Plasma efavirenz concentration inversely correlates with increased risk of cytomegalovirus infection in HIV-infected pregnant women

Background. Effective combination antiretroviral therapy (cART) has tremendously reduced HIV-associated morbidity, mortality and mother-to-child transmission. However, the benefits of cART are threatened by comorbidities, adverse drug reactions and virus resistance to existing treatment regimens. One of the most occurring comorbidities is cytomegalovirus (CMV) infection. Objectives. To investigate the effects of cART on the occurrence of CMV infection among pregnant women. Methods. Using a cross-sectional study design, 175 HIV-infected pregnant women were recruited, and data were obtained from their clinical records. Blood samples were collected for host DNA, CMV DNA and plasma efavirenz (EFV) measurement. CMV DNA was measured using real-time polymerase chain reaction (PCR). CYP2B6 c.516G>T and CYP2B6 c.983T>C single nucleotide polymorphisms were characterised using PCR/restriction fragment length polymorphism and TaqMan assays, respectively. Plasma EFV concentrations were determined using high-performance liquid chromatography.Results. There was an inverse association between plasma EFV concentration and CMV DNA. Participants with lower plasma EFV concentrations were significantly (p<0.001) more likely to be CMV DNA positive than those with higher plasma concentrations. This result is also supported by the observation that carriers of CYP2B6 poor-metaboliser genotypes (CYP2B6 c.516T/T and CYP2B6 c.983T/C) were less likely to be positive for CMV DNA. Furthermore, poor metabolism as denoted by CYP2B6 c.516T/T and CYP2B6 c.983T/C genotypes was significantly associated with lower CMV viral load. Conclusions. HIV treatment disrupts the balance between host and co-infecting microbes. Reduced or subtherapeutic levels of antiretroviral drugs, which could be exacerbated by genetic polymorphisms in drug metabolism genes and non-adherence, predispose infected individuals to an increased risk of CMV infection in pregnancy.

CYP3A5 polymorphisms and their effects on tacrolimus exposure in an ethnically diverse South African renal transplant population

Background. Tacrolimus forms the cornerstone for immunosuppression in solid-organ transplantation. It has a narrow therapeutic window with wide inter- and intra-patient variability (IPV). Cytochrome P-450 3A5 (CYP3A5) is the main enzyme involved in tacrolimus metabolism, and rs776746A>G is the most frequently studied polymorphism in the CYP3A5 gene. The rs776746A>G (i.e. CYP3A5*3) single-nucleotide polymorphism in CYP3A5 alters tacrolimus predose trough concentration (C0) and may also affect IPV, which may lead to immune- and/or drug-mediated allograft injury. CYP3A5*3 may result in absent (*3/*3), partial (*1/*3) or normal (*1/*1) CYP3A5 expression. The effect of CYP3A5*3 on tacrolimus exposure and variability has not been examined in South African (SA) transplant recipients.Objectives. To determine the frequencies and effect of CYP3A5 and adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms on tacrolimus C0/dose ratios in different ethnic groups attending a tertiary renal transplant clinic in SA, and other factors that may explain inter- and IPV in tacrolimus C0.Methods. All consenting stable renal transplant recipients on tacrolimus at the Livingstone Hospital Renal Unit in Port Elizabeth, SA, were included. Tacrolimus concentrations were obtained using a microparticle enzyme immunoassay method (ARCHITECT analyser, Abbott Laboratories). Polymerase chain reaction/restriction fragment length polymorphism was used to genotype for CYP3A5*3 and *6 allelic variants.Results. There were 43 participants (35% black African, 44% mixed ancestry and 21% white), with a mean age of 44.5 years, median duration post-transplant of 47 months and median (interquartile range) creatinine and estimated glomerular filtration rate levels of 118 (92 - 140) µmol/L and 62 (49 - 76) mL/min at study inclusion. The mean tacrolimus C0 in the study was 6.7 ng/mL, with no difference across the different ethnic groups. However, the mean total daily dose of tacrolimus required was 9.1 mg (0.12 mg/kg), 7.2 mg (0.09 mg/kg) and 4.3 mg (0.06 mg/kg) in black, mixed-ancestry and white patients, respectively (p=0.017). The frequencies for CYP3A5 expressors (i.e. CYP3A5*1/*1 + CYP3A5*1/*3 genotypes) were 72%, 100%, 76% and 12% for all patients combined and black, mixed-ancestry and white patients, respectively. The frequencies for CYP3A5 non-expressors (i.e. CYP3A5*3/*3 genotypes) were 0%, 24% and 88% among the black, mixed-ancestry and white patients, respectively. None of the patients carried the CYP3A5*6 allele. CYP3A5*1/*1 and CYP3A5*1/*3 genotype carriers required a two-fold increase in dose compared with the non-expressor genotype carriers, CYP3A5*3/*3 (p<0.05). CYP3A5*3/*3 carriers also demonstrated higher IPV than CYP3A5*1/*1 and *1/*3 carriers (18.1% v. 14.2%; p=0.125).Conclusions. Compared with global transplant populations, SA renal transplant recipients demonstrated a very high rate of CYP3A5 expression, with a significant impact on tacrolimus pharmacokinetics. Genetic variation in CYP3A5 expression affects tacrolimus dosing requirements, and knowing the CYP3A5 genotype of transplant patients may allow better dose prediction compared with current standard dosing recommendations in a multi-ethnic population. Overall, black African patients required higher doses of tacrolimus than their white counterparts. While further prospective studies are needed to better evaluate dosing algorithms, it would appear that the starting dose of tacrolimus should be higher in black and mixed-race patients.

Evaluating the contribution of APOBEC3G haplotypes, on influencing HIV infection in a Zimbabwean paediatric population

Background. Apolipoprotein B mRNA-editing catalytic polypeptide like-3G (APOBEC3G) is an antiviral enzyme that reduces viral fitness by introducing uracil to thymidine hypermutations in viral genomes. Thus, polymorphisms in the APOBEC3G gene have been implicated in differential outcomes of HIV infection and disease progression. However, there is insufficient evidence on the role of APOBEC3G gene variants on HIV infection, especially in African populations. This study therefore describes polymorphisms in the APOBEC3G gene in a Zimbabwean paediatric population and evaluates their effects on susceptibility to HIV infection among children born to HIV-infected mothers. Methods. A total of 104 children aged between 7 and 9 years, comprising 68 perinatally exposed to HIV (32 born infected (EI) and 36 born uninfected (EU)) and 36 unexposed and uninfected (UEUI) controls were recruited. Allelic variants (n=5) in the APOBEC3G gene were characterised. Results. Frequencies for minor APOBEC3G alleles in the HIV-uninfected groups (EU and UEUI) were c.557G (40%), g.-90C (32%), g.-571C (12%), c.467-85C (42%), and c.582-162G (6%). APOBEC3G c.467-85C frequency was statistically significantly different when compared to the Masai of Kinyawa, Kenya population (42% v. 18%). None of the single nucleotide polymorphisms individually or as part of haplotypes were significantly associated with HIV infection when comparing the EI and EU groups. Conclusions. Our findings suggest that APOBEC3G polymorphisms alone may not have significant predictive power for inferring genetic susceptibility to vertical transmission of HIV in children perinatally exposed to HIV

Clinical Practice: Direct-to-consumer genetic testing: To test or not to test, that is the question

In direct-to-consumer (DTC) genetic testing, laboratory-based genetic services are offered directly to the public without an independent healthcare professional being involved. The committee of the Southern African Society for Human Genetics (SASHG) appeals to the public and clinicians to be cautious when considering and interpreting such testing. It is important to stress that currently, the clinical validity and utility of genetic tests for complex multifactorial disorders such as type 2 diabetes mellitus and cardiovascular diseases is questionable. The majority of such tests are not scientifically validated and are based on a few preliminary studies. Potential consumers should be aware of the implications of genetic testing that could lead to stigmatisation and discrimination by insurance companies or potential employers of themselves and their family members. Guidelines and recommendations for DTC genetic testing in South Africa (SA) are currently lacking. We provide recommendations that seek to protect consumers and healthcare providers in SA from possible exploitation

Ictiofauna de lagos de várzea da Reserva de Desenvolvimento Sustentável Piagaçu-Purus (RDS-PP), baixo rio Purus

The ichthyofauna of the rio Purus has been little investigated, especially in its lower portion, characterized by diverse aquatic environments, especially in flooded areas. We inventoried the ichthyofauna of floodplain lakes with different management efforts in Reserva de Desenvolvimento Sustentável Piagaçu-Purus (RDS-PP), which represent important resource for commercial fishing in North region, in the first illustrated inventory of the fish fauna from lower rio Purus. We surveyed 20 lakes, classified as open access (eight lakes) and protected (12 lakes) during 2009 low water levels. A total of 2,299 individuals were collected, represented by seven orders, 25 families and 74 species. Characiformes was the most representative order in number of species and families, followed by Siluriformes, Cichliformes, Gymnotiformes, Clupeiformes, and Osteoglossiformes. Most abundant and frequent species were Pygocentrus nattereri, Triportheus angulatus, Serrasalmus sp. "2n=58", Pterygoplichthys gibbiceps, and Osteoglossum bicirrhosum. Protected lakes presented higher species richness compared to open access lakes. Similarly, protected lakes possessed 26 species occurring exclusively, with emphasis on Colossoma macropomum, an important species for fisheries due to its commercial importance. We added 44 new records of fish species for the lower rio Purus. Our results indicate the potential efficiency of zoning systems of open access and protected lakes established by local population and ruled by RDS-PP for fisheries management. Therefore, we strongly suggest its maintenance for conservation of ichthyofauna of floodplain lakes of lower rio Purus. © 2019, Universidade Estadual de Campinas UNICAMP. All rights reserved

Mortality inequalities measured by socioeconomic indicators in Brazil: a scoping review

OBJECTIVE Summarize the literature on the relationship between composite socioeconomic indicators and mortality in different geographical areas of Brazil. METHODS This scoping review included articles published between January 1, 2000, and August 31, 2020, retrieved by means of a bibliographic search carried out in the Medline, Scopus, Web of Science, and Lilacs databases. Studies reporting on the association between composite socioeconomic indicators and all-cause, or specific cause of death in any age group in different geographical areas were selected. The review summarized the measures constructed, their associations with the outcomes, and potential study limitations. RESULTS Of the 77 full texts that met the inclusion criteria, the study reviewed 24. The area level of composite socioeconomic indicators analyzed comprised municipalities (n = 6), districts (n = 5), census tracts (n = 4), state (n = 2), country (n = 2), and other areas (n = 5). Six studies used composite socioeconomic indicators such as the Human Development Index, Gross Domestic Product, and the Gini Index; the remaining 18 papers created their own socioeconomic measures based on sociodemographic and health indicators. Socioeconomic status was inversely associated with higher rates of all-cause mortality, external cause mortality, suicide, homicide, fetal and infant mortality, respiratory and circulatory diseases, stroke, infectious and parasitic diseases, malnutrition, gastroenteritis, and oropharyngeal cancer. Higher mortality rates due to colorectal cancer, leukemia, a general group of neoplasms, traffic accident, and suicide, in turn, were observed in less deprived areas and/or those with more significant socioeconomic development. Underreporting of death and differences in mortality coverage in Brazilian areas were cited as the main limitation. CONCLUSIONS Studies analyzed mortality inequalities in different geographical areas by means of composite socioeconomic indicators, showing that the association directions vary according to the mortality outcome. But studies on all-cause mortality and at the census tract level remain scarce. The results may guide the development of new composite socioeconomic indicators for use in mortality inequality analysis

Association of a Deletion of GSTT2B with an Altered Risk of Oesophageal Squamous Cell Carcinoma in a South African Population: A Case-Control Study

Polymorphisms in the Glutathione S-transferase genes are associated with altered risks in many cancers, but their role in oesophageal cancer is unclear. Recently a 37-kb deletion polymorphism of GSTT2B that reduces expression of GSTT2 has been described. We evaluated the influence of the GSTT1 and GSTT2B deletion polymorphisms, and the GSTP1 Ile105Val polymorphism (rs1695) on susceptibility to oesophageal squamous cell carcinoma (OSCC) in the Black and Mixed Ancestry populations of South Africa.The GSTT1, GSTT2B and GSTP1 variants were genotyped in 562 OSCC cases and 907 controls, and tested for association with OSCC and for interaction with smoking and alcohol consumption. Linkage disequilibrium (LD) between the deletions at GSTT1 and GSTT2B was determined, and the haplotypes tested for association with OSCC. Neither the GSTT1 deletion nor the GSTP1 Ile105Val polymorphism was associated with OSCC risk in the Black or Mixed Ancestry populations. The GSTT2B deletion was not associated with OSCC risk in the Black population, but was associated with reduced risk of OSCC in the Mixed Ancestry population (OR=0.71; 95% CI 0.57-0.90, p=0.004). Case-only analysis showed no interaction between the GST polymorphisms and smoking or alcohol consumption. LD between the neighboring GSTT1 and GSTT2B deletions was low in both populations (r(2)(Black)=0.04; r(2)(MxA)=0.07), thus these deletions should be assessed independently for effects on disease risk.Although there was no association between the GSTT1 deletion polymorphism or the GSTP1 Ile105Val polymorphism with OSCC, our results suggest that the presence of the recently described GSTT2B deletion may have a protective effect on the risk of OSCC in the Mixed Ancestry South African population. This is the first report of the contribution of the GSTT2B deletion to cancer risk

Genome-wide association study of nevirapine hypersensitivity in a sub-Saharan African HIV-infected population

The initial GWAS was funded by the International Serious Adverse Events Consortium (iSAEC). The iSAEC is a non-profit organization dedicated to identifying and validating DNA variants useful in predicting the risk of drug-related serious adverse events. The Consortium brings together the pharmaceutical industry, regulatory authorities and academic centres to address clinical and scientific issues associated with the genetics of drug-related serious adverse events. The iSAEC’s current funding members include: Abbott, Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Merck, Novartis, Pfizer, Takeda and the Wellcome Trust. Mas Chaponda was funded by a 3 year Wellcome Trust training fellowship WT078857MA administered through the University of Liverpool. Malawi-Liverpool-Wellcome Trust Clinical Research Programme is funded through a Core Programme Grant award from the Wellcome Trust. Munir Pirmohamed is a National Institute for Health Research Senior Investigator, and also wishes to thank the MRC Centre for Drug Safety Science for support. The DART study was supported by the UK Medical Research Council (grant number G0600344), the UK Department for International Development and the Rockefeller Foundation. Andrew P. Morris is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (grant number WT098017). Louise Y. Takeshita is funded by a PhD fellowship from CNPq (National Council for Scientific and Technological Development, Brazil). Panos Deloukas’ work forms part of the research themes contributing to the translational research portfolio of Barts Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute for Health Research