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Sequence-based HLA-A, B, C, DP, DQ, and DR typing of 159 individuals from the Worcester region of the Western Cape province of South Africa.
Grifoni A, Sidney J, Carpenter C, Phillips E, Mallal S, Scriba TJ, Sette A, Lindestam Arlehamn CS
(2018) Hum Immunol 79: 143-144
MeSH Terms: Databases, Genetic, Gene Frequency, Genotype, HLA-A Antigens, HLA-B Antigens, HLA-C Antigens, HLA-DQ Antigens, HLA-DR Antigens, Humans, Lymphocyte Activation, Mycobacterium tuberculosis, Sequence Analysis, DNA, South Africa, T-Lymphocytes, Tuberculosis
Show Abstract · Added March 30, 2020
DNA sequence-based typing at the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1, and -DRB3/4/5 loci was performed on samples provided by 159 individuals from the Worcester region of the Western Cape province of South Africa. The purpose of the study was to characterize allele frequencies in the local population, to support studies of T cell immunity against pathogens, including Mycobacterium tuberculosis. There are no detectable deviations from Hardy Weinberg proportions for the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, and -DRB1 loci. A minor deviation was detected at the HLA-DQB1 locus due to an excess of homozygotes. The genotype data are available in the Allele Frequencies Net Database under identifier 3425.
Copyright © 2018. Published by Elsevier Inc.
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Patterns of prevalent HPV and STI co-infections and associated factors among HIV-negative young Western Cape, South African women: the EVRI trial.
Menezes LJ, Pokharel U, Sudenga SL, Botha MH, Zeier M, Abrahamsen ME, Glashoff RH, Engelbrecht S, Schim van der Loeff MF, van der Laan LE, Kipping S, Taylor D, Giuliano AR
(2018) Sex Transm Infect 94: 55-61
MeSH Terms: Adolescent, Alcohol Drinking, Chlamydia trachomatis, Coinfection, Female, Genotype, Gonorrhea, HIV Infections, HIV Seronegativity, Herpes Genitalis, Herpesvirus 2, Human, Humans, Medically Underserved Area, Papillomaviridae, Papillomavirus Infections, Papillomavirus Vaccines, Prevalence, Sexual Behavior, Sexual Partners, Sexually Transmitted Diseases, South Africa, Syphilis, Young Adult
Show Abstract · Added August 15, 2017
OBJECTIVE - To estimate the prevalence and describe the patterns of concurrent human papillomavirus (HPV) and STIs and associated factors among HIV-negative young Western Cape, South African women participating in the Efficacy of HPV Vaccine to Reduce HIV Infection (EVRI) trial.
METHODS - HIV-negative women aged 16-24 years old were enrolled in the EVRI trial (NCT01489527) and randomised to receive the licensed four-valent HPV vaccine or placebo. At study entry, participants were clinically evaluated for five STIs: herpes simplex virus type 2 (HSV-2), chlamydia, gonorrhoea, syphilis and disease-causing HPV genotypes (6/11/16/18/31/33/35/39/45/51/52/56/58/59/68). Demographic and sexual history characteristics were compared among women with STI co-infections, single infection and no infection using Pearson χ and Mann-Whitney tests. ORs were calculated to evaluate factors associated with STI co-infection prevalence.
RESULTS - Among 388 young women, STI co-infection prevalence was high: 47% had ≥2 concurrent STIs, 36% had a single STI and 17% had none of the five evaluated STIs. HPV/HSV-2 (26%) was the most prevalent co-infection detected followed by HPV/HSV-2/ (CT) (17%) and HPV/CT (15%). Co-infection prevalence was independently associated with alcohol use (adjusted OR=2.01, 95% CI 1.00 to 4.06) and having a sexual partner with an STI (adjusted OR=6.96, 95% CI 1.53 to 30.08).
CONCLUSIONS - Among high-risk young women from underserved communities such as in Southern Africa, a multicomponent prevention strategy that integrates medical and behavioural interventions targeting both men and women is essential to prevent acquisition of concurrent STI infections and consequent disease.
TRIAL REGISTRATION NUMBER - NCT01489527; Post-results.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Isoniazid-monoresistant tuberculosis is associated with poor treatment outcomes in Durban, South Africa.
van der Heijden YF, Karim F, Mufamadi G, Zako L, Chinappa T, Shepherd BE, Maruri F, Moosa MS, Sterling TR, Pym AS
(2017) Int J Tuberc Lung Dis 21: 670-676
MeSH Terms: Adult, Antitubercular Agents, Drug Resistance, Bacterial, Female, HIV Infections, Humans, Isoniazid, Logistic Models, Longitudinal Studies, Male, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Retrospective Studies, South Africa, Treatment Failure, Treatment Outcome, Tuberculosis
Show Abstract · Added March 14, 2018
SETTING - A large tuberculosis (TB) clinic in Durban, South Africa.
OBJECTIVE - To determine the association between isoniazid (INH) monoresistant TB and treatment outcomes.
DESIGN - We performed a retrospective longitudinal study of patients seen from 2000 to 2012 to compare episodes of INH-monoresistant TB with those of drug-susceptible TB using logistic regression with robust standard errors. INH-monoresistant TB was treated with modified regimens.
RESULTS - Among 18 058 TB patients, there were 19 979 TB episodes for which drug susceptibility testing was performed. Of these, 557 were INH-monoresistant and 16 311 were drug-susceptible. Loss to follow-up, transfer, and human immunodeficiency virus (HIV) co-infection (41% had known HIV status) were similar between groups. INH-monoresistant episodes were more likely to result in treatment failure (4.1% vs. 0.6%, P < 0.001) and death (3.2% vs. 1.8%, P = 0.01) than drug-susceptible episodes. After adjustment for age, sex, race, retreatment status, and disease site, INH-monoresistant episodes were more likely to have resulted in treatment failure (OR 6.84, 95%CI 4.29-10.89, P < 0.001) and death (OR 1.81, 95%CI 1.11-2.95, P = 0.02).
CONCLUSION - INH monoresistance was associated with worse clinical outcomes than drug-susceptible TB. Our findings support the need for rapid diagnostic tests for INH resistance and improved treatment regimens for INH-monoresistant TB.
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17 MeSH Terms
Cervical HPV natural history among young Western Cape, South African women: The randomized control EVRI Trial.
Sudenga SL, Torres BN, Botha MH, Zeier M, Abrahamsen ME, Glashoff RH, Engelbrecht S, Schim Van der Loeff MF, Van der Laan LE, Kipping S, Taylor D, Giuliano AR
(2016) J Infect 72: 60-9
MeSH Terms: Adolescent, Adult, Female, Humans, Papillomavirus Infections, Papillomavirus Vaccines, Prevalence, Risk Factors, South Africa, Young Adult
Show Abstract · Added August 15, 2017
OBJECTIVE - The objective of this analysis was to assess human papillomavirus (HPV) infection persistence and incidence 7-months post-enrollment by HPV vaccine study arm (vaccine or placebo).
METHODS - HIV-negative, sexually active women aged 16-24 years in the Western Cape, South Africa, were enrolled in the EVRI Trial and were randomized to receive 4-valent HPV vaccine or placebo. Cervical specimens were collected at enrollment and at the 7-month visit and were genotyped for HPV. HPV prevalence, persistence, and incidence were calculated. Prevalence ratios and odds ratios were calculated to assess factors associated with a prevalent and incident HPV infection.
RESULTS - HPV incidence rates were marginally higher for the placebo group (n = 163) compared to the vaccine group (n = 169). A large proportion of the prevalent high-risk (HR-HPV) HPV types (49%) persisted over the 7-month period in both arms. Prevalent HR-HPV infection was significantly associated with a prevalent gonorrhea infection and detection of Herpes simplex type 2 antibodies. Incident HR-HPV infection was significantly associated with abnormal cervical cytology at enrollment and younger age.
CONCLUSIONS - Women living in geographic areas, such as southern Africa, at high-risk for HPV need to receive HPV vaccination at a very young age to maximally prevent infection and subsequent disease.
Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
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Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study.
Luetkemeyer AF, Rosenkranz SL, Lu D, Grinsztejn B, Sanchez J, Ssemmanda M, Sanne I, McIlleron H, Havlir DV, Haas DW, Adult AIDS Clinical Trials Group A5221 and A5243 Study Teams
(2015) Clin Infect Dis 60: 1860-3
MeSH Terms: Antitubercular Agents, Arylamine N-Acetyltransferase, Benzoxazines, Cytochrome P-450 CYP2B6, Female, Genotype, HIV Infections, Humans, Male, Peru, Pharmacogenetics, Rifampin, South Africa, Tuberculosis, Uganda
Show Abstract · Added March 13, 2015
In STRIDE, slow metabolizer CYP2B6 and NAT2 genotypes were each associated with increased plasma efavirenz concentrations during antituberculosis therapy. Concentrations were greater on therapy than off therapy in 58% with CYP2B6 and 93% with NAT2 slow metabolizer genotypes. Individuals with slow metabolizer genotypes in both genes had markedly elevated concentrations.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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15 MeSH Terms
Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa.
Sinxadi PZ, Leger PD, McIlleron HM, Smith PJ, Dave JA, Levitt NS, Maartens G, Haas DW
(2015) Br J Clin Pharmacol 80: 146-56
MeSH Terms: Adolescent, Adult, African Continental Ancestry Group, Anti-HIV Agents, Benzoxazines, Child, Child, Preschool, Cytochrome P-450 CYP2B6, Female, Genotype, HIV Infections, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, South Africa, Young Adult
Show Abstract · Added March 13, 2015
AIMS - Genetic factors, notably CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children.
METHODS - Steady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3.
RESULTS - Among 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516G→T, 983T→C, and 15582C→T [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose efavirenz concentrations were 1.44 (1.21-1.93) µg ml(-1), 2.08 (1.68-2.94) µg ml(-1) and 7.26 (4.82-8.34) µg ml(-1) for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations (β = 0.28, 95% CI 0.21, 0.35, P = 2.4 × 10(-11)). Among individual CYP2B6 polymorphisms, 516G→T best predicted efavirenz concentrations (β = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10(-6)). There was also associations with 983T→C (β = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582C→T (β = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations.
CONCLUSIONS - Composite CYP2B6 genotype based on CYP2B6 516G→T, 983T→C, and 15582C→T best described efavirenz exposure in HIV-infected Black South African adults and children.
© 2015 The British Pharmacological Society.
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17 MeSH Terms
High HIV, HPV, and STI prevalence among young Western Cape, South African women: EVRI HIV prevention preparedness trial.
Giuliano AR, Botha MH, Zeier M, Abrahamsen ME, Glashoff RH, van der Laan LE, Papenfuss M, Engelbrecht S, Schim van der Loeff MF, Sudenga SL, Torres BN, Kipping S, Taylor D
(2015) J Acquir Immune Defic Syndr 68: 227-35
MeSH Terms: Adolescent, Female, Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18, Humans, Papillomavirus Vaccines, Placebos, Prevalence, Sexually Transmitted Diseases, South Africa, Young Adult
Show Abstract · Added August 15, 2017
BACKGROUND - This study sought to assess the feasibility of conducting a phase III HIV prevention trial using a multivalent human papillomavirus (HPV) vaccine (Gardasil; Merck, Whitehouse Station, NJ).
METHODS - A total of 479 sexually active women aged 16-24 years in the Western Cape, South Africa, were enrolled in the Efficacy of HPV Vaccine to Reduce HIV Infection (EVRI) Trial. Of these, 402 were HIV negative, nonpregnant, and randomized 1:1 to receive Gardasil or a saline placebo vaccine. Vaccine doses were administered at enrollment, month 2, and month 6, and participants were followed for 1 month after the third dose. Enrollment HIV, HPV, other sexually transmitted infections (STIs), and cervical cytology were evaluated. Rates of accrual, vaccine compliance, and adherence to protocol were monitored.
RESULTS - High rates of accrual of eligible females to study (93%) and completion of the 3-dose vaccine series (91%) were noted, with few protocol violations. Ineligibility due to reported HIV positivity was 19%, and another 12% of those enrolled tested HIV positive. STI prevalence was high, with 6.2%, 10.9%, and 32.8% testing positive for syphilis, gonorrhea, and chlamydia, respectively. Cervical prevalence of ≥1 of 37 HPV types was 71%. STI and HPV prevalence was highest among the youngest women (<19 years).
CONCLUSIONS - Feasibility (successful accrual, retention, and vaccination) of conducting randomized placebo-controlled trials of HPV vaccines among HIV high-risk women in South Africa was demonstrated. This work demonstrates that phase III HIV prevention trials need to intervene at young ages and screen and treat multiple STIs concurrently to have a measurable impact on HIV acquisition.
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10 MeSH Terms
Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection.
Dooley KE, Denti P, Martinson N, Cohn S, Mashabela F, Hoffmann J, Haas DW, Hull J, Msandiwa R, Castel S, Wiesner L, Chaisson RE, McIlleron H, TSHEPISO Study Team
(2015) J Infect Dis 211: 197-205
MeSH Terms: Adolescent, Adult, Anti-HIV Agents, Benzoxazines, Cohort Studies, Coinfection, Female, HIV Infections, HIV-1, Humans, Plasma, Pregnancy, Pregnancy Complications, Infectious, Prospective Studies, South Africa, Tuberculosis, Viral Load, Young Adult
Show Abstract · Added March 13, 2015
BACKGROUND - Pregnancy and tuberculosis treatment or prophylaxis can affect efavirenz pharmacokinetics, maternal human immunodeficiency virus type 1 (HIV-1) treatment outcomes, and mother-to-child transmission (MTCT) risk.
METHODS - We evaluated a prospective cohort of pregnant, HIV-infected women with and without tuberculosis in Soweto, South Africa. Pharmacokinetic sampling was performed at gestation week 37 and during the postpartum period. Efavirenz trough concentrations (Cmin) were predicted using population pharmacokinetic models. HIV-viral load was measured at delivery for mothers and at 6 weeks of age for infants.
RESULTS - Ninety-seven women participated; 44 had tuberculosis. Median efavirenz Cmin during pregnancy was 1.35 µg/mL (interquartile range [IQR], 0.90-2.07 µg/mL; 27% had an efavirenz Cmin of < 1 µg/mL), compared with a median postpartum value of 2.00 µg/mL (IQR, 1.40-3.59 µg/mL; 13% had an efavirenz Cmin of < 1 µg/mL). A total of 72% of pregnant women with extensive CYP2B6 genotypes had an efavirenz Cmin of <1 µg/mL. Rifampin did not reduce the efavirenz Cmin. Isoniazid (for prophylaxis or treatment), though, reduced the rate of efavirenz clearance. At delivery, median durations of ART were 13 weeks (IQR, 9-18 weeks) and 21 weeks (IQR, 13-64 weeks) for women with and those without tuberculosis, respectively; 55% and 83%, respectively, had a viral load of <20 copies/mL (P = .021). There was 1 case of MTCT.
CONCLUSIONS - Pregnancy increased the risk of low efavirenz concentrations, but MTCT was rare. A detectable HIV-viral load at delivery was more common among pregnant women with tuberculosis, in whom ART was generally initiated later.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Mitochondrial genomics and antiretroviral therapy-associated metabolic complications in HIV-infected Black South Africans: a pilot study.
Sinxadi PZ, Dave JA, Samuels DC, Heckmann JM, Maartens G, Levitt NS, Wester CW, Haas DW, Hulgan T
(2013) AIDS Res Hum Retroviruses 29: 1031-9
MeSH Terms: Adult, African Continental Ancestry Group, Anti-HIV Agents, Cross-Sectional Studies, DNA, Mitochondrial, Female, Genetic Predisposition to Disease, Genetic Variation, Genome, Mitochondrial, HIV Infections, HIV-Associated Lipodystrophy Syndrome, Humans, Hypertriglyceridemia, Male, Metabolic Diseases, Pilot Projects, Polyneuropathies, South Africa
Show Abstract · Added December 12, 2013
Studies suggest that mitochondrial DNA (mtDNA) haplogroups are associated with antiretroviral therapy (ART)-related metabolic complications and distal sensory polyneuropathy (DSP), but there have been few studies in persons of African descent. We explored such associations in South African adults. Clinical and laboratory data and DNA specimens from a cross-sectional study were used. Sequencing and Phylotree determined African mtDNA subhaplogroups. Wilcoxon and regression analyses determined associations between mtDNA subhaplogroups and ART-related complications. The 171 participants represented six major haplogroups: L0 (n=78), L1 (n=3), L2 (n=30), L3 (n=53), L4 (n=1), and L5 (n=6). Analyses were restricted to 161 participants representing L0, L2, and L3: 78% were female; the median age was 36 years. All had been exposed to thymidine analogues, 42% were on lopinavir/ritonavir (lopinavir/r), and 58% were on either efavirenz or nevirapine. Median (IQR) ART duration was 22 (14-36) months. Median fasting triglycerides were 1.60 (1.13-1.75) and 1.04 (0.83-1.45) mmol/liter among L3e1 (n=22) and other subhaplogroups, respectively (p=0.003). Subhaplogroup L3e1 [adjusted OR (aOR) 3.16 (95% CI: 1.11-8.96); p=0.03] and exposure to lopinavir/r [aOR 2.98 (95% CI: 1.02-8.96); p=0.05] were independently associated with hypertriglyceridemia, after adjusting for age, sex, and ART duration. There were no significant associations between mtDNA haplogroups and cholesterol, dysglycemia, hyperlactatemia, or lipoatrophy, or DSP. Subhaplogroup L3e1 and lopinavir/r exposure were independently associated with hypertriglyceridemia in black South Africans on ART. This is the first report to link an African mtDNA variant with hypertriglyceridemia. If replicated, these findings may provide new insights into host factors affecting metabolic complications.
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18 MeSH Terms
Associations between HLA-DRB1*0102, HLA-B*5801, and hepatotoxicity during initiation of nevirapine-containing regimens in South Africa.
Phillips E, Bartlett JA, Sanne I, Lederman MM, Hinkle J, Rousseau F, Dunn D, Pavlos R, James I, Mallal SA, Haas DW
(2013) J Acquir Immune Defic Syndr 62: e55-7
MeSH Terms: Adult, Alanine Transaminase, Anti-HIV Agents, Aryl Hydrocarbon Hydroxylases, Aspartate Aminotransferases, Chemical and Drug Induced Liver Injury, Cytochrome P-450 CYP2B6, Double-Blind Method, Female, Genotype, HIV Infections, HLA-B Antigens, HLA-DRB1 Chains, Humans, Male, Multivariate Analysis, Nevirapine, Oxidoreductases, N-Demethylating, Phenotype, Reverse Transcriptase Inhibitors, South Africa
Added March 13, 2015
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21 MeSH Terms