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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.
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/.
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.
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.
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: firstname.lastname@example.org.
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.
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.
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: email@example.com.
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.