECTIVE: Phenobarbital hypersensitivity is one of the common drug hypersensitivity syndromes in children. Clinical symptoms of phenobarbital hypersensitivity vary from maculopapular rashes (MPs) to severe cutaneous adverse drug reactions (SCARs) including drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Drug hypersensitivity has been demonstrated to be associated with variations in the HLA genotypes. This study was to investigate the association between the variations of HLA genotypes and phenobarbital hypersensitivity in Thai children. METHODS: The cases were Thai children, between 0 and 18 years of age, who were diagnosed with phenobarbital hypersensitivity, which included SCARs and MPs. The control patients were Thai children of a corresponding age who had taken phenobarbital for at least 12 weeks without any hypersensitivity reaction. Blood samples were collected for HLA genotyping by using a reverse-sequence-specific oligonucleotide (SSO) probes method. The carrier rates of HLA alleles were compared between 47 cases (27 SCARs and 20 MPs) and 54 controls. RESULTS: The carrier rates of HLA-A*01:01 and HLA-B*13:01 were significantly higher in the phenobarbital-induced SCARs than in the tolerant controls (18.5% vs. 1.85%, p = 0.01, odds ratio [OR] 11.66, 95% confidence interval [CI] 1.21-578.19; 37.04% vs. 11.11%, p = 0.009, OR 4.60, 95%CI 1.29-17.98). There was a trend of a higher carrier rate of HLA-C*06:02 in the phenobarbital-induced SCARs when compared with those in the tolerant controls (29.63% vs. 11.11%, p = 0.059, OR 3.31, 95% CI 0.88-13.31). In contrast to the phenobarbital-induced SCARs, only the HLA-A*01:01 carrier rate in the phenobarbital-induced MPs was significantly higher than those in the tolerant controls (20% vs. 1.85%, p = 0.017, OR 12.69, 95% CI 1.15-661.62). SIGNIFICANCE: An association between phenobarbital hypersensitivity and HLA-A*01:01 and HLA-B*13:01 has been demonstrated in Thai children.

Candidate HLA genes for prediction of co-trimoxazole-induced severe cutaneous reactions.

BACKGROUND: Co-trimoxazole is a sulfonamide-containing antibiotic that is effective in the treatment of several infections and for prophylaxis of Pneumocystis jiroveci pneumonia. This drug has been reported as a common culprit drug for the Stevens-Johnson syndrome (SJS) and for toxic epidermal necrolysis (TEN). Human leukocyte antigens (HLAs) play a key role in the immunopathogenesis of severe cutaneous reactions induced by several drugs. This study investigated the association between the HLA class I and HLA-DRB1 polymorphisms and co-trimoxazole-induced SJS/TEN in a Thai population. METHODS: Forty-three patients with co-trimoxazole-induced SJS/TEN and 91 co-trimoxazole-tolerant patients were enrolled in the study. HLA class I and HLA-DRB1 were genotyped using the reverse sequence-specific oligonucleotide probe method. RESULTS: The frequencies of three alleles of HLA, namely HLA-B*15:02, HLA-C*06:02, and HLA-C*08:01, were significantly higher in the co-trimoxazole-induced SJS/TEN group compared with controls. The risks for co-trimoxazole-induced SJS/TEN in patients with the HLA-B*15:02, HLA-C*06:02, or HLA-C*08:01 allele were about 3-11-fold higher when compared with those who did not carry one of these alleles. Individuals who carried the HLA-B*15:02-C*08:01 haplotype had a 14-fold higher risk for co-trimoxazole-induced SJS/TEN. CONCLUSION: Evidence of associations between co-trimoxazole-induced SJS/TEN and HLA alleles including HLA-B*15:02, HLA-C*06:02, and HLA-C*08:01 were found in the study population. These findings may suggest that apart from the HLA molecules, other molecules involved in the molecular pathogenesis of these severe cutaneous adverse drug reactions may play an important role in the susceptibility of individuals to SJS/TEN caused by co-trimoxazole.

Association analysis of CYP2C9*3 and phenytoin-induced severe cutaneous adverse reactions (SCARs) in Thai epilepsy children.

CYP2C9 is the key enzyme in aromatic antiepileptic drugs (AEDs) metabolism. CYP2C9*3 is a loss of function polymorphism. This study was designed to investigate genetic association between CYP2C9*3 and aromatic AED-induced severe cutaneous adverse reactions (SCARs) in Thai children. The 37 aromatic AED-induced SCARs patients (20 phenobarbital and 17 phenytoin) and 35 tolerances (19 phenobarbital and 16 phenytoin) were enrolled. CYP2C9*3 was genotyped by allele-specific PCRs. The association between CYP2C9*3 with phenytoin-induced SCARs and phenobarbital-induced SCARs were analyzed in comparison with tolerances and healthy samples. Significant association between phenytoin-induced SCARs and CYP2C9*3 was discovered (odds ratio=14.52; 95% confidence interval (CI)=1.18-∞, P-value=0.044). CYP2C9*3 was not associated with phenobarbital-induced SCARs. This study is the first report of CYP2C9*3 association to phenytoin-induced SCARs in Thai epileptic children. The CYP2C9*3 is a reasonable predictive genetic marker to anticipate SCARs from phenytoin.

A replication study confirms the association of GWAS-identified SNPs at MICB and PLCE1 in Thai patients with dengue shock syndrome.

BACKGROUND: Dengue shock syndrome (DSS), a severe life-threatening form of dengue infection, mostly occurs in children. A recent genome wide association study (GWAS) identified two SNPs, rs3132468 of major histocompatibility complex class I polypeptide-related sequence B (MICB) and rs3765524 of phospholipase C, epsilon 1 (PLCE1), associated with DSS in Vietnamese children. In this study, to examine whether an identical association is found in a different population, the association of these two SNPs with DSS was assessed in Thai children with dengue. METHODS: The rs3132468 and rs3765524 SNPs were genotyped in 917 Thai children with dengue: 76 patients with DSS and 841 patients with non-DSS. The allele frequencies were compared between DSS and non-DSS groups by one-sided Fisher's exact test. The association of rs3132468 and rs3765524 with the mRNA expression levels of MICB and PLCE1 were assessed in EBV-transformed lymphoblastoid cell lines. RESULTS: The reported DSS-risk alleles were significantly associated with DSS in Thai patients with dengue (one-sided P = 0.0213 and odds ratio [OR] = 1.58 for rs3132468-C and one-sided P = 0.0252 and OR = 1.49 for rs3765524-C). The rs3132468-C allele showed a significant association with lower mRNA level of MICB (P = 0.0267), whereas the rs3765524-C allele did not. These results imply that the MICB molecule may play an important role in the prevention of DSS in dengue infection. CONCLUSIONS: Together with previous association studies, we conclude that rs3132468-C at MICB and rs3765524-C at PLCE1 confer risk of DSS in Southeast Asians.

Incidence and predictors of regimen-modification from first-line antiretroviral therapy in Thailand: a cohort study.

BACKGROUND: Antiretroviral therapy markedly reduced mortality in HIV-infected individuals. However, in the previous studies, up to 50% of patients are compelled to modify their regimen in middle and low-income countries where salvage drug is still limited. This cohort study aimed to investigate the incidence and predictors of regimen modification from the first-line antiretroviral regimen in northern Thailand. METHODS: All HIV-infected patients starting antiretroviral therapy (ART) with generic drug (GPOvir®; stavudine, lamivudine and nevirapine) at a governmental hospital in northern Thailand from 2002 to 2007 were recruited. Baseline characteristics and detailed information of regimen modification until the end of 2010 were ascertained from cohort database and medical charts. As a potential genetic predictor of regimen modification, HLA B allele was determined by bead-based array hybridization (WAKFlow® HLA typing kit). We investigated predictors of the regimen modification using Cox's proportional hazard models. RESULTS: Of 979 patients, 914 were eligible for the analysis. The observed events of regimen modification was 377, corresponding to an incidence 13.8/100 person-year-observation (95% CI:12.5-15.3) over 2,728 person years (PY) follow up. The main reasons for regimen modification were adverse effects (73.5%), especially lipodystrophy (63.2%) followed by rash (17.7%). Sixty three patients (17.1%) changed the regimen due to treatment failure. 2% and 19% of patients had HLA-B*35:05 and B*4001, respectively. HLA-B*35:05 was independently associated with rash-related regimen modification (aHR 7.73, 95% CI:3.16-18.9) while female gender was associated with lipodystrophy (aHR 2.11, 95% CI:1.51-2.95). Female gender (aHR 0.54, 95% CI: 0.30-0.96), elder age (aHR 0.56, 95% CI: 0.32-0.99) and having HLA-B*40:01 (aHR 0.29, 95% CI: 0.10-0.82) were protective for treatment failure related modification. CONCLUSION: HLA-B*35:05 and female gender were strong predictors of regimen modification due to rash and lipodystrophy, respectively. Female gender, elder age, and having HLA-B*40:01 had protective effects on treatment failure-related regimen modification. This study provides further information of regimen modification for future tailored ART in Asia.

Frequencies of HLA-B alleles in Indonesian Malay Ethnic.

Background: The HLA-B alleles have been used as a marker to predict drug-induced adverse reactions and as a major contributor to hypersensitivity reactions. We examined the feasibility of HLA-B alleles as pharmacogenomic markers of drug-induced hypersensitivity in an Indonesian Malay Ethnic. Methods: Fifty-eight Indonesian individuals of Malay ethnicity were enrolled in this study. HLA-B alleles were determined using reverse sequence-specific oligonucleotide probe coupled with xMAP technology. Results: HLA-B*15:02 (15.52%), HLA-B*35:05 (9.48%), and HLA-B*07:05 (7.76%) were frequent alleles in the Indonesian Malay ethnic populations. We discovered at least eight pharmacogenomics markers of drug-induced hypersensitivity: HLA-B*15:02, HLA-B*15:21, HLA-B*13:01, HLA-B*35:05, HLA-B*38:02, HLA-B*51:01, HLA-B*57:01, and HLA-B*58:01. HLA-B*15:02 was in the same serotype group with HLA-B*15:21, which is a B-75 serotype associated with genetic predisposition for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis. The Indonesian population, represented by Malay, Javanese, and Sundanese ethnicities, was similar to South East Asian, Han Chinese, and Taiwanese populations based on HLA-B*15:02 frequency as the most common allele found in Malay ethnics. Conclusion: We provided valuable information on the frequency of drug hypersensitivity-associated HLA-B alleles in Indonesian Malay ethnic population, which can improve treatment safety.

Multi-platform whole genome sequencing for tuberculosis clinical and surveillance applications.

Whole genome sequencing (WGS) of Mycobacterium tuberculosis offers valuable insights for tuberculosis (TB) control. High throughput platforms like Illumina and Oxford Nanopore Technology (ONT) are increasingly used globally, although ONT is known for higher error rates and is less established for genomic studies. Here we present a study comparing the sequencing outputs of both Illumina and ONT platforms, analysing DNA from 59 clinical isolates in highly endemic TB regions of Thailand. The resulting sequence data were used to profile the M. tuberculosis pairs for their lineage, drug resistance and presence in transmission chains, and were compared to publicly available WGS data from Thailand (n = 1456). Our results revealed isolates that are predominantly from lineages 1 and 2, with consistent drug resistance profiles, including six multidrug-resistant strains; however, analysis of ONT data showed longer phylogenetic branches, emphasising the technologies higher error rate. An analysis incorporating the larger dataset identified fifteen of our samples within six potential transmission clusters, including a significant clade of 41 multi-drug resistant isolates. ONT's extended sequences also revealed strain-specific structural variants in pe/ppe genes (e.g. ppe50), which are candidate loci for vaccine development. Despite some limitations, our results show that ONT sequencing is a promising approach for TB genomic research, supporting precision medicine and decision-making in areas with less developed infrastructure, which is crucial for tackling the disease's significant regional burden.

A Multiplexed Cas13-Based Assay with Point-of-Care Attributes for Simultaneous COVID-19 Diagnosis and Variant Surveillance.

Point-of-care (POC) nucleic acid detection technologies are poised to aid gold-standard technologies in controlling the COVID-19 pandemic, yet shortcomings in the capability to perform critically needed complex detection-such as multiplexed detection for viral variant surveillance-may limit their widespread adoption. Herein, we developed a robust multiplexed clustered regularly interspaced short palindromic repeats (CRISPR)-based detection using LwaCas13a and PsmCas13b to simultaneously diagnose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pinpoint the causative SARS-CoV-2 variant of concern (VOC)-including globally dominant VOCs Delta (B.1.617.2) and Omicron (B.1.1.529)-all the while maintaining high levels of accuracy upon the detection of multiple SARS-CoV-2 gene targets. The platform has several attributes suitable for POC use: premixed, freeze-dried reagents for easy use and storage; convenient direct-to-eye or smartphone-based readouts; and a one-pot variant of the multiplexed detection. To reduce reliance on proprietary reagents and enable sustainable use of such a technology in low- and middle-income countries, we locally produced and formulated our own recombinase polymerase amplification reaction and demonstrated its equivalent efficiency to commercial counterparts. Our tool-CRISPR-based detection for simultaneous COVID-19 diagnosis and variant surveillance that can be locally manufactured-may enable sustainable use of CRISPR diagnostics technologies for COVID-19 and other diseases in POC settings.

Genome-wide association studies of tuberculosis in Asians identify distinct at-risk locus for young tuberculosis.

Tuberculosis (TB) is one of the most devastating chronic infectious diseases, but the role of host genetics in disease development after infection in this disease remains unidentified. Genome-wide association studies (GWASs) in Thais and Japanese were carried out and separately analyzed, attempted replication, then, combined by meta-analysis were not yielding any convincing association evidences; these results suggested that moderate to high effect-size genetic risks are not existed for TB per se. Because of failure in replication attempt of the top 50 single-nucleotide polymorphisms (SNPs) identified form meta-analysis data, we empirically split TB cases into young TB case/control data sets (GWAS-T(young)=137/295 and GWAS-J(young)=60/249) and old TB case/control data sets (GWAS-T(old)=300/295 and GWAS-J(old)=123/685), re-analyzed GWAS based on age-stratified data and replicated the significant findings in two independent replication samples (young TB; Rep-T(young)=155/249, Rep-J(young)=41/462 and old TB; Rep-T(old)=212/187, Rep-J(old)=71/619). GWAS and replication studies conducted in young TB identified at-risk locus in 20q12. Although the locus is located in inter-genic region, the nearest genes (HSPEP1-MAFB) from this locus are promising candidates for TB susceptibility. This locus was also associated with anti-TNF responsiveness, drug with increased susceptibility for TB. Moreover, eight SNPs in an old TB meta-analysis and six SNPs in young TB meta-analysis provided replication evidences but did not survive genome-wide significance.These findings suggest that host genetic risks for TB are affected by age at onset of TB, and this approach may accelerate the identification of the major host factors that affect TB in human populations.

Influence of ABCB-1 C3435T polymorphisms on plasma nevirapine and efavirenz levels and their effects on virologic and immunological outcomes in HIV/TB co-infected Thai adults under anti-retroviral therapy.

ATP-binding cassette, sub-family B (encoded by ABCB-1 or MDR-1) has an important role in cellular export of antiretroviral agents. A previous study showed that ABCB-1 C3435T polymorphism affects plasma efavirenz and nelfinavir concentrations and rate of CD4+ T cell recovery after starting antiretroviral treatment (ART). The present study examined the influence of ABCB-1 polymorphisms on plasma nevirapine and efavirenz levels when co-administered with rifampicin in 124 HIV/TB patients who received nevirapine- (400 mg/day) (n = 59) and efavirenz- (600 mg/day) (n = 65) based ART. ABCB-1 C3435T polymorphisms were genotyped using real-time PCR. CD4 T cell counts and HIV-1 viral RNA were evaluated in response to ART. The frequencies of CC, CT and TT genotypes of ABCB-1 C3435T polymorphism were 34% (n = 42), 55% (n = 68) and 12% (n = 14), respectively. Contrary to the previous report, no association was found among these genotypes and plasma drug concentrations at weeks 6 and 12 of ART and after rifampicin discontinuation. We also observed no differences in CD4+ T cell recovery rate among different ABCB-1 C3435T genotypes. In nevirapine group, however, all the patients with CT genotype achieved HIV-1 RNA levels of < 50 copies/ml, while 67% of those with TT and 95% with CC genotypes achieved < 50 copies/ml (p = 0.040). These data suggested that ABCB-1 C3435T polymorphisms do not affect plasma nevirapine and efavirenz concentrations in HIV/TB co-infected Thai patients or their immunological outcome, but had an effect on virologic outcome in the nevirapine-treated group.

Early treatment of Favipiravir in COVID-19 patients without pneumonia: a multicentre, open-labelled, randomized control study.

We investigated Favipiravir (FPV) efficacy in mild cases of COVID-19 without pneumonia and its effects towards viral clearance, clinical condition, and risk of COVID-19 pneumonia development. PCR-confirmed SARS-CoV-2-infected patients without pneumonia were enrolled (2:1) within 10 days of symptomatic onset into FPV and control arms. The former received 1800 mg FPV twice-daily (BID) on Day 1 and 800 mg BID 5-14 days thereafter until negative viral detection, while the latter received only supportive care. The primary endpoint was time to clinical improvement, defined by a National Early Warning Score (NEWS) of ≤1. 62 patients (41 female) comprised the FPV arm (median age: 32 years, median BMI: 22 kg/m²) and 31 patients (19 female) comprised the control arm (median age: 28 years, median BMI: 22 kg/m²). The median time to sustained clinical improvement, by NEWS, was 2 and 14 days for FPV and control arms, respectively (adjusted hazard ratio (aHR) of 2.77, 95% CI 1.57-4.88, P < .001). The FPV arm also had significantly higher likelihoods of clinical improvement within 14 days after enrolment by NEWS (79% vs. 32% respectively, P < .001). 8 (12.9%) and 7 (22.6%) patients in FPV and control arms developed mild pneumonia at a median (range) of 6.5 (1-13) and 7 (1-13) days after treatment, respectively (P = .316). All recovered well without complications. We can conclude that early treatment of FPV in symptomatic COVID-19 patients without pneumonia was associated with faster clinical improvement.Trial registration: Thai Clinical Trials Registry identifier: TCTR20200514001.

SARS-CoV-2 Seroprevalence in Unvaccinated Adults in Thailand in November 2021.

Between the first case of COVID-19 in January 2020 and the end of 2021, Thailand experienced four waves of the epidemic. The third and fourth waves were caused by the alpha and delta strains from April 2021 to November 2021. Serosurveillance studies provide snapshots of the true scale of the outbreak, including the asymptomatic infections that could not be fully captured by a hospital-based case detection system. We aimed to investigate the distribution of SARs-CoV-2 seroprevalence in unvaccinated adults after the delta wave outbreak. From November to December 2021, we conducted a cross-sectional survey study in 12 public health areas (PHAs) across Thailand. A total of 26,717 blood samples were collected and tested for SARs-CoV-2 antibodies (anti-S IgG) using a qualitative immunoassay. The results showed that seropositive prevalence in this cohort was 1.4% (95% CI: 1.24 to 1.52). The lowest prevalence was in the northern region (PHA 1) and in central Thailand (PHA 3) at 0.4% (95% CI: 0.15 to 0.95), while the highest was in the southern region of Thailand (PHA 12) at 5.8% (95% CI: 4.48 to 7.29). This seropositive prevalence was strikingly lower than the reports from other countries. Our serosurveillance results suggest that the vaccination of unvaccinated groups should be accelerated, especially in the public health areas with the lowest seroprevalence.

HLA-A*24:07 as a potential biomarker for carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Filipino patients.

Aim: A case-control study was conducted in Filipino patients to determine the association between HLA alleles and carbamazepine-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Materials & methods: A retrospective review of medical records and data collection were performed. A total of 10 carbamazepine-induced SJS/TEN cases and 40 tolerant controls were recruited. Genomic DNA extracted from saliva samples was genotyped. Statistical analysis was done. Results: The HLA-B75 serotype (p = 0.003; odds ratio [OR] = 13.8; 95% CI = 2.5-76.8), HLA-B*15:21 (p = 0.041; OR = 4.7; 95% CI = 1.1-20.8) and HLA-A*24:07 (p = 0.032; OR = 6; 95% CI = 1.2-30.7) were significantly associated with carbamazepine-induced SJS/TEN. Conclusion: The HLA-B75 serotype, HLA-B*15:21 or HLA-A*24:07 may be used for pharmacogenetic screening prior to prescribing carbamazepine in Filipinos.