Determinants of Successful Human Immunodeficiency Virus Treatment Outcomes: A Linkage of National Data Sources in Malaysia.

Background: Concerted efforts have been undertaken to reduce the human immunodeficiency virus (HIV) infection by the year 2030 in Malaysia. A situational analysis of the performance of successful HIV treatment and its determinants is vital; however, this information remains scarce. This study aimed to identify the determinants of undetectable viral load among people living with HIV (PLHIV). Methods: Newly diagnosed HIV cases (n = 493) registered under the Malaysia HIV/AIDS-related national databases from June 2018 to December 2019 were studied. The deterministic matching method was applied to link the records in two national databases (at Kuala Lumpur and Putrajaya Federal Territories Health Department, JKWPKLP HIV line-listing database and National AIDS Registry). Successful HIV treatment, an outcome variable, was measured by the undetectable viral load < 200 copies/mL after 1 year of antiretroviral therapy initiation. Logistic regression analysis was applied in the current study. Results: Results showed that 454/493 (92.2%; 95% confidence interval [CI]: 89.8%, 94.6%) PLHIV had successful HIV treatment. Study participants had a mean (SD) age of 30 (8.10) years old, predominantly male (96.1%) and sexually transmission (99.9%). The multiple logistic regression analysis revealed two significant determinants including the timing of ART initiation (AOR = 3.94; 95% CI: 1.32, 11.70; P = 0.014) and establishment of Sexually Transmitted Infection Friendly Clinic (STIFC) (AOR = 3.40; 95% CI: 1.47, 7.85; P = 0.004). Non-significant variables included gender, education level, HIV risk exposure, and co-infections of tuberculosis and Hepatitis C. Conclusion: JKWPKLP is on the right track to achieving universal treatment as a prevention strategy. Reinforcement of early ART initiation and establishment of STIFC are recommended.

A study on the genetic polymorphisms of CYP3A5 among the Orang Asli in Malaysia using a next generation sequencing platform.

BACKGROUND: CYP3A5 is the predominant sub-family of biotransformation enzymes in the liver and the genetic variations in CYP3A5 are an important determinant of inter-individual and inter-ethnic differences in CYP3A-mediated drug disposition and response. AIM: This study aims to investigate the genetic polymorphisms of CYP3A5 among the Orang Asli in Peninsular Malaysia using a next generation sequencing platform. METHODS: Genomic DNAs were extracted from blood samples of the three main Orang Asli tribes and whole-genome sequencing was performed. RESULTS: A total of 61 single nucleotide polymorphisms were identified and all the SNPs were located in introns except rs15524, which is in the 3'UTR, and 11 of these polymorphisms were novel. Two allelic variants and three genotypes were identified in the Orang Asli. The major allelic variant was the non-functional CYP3A5*3 (66.4%). The percentages of Orang Asli with CYP3A5*3/*3 (47.2%) and CYP3A5*1/*3 (38.1%) genotypes are more than twice the percentage of Orang Asli with CYP3A5*1/*1 (14.8%) genotype. Almost half of the Orang Asli harboured CYP3A5 non-expressor genotype (CYP3A5*3/*3). CONCLUSIONS: The predominance of the CYP3A5 non-expressor genotype among the Orang Asli was unravelled and the findings in this study may serve as a guide for the optimisation of pharmacotherapy for the Orang Asli community.

Inference of the Genetic Polymorphisms of CYP2D6 in Six Subtribes of the Malaysian Orang Asli from Whole-Genome Sequencing Data.

AIMS: CYP2D6 is one of the major enzymes in the cytochrome P450 monooxygenase system. It metabolizes ∼25% of prescribed drugs and hence, the genetic diversity of a CYP2D6 gene has continued to be of great interest to the medical and pharmaceutical industries. This study was designed to perform a systematic analysis of the CYP2D6 gene in six subtribes of the Malaysian Orang Asli. METHODS: Genomic DNAs were extracted from the blood samples followed by whole-genome sequencing. The reads were aligned to the reference human genome hg19 and variants in the CYP2D6 gene were analyzed. CYP2D6*5 and duplication of CYP2D6 were analyzed using previously established methods. RESULTS: A total of 72 single nucleotide polymorphisms were identified. CYP2D6*1, *2, *4, *5, *10,*41, and duplication of the gene were found in the Orang Asli, whereby CYP2D6*2 and *41 alleles are reported for the first time in the Malaysian population. CONCLUSION: The findings in this study provide insights into the genetic polymorphisms of CYP2D6 in the Orang Asli of Peninsular Malaysia.

Detection of CYP2C19 Genetic Variants in Malaysian Orang Asli from Massively Parallel Sequencing Data.

The human cytochrome P450 (CYP) is a superfamily of enzymes that have been a focus in research for decades due to their prominent role in drug metabolism. CYP2C is one of the major subfamilies which metabolize more than 10% of all clinically used drugs. In the context of CYP2C19, several key genetic variations that alter the enzyme's activity have been identified and catalogued in the CYP allele nomenclature database. In this study, we investigated the presence of well-established variants as well as novel polymorphisms in the CYP2C19 gene of 62 Orang Asli from the Peninsular Malaysia. A total of 449 genetic variants were detected including 70 novel polymorphisms; 417 SNPs were located in introns, 23 in upstream, 7 in exons, and 2 in downstream regions. Five alleles and seven genotypes were inferred based on the polymorphisms that were found. Null alleles that were observed include CYP2C19*3 (6.5%), *2 (5.7%) and *35 (2.4%) whereas allele with increased function *17 was detected at a frequency of 4.8%. The normal metabolizer genotype was the most predominant (66.1%), followed by intermediate metabolizer (19.4%), rapid metabolizer (9.7%) and poor metabolizer (4.8%) genotypes. Findings from this study provide further insights into the CYP2C19 genetic profile of the Orang Asli as previously unreported variant alleles were detected through the use of massively parallel sequencing technology platform. The systematic and comprehensive analysis of CYP2C19 will allow uncharacterized variants that are present in the Orang Asli to be included in the genotyping panel in the future.

Meningitis Caused by Rhodotorula mucilaginosa in HIV-Infected Patient: A Case Report and Review of the Literature.

Rhodotorula species are increasingly being identified as a cause of fungal infection in the central nervous system, especially in patients with compromised immunity. The diagnosis could easily be missed due to low index of suspicion, as cryptococcus meningitis and cerebral toxoplasmosis are more common amongst immunocompromised hosts. To date, there are six cases of Rhodotorula-related meningitis reported, and three are associated with human immunodeficiency virus infection. In this report, a case of a Malaysian male with underlying human immunodeficiency virus infection who developed Rhodotorula mucilaginosa meningitis is presented. High-grade fever and severe headaches were the complaints presented in three previous case reports. India ink and nigrosin stainings were performed in the two previous reports and both revealed positive results. R. mucilaginosa were isolated from the culture of the patient's cerebrospinal fluid in all three previous reports. Predominant lymphocyte infiltration in the cerebrospinal fluid examination was documented in two reports. CD4 counts were above 100/µl in two previously published reports, while another report documented CD4 count as 56/µl. Amphotericin B and itraconazole are identified to be the first line of antifungal used and as the maintenance therapy, respectively. The possibility of relapse cannot be excluded as it was reported in the first report. It was also revealed that the current case has almost similar clinical presentation and therapeutic outcome as compared to the published reports, but some differences in diagnostic details were to be highlighted.