Publications by authors named "Koleka Mlisana"

133 Publications

Performance of TaqMan probes for the detection of sexually transmitted infections in South African women.

Afr J Lab Med 2021 31;10(1):1124. Epub 2021 Mar 31.

Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.

and are the four main aetiologies of sexually transmitted infections responsible for vaginal discharge syndrome (VDS). Commercially available multiplex polymerase chain reaction (PCR) assays are expensive and generally not customisable. We evaluated a highly customisable singleplex PCR approach by testing it in parallel with the Anyplex™ II STI-7 detection assay in a cohort of South African women that presented with VDS between May 2016 and January 2017. Our multiple singleplex PCR strategy proved to be a simple, accurate, rapid, affordable and scalable option for diagnosing VDS.
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http://dx.doi.org/10.4102/ajlm.v10i1.1124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063552PMC
March 2021

Effectiveness and cardiac safety of bedaquiline-based therapy for drug-resistant tuberculosis: a prospective cohort study.

Clin Infect Dis 2021 Apr 21. Epub 2021 Apr 21.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, and Department of Medicine, University of Cape Town, Cape Town, South Africa.

Background: Bedaquiline improves treatment outcomes in patients with rifampin-resistant TB (RR-TB) but prolongs the QT-interval and carries a black-box warning by the U.S. Food and Drug Administration. The World Health Organization recommends that all patients with RR-TB receive a regimen containing bedaquiline, yet a phase 3 clinical trial demonstrating its cardiac safety has not been published.

Methods: We conducted an observational cohort study of RR-TB patients from 3 provinces in South Africa who received regimens containing bedaquiline. We performed rigorous cardiac monitoring, including electrocardiograms (ECGs) performed in triplicate at four time points during bedaquiline therapy. Participants were followed until the end of therapy or 24 months. Outcomes included final tuberculosis treatment outcome and QT-prolongation, defined as any QTcF>500 ms or an absolute change from baseline (△ QTcF) >60 ms.

Results: We enrolled 195 eligible participants, of whom 40% had extensively drug-resistant (XDR) TB. Most participants (97%) received concurrent clofazimine. 74% of participants were cured or successfully completed treatment, and outcomes did not differ by HIV status. QTcF continued to increase throughout bedaquiline therapy, with a mean increase of 23.7 (SD 22.7) ms from baseline to month 6. Four participants experienced a QTcF>500 ms and 19 experienced a △QTcF>60 ms. Older age was independently associated with QT-prolongation. QT-prolongation was neither more common nor severe in participants receiving concurrent lopinavir-ritonavir.

Conclusions: Severe QT-prolongation was uncommon and did not require permanent discontinuation of either bedaquiline or clofazimine. Close QT-monitoring may be advisable in older patients.
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http://dx.doi.org/10.1093/cid/ciab335DOI Listing
April 2021

Variation in HIV care and treatment outcomes by facility in South Africa, 2011-2015: A cohort study.

PLoS Med 2021 Mar 31;18(3):e1003479. Epub 2021 Mar 31.

Department of Global Health, Boston University School of Public Health, BA, United States of America.

Background: Despite widespread availability of HIV treatment, patient outcomes differ across facilities. We propose and evaluate an approach to measure quality of HIV care at health facilities in South Africa's national HIV program using routine laboratory data.

Methods And Findings: Data were extracted from South Africa's National Health Laboratory Service (NHLS) Corporate Data Warehouse. All CD4 counts, viral loads (VLs), and other laboratory tests used in HIV monitoring were linked, creating a validated patient identifier. We constructed longitudinal HIV care cascades for all patients in the national HIV program, excluding data from the Western Cape and very small facilities. We then estimated for each facility in each year (2011 to 2015) the following cascade measures identified a priori as reflecting quality of HIV care: median CD4 count among new patients; retention 12 months after presentation; 12-month retention among patients established in care; viral suppression; CD4 recovery; monitoring after an elevated VL. We used factor analysis to identify an underlying measure of quality of care, and we assessed the persistence of this quality measure over time. We then assessed spatiotemporal variation and facility and population predictors in a multivariable regression context. We analyzed data on 3,265 facilities with a median (IQR) annual size of 441 (189 to 988) lab-monitored HIV patients. Retention 12 months after presentation increased from 42% to 47% during the study period, and viral suppression increased from 66% to 79%, although there was substantial variability across facilities. We identified an underlying measure of quality of HIV care that correlated with all cascade measures except median CD4 count at presentation. Averaging across the 5 years of data, this quality score attained a reliability of 0.84. Quality was higher for clinics (versus hospitals), in rural (versus urban) areas, and for larger facilities. Quality was lower in high-poverty areas but was not independently associated with percent Black. Quality increased by 0.49 (95% CI 0.46 to 0.53) standard deviations from 2011 to 2015, and there was evidence of geospatial autocorrelation (p < 0.001). The study's limitations include an inability to fully adjust for underlying patient risk, reliance on laboratory data which do not capture all relevant domains of quality, potential for errors in record linkage, and the omission of Western Cape.

Conclusions: We observed persistent differences in HIV care and treatment outcomes across South African facilities. Targeting low-performing facilities for additional support could reduce overall burden of disease.
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http://dx.doi.org/10.1371/journal.pmed.1003479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012100PMC
March 2021

Detection of a SARS-CoV-2 variant of concern in South Africa.

Nature 2021 04 9;592(7854):438-443. Epub 2021 Mar 9.

Molecular Diagnostics Services, Durban, South Africa.

Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data-which show rapid expansion and displacement of other lineages in several regions-suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape.
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http://dx.doi.org/10.1038/s41586-021-03402-9DOI Listing
April 2021

Genome Sequences of Five Novel Neisseria gonorrhoeae Sequence Types Isolated in KwaZulu-Natal, South Africa.

Microbiol Resour Announc 2021 Mar 4;10(9). Epub 2021 Mar 4.

School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.

Africa has the highest incidence of infections globally, but data on these isolates is scarce. Here, we report six genome sequences with five novel sequence types isolated from patients with uncomplicated genitourinary gonorrhea in South Africa.
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http://dx.doi.org/10.1128/MRA.01424-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936638PMC
March 2021

COVID-19: lessons and experiences from South Africa's first surge.

BMJ Glob Health 2021 02;6(2)

COVID-19, Clinton Health Access Initiative, Pretoria, Gauteng, South Africa.

On 5 March 2020, South Africa recorded its first case of imported COVID-19. Since then, cases in South Africa have increased exponentially with significant community transmission. A multisectoral approach to containing and mitigating the spread of SARS-CoV-2 was instituted, led by the South African National Department of Health. A National COVID-19 Command Council was established to take government-wide decisions. An adapted World Health Organiszion (WHO) COVID-19 strategy for containing and mitigating the spread of the virus was implemented by the National Department of Health. The strategy included the creation of national and provincial incident management teams (IMTs), which comprised of a variety of work streams, namely, governance and leadership; medical supplies; port and environmental health; epidemiology and response; facility readiness and case management; emergency medical services; information systems; risk communication and community engagement; occupational health and safety and human resources. The following were the most salient lessons learnt between March and September 2020: strengthened command and control were achieved through both centralised and decentralised IMTs; swift evidenced-based decision-making from the highest political levels for instituting lockdowns to buy time to prepare the health system; the stringent lockdown enabled the health sector to increase its healthcare capacity. Despite these successes, the stringent lockdown measures resulted in economic hardship particularly for the most vulnerable sections of the population.
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http://dx.doi.org/10.1136/bmjgh-2020-004393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907826PMC
February 2021

Impact of point-of-care testing and treatment of sexually transmitted infections and bacterial vaginosis on genital tract inflammatory cytokines in a cohort of young South African women.

Sex Transm Infect 2021 Feb 19. Epub 2021 Feb 19.

Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.

Objectives: STIs cause inflammation that is detrimental for both HIV risk and reproductive health. We assessed the impact of point-of-care (POC) STI testing, immediate treatment and expedited partner therapy (EPT) on genital tract cytokines among a cohort of young South African women.

Methods: HIV-negative women underwent POC testing for (CT), (NG) and (TV) by Xpert CT/NG and OSOM TV, and for bacterial vaginosis (BV) by microscopy. Women with STIs and/or BV received immediate treatment, EPT for STIs and retested after 6 and 12 weeks. Concentrations of 48 cytokines were measured in cervicovaginal fluid at each visit using multiplex ELISA technology. The impact of STI treatment on cytokine concentrations was assessed by multivariable linear mixed models and principal component analysis.

Results: The study enrolled 251 women with median age of 23 years (IQR 21-27). The prevalence of CT, NG and TV were 14.3%, 4.4% and 4.0%, and 34.3% had BV. Women with STIs or BV at baseline (n=94) had significantly higher concentrations of pro-inflammatory cytokines (interleukin (IL)-1α, IL-1β, IL-6, tumour necrosis factor (TNF)-α, TNF-β, IL-18 and macrophage inflammatory factor (MIF)) and chemokines (IL-8, IL-16, macrophage inflammatory protein (MIP)-1α, IFN-α2, monokine induced by gamma interferon (MIG), monocyte chemoattractant protein (MCP)-3, regulated on activation normal T cell expressed and secreted and eotaxin) compared with women without (n=157). STI treatment was strongly associated with reduced concentrations of pro-inflammatory cytokines IL-6 (p=0.004), IL-1β (p=0.013), TNF-α (p=0.018) and chemokines MIG (p=0.008) and growth-related oncogene (GRO)-α (p=0.025). A lower Nugent score was associated with a reduction in pro-inflammatory cytokines IL-1α (p=0.003), TNF-related apoptosis-inducing ligand (p=0.004), MIF (p=0.010) and IL-18 (p<0.001), but an increase in chemokines MIG (p=0.020), GRO-α (p<0.001), IP-10 (p<0.001), MIP-1β (p=0.008) and MCP-1 (p=0.005). Principal component analysis showed differences in STI and BV-related inflammatory profiles, but that resolution restored a profile consistent with vaginal health.

Conclusions: A comprehensive STI intervention effectively reduced genital inflammation among young women, thereby improving vaginal health and potentially reducing HIV risk.
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http://dx.doi.org/10.1136/sextrans-2020-054740DOI Listing
February 2021

'We had to manage what we had on hand, in whatever way we could': adaptive responses in policy for decentralized drug-resistant tuberculosis care in South Africa.

Health Policy Plan 2021 Apr;36(3):249-259

Department of Infectious Diseases, Livingstone Hospital, Lindsay Rd, Industrial, Port Elizabeth, 6020, South Africa.

In 2011, the South African National TB Programme launched a policy of decentralized management of drug-resistant tuberculosis (DR-TB) in order to expand the capacity of facilities to treat patients with DR-TB, minimize delays to access care and improve patient outcomes. This policy directive was implemented to varying degrees within a rapidly evolving diagnostic and treatment landscape for DR-TB, placing new demands on already-stressed health systems. The variable readiness of district-level systems to implement the policy prompted questions not only about differences in health systems resources but also front-line actors' capacity to implement change in resource-constrained facilities. Using a grounded theory approach, we analysed data from in-depth interviews and small group discussions conducted between 2016 and 2018 with managers (n = 9), co-ordinators (n = 15), doctors (n = 7) and nurses (n = 18) providing DR-TB care. Data were collected over two phases in district-level decentralized sites of three South African provinces. While health systems readiness assessments conventionally map the availability of 'hardware', i.e. resources and skills to deliver an intervention, a notable absence of systems 'hardware' meant that systems 'software', i.e. health care workers (HCWs) agency, behaviours and interactions provided the basis of locally relevant strategies for decentralized DR-TB care. 'Software readiness' was manifest in four areas of DR-TB care: re-organization of service delivery, redressal of resource shortages, creation of treatment adherence support systems and extension of care parameters for vulnerable patients. These strategies demonstrate adaptive capacity and everyday resilience among HCW to withstand the demands of policy change and innovation in stressed systems. Our work suggests that a useful extension of health systems 'readiness' assessments would include definition and evaluation of HCW 'software' and adaptive capacities in the face of systems hardware gaps.
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http://dx.doi.org/10.1093/heapol/czaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059133PMC
April 2021

Sixteen novel lineages of SARS-CoV-2 in South Africa.

Nat Med 2021 03 2;27(3):440-446. Epub 2021 Feb 2.

Laboratorio de Flavivirus, Fundacao Oswaldo Cruz, Rio de Janeiro, Brazil.

The first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in South Africa was identified on 5 March 2020, and by 26 March the country was in full lockdown (Oxford stringency index of 90). Despite the early response, by November 2020, over 785,000 people in South Africa were infected, which accounted for approximately 50% of all known African infections. In this study, we analyzed 1,365 near whole genomes and report the identification of 16 new lineages of SARS-CoV-2 isolated between 6 March and 26 August 2020. Most of these lineages have unique mutations that have not been identified elsewhere. We also show that three lineages (B.1.1.54, B.1.1.56 and C.1) spread widely in South Africa during the first wave, comprising ~42% of all infections in the country at the time. The newly identified C lineage of SARS-CoV-2, C.1, which has 16 nucleotide mutations as compared with the original Wuhan sequence, including one amino acid change on the spike protein, D614G (ref. ), was the most geographically widespread lineage in South Africa by the end of August 2020. An early South African-specific lineage, B.1.106, which was identified in April 2020 (ref. ), became extinct after nosocomial outbreaks were controlled in KwaZulu-Natal Province. Our findings show that genomic surveillance can be implemented on a large scale in Africa to identify new lineages and inform measures to control the spread of SARS-CoV-2. Such genomic surveillance presented in this study has been shown to be crucial in the identification of the 501Y.V2 variant in South Africa in December 2020 (ref. ).
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http://dx.doi.org/10.1038/s41591-021-01255-3DOI Listing
March 2021

Benign ethnic neutropenia in a South African population, and its association with HIV acquisition and adverse event reporting in an HIV vaccine clinical trial.

PLoS One 2021 22;16(1):e0241708. Epub 2021 Jan 22.

Faculty of Health Sciences, Perinatal HIV Research Unit, University of Witwatersrand, Johannesburg, South Africa.

Benign ethnic neutropenia (BEN) is defined as a neutrophil count of <1.5×109 cells/L in healthy individuals and is more common in populations of certain ethnicities, e.g. African or Middle Eastern ethnicity. Neutrophil values are commonly included in eligibility criteria for research participation, but little is known about the relationship between BEN, HIV acquisition, and the occurrence of adverse events during clinical trials. We investigated these relationships using data from an HIV vaccine efficacy trial of healthy adults from 5 South African sites. We analysed data from the double-blind, placebo-controlled, randomized trial HVTN 503, and its follow-on study HVTN 503-S to assess the prevalence of BEN, its association with HIV infection, and adverse event reporting. These data were then compared with a time- and age-matched, non-pregnant cohort from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007-2008 in the United States (US). The 739 South African participants had a median age of 22.0 years (interquartile range = 20-26) and 56% (n = 412) were male. Amongst the US cohort of 845 participants, the median age was 26 (IQR: 21-30) and the majority (54%, 457/745) were also male. BEN was present at enrolment in 7.0% (n = 52) of South African participants (6% in the placebo group versus 8% in the vaccine group); 81% (n = 42) of those with BEN were male. Pretoria North had the highest prevalence of BEN (11.6%, 5/43), while Cape Town had the lowest (0.7%, 1/152). Participants with BEN had a lower median neutrophil count (1.3 vs. 3.2x109 cells/L; p<0.001) and BMI (20.8 vs. 22.3 kg/m2; p<0.001) when compared to those without BEN. A greater proportion of Black South Africans had neutrophil counts <1.5×109 cells/L compared to US non-Hispanic Whites from the NHANES cohort (7% [52/739] vs. 0.6% [3/540]; p<0.001). BEN did not increase the odds for HIV infection (adjusted odds ratio [aOR]: 1.364, 95% confidence interval [95% CI]: 0.625-2.976; p = 0.4351). However, female gender (aOR: 1.947, 95% CI: 1.265-2.996; p = 0.0025) and cannabis use (aOR: 2.192, 95% CI: 1.126-4.266; p = 0.0209) increased the odds of HIV acquisition. The incidence rates of adverse events were similar between participants in the placebo group with BEN, and those without: 12.1 (95% CI: 7.3-20.1) vs. 16.5 (95% CI: 14.6-18.7; p = 0.06) events per 100 person-years (py) were noted in the infections and infestations system organ class, respectively. The vaccine group had an event incidence rate of 19.7 (95% CI: 13.3-29.2) vs. 14.8 (95% CI: 13.0-16.8; p = 0.07) events per 100py in the group with, and without BEN, respectively. BEN is more prevalent in Black South Africans compared to US Non-Hispanic Whites. Our data do not support excluding populations from HIV vaccine trials because of BEN. BEN was not associated with increased risk for HIV infection or Adverse events on a vaccine trial. Predictors of HIV infection risk were females and cannabis use, underlying the continued importance of prevention programmes in focusing on these populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241708PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822320PMC
April 2021

First genome sequence of Aeromonas hydrophilia novel sequence type 658 strain isolated from livestock in South Africa.

J Glob Antimicrob Resist 2021 Mar 15;24:175-177. Epub 2021 Jan 15.

Antimicrobial Research Unit, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.

Objectives: The underlying resistance mechanisms, defence systems, mobilome, virulome, clonality and global phylogenetic relationship of a novel sequence type (ST) 658 Aeromonas hydrophilia (A34a) isolated from a pig abattoir in South Africa was determined using whole-genome sequence (WGS) technology.

Methods: Following isolation on chromogenic agar (CHROMID® CARBA SMART), microbial identification and antibiotic susceptibility testing were performed using a VITEK®2 platform. Genotyping involved WGS performed with an Illumina MiSeq platform.

Results: The antibiotic resistome agreed with the resistance phenotype of the isolate and included antibiotic resistance determinants for β-lactams (bla and bla). BLASTn analysis of resistome-encoding contigs affirmed chromosomally-mediated resistance. BURST algorithmic analysis identified the novel ST658 as a satellite variant. Virulome analysis predicted virulence genes of Aeromonas whose expression are critical for establishing infection in the host. Global phylogenomic analyses showed strain A34a is closely related to two international isolates from Sri Lanka (Ae25) and the USA (RU34A), although there is little to suggest that it was imported from abroad.

Conclusion: This is the first report on the genomic analysis of a novel ST658 A. hydrophilia, offering useful insights into its pathogenicity and global phylogenetics.
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http://dx.doi.org/10.1016/j.jgar.2020.12.021DOI Listing
March 2021

Comparative Pathogenomics of from Pigs in South Africa: Dominance of the Novel ST657 Clone.

Microorganisms 2020 Dec 16;8(12). Epub 2020 Dec 16.

Antimicrobial Research Unit, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.

The pathogenomics of carbapenem-resistant isolates recovered from pigs in KwaZulu-Natal, South Africa, was explored by whole genome sequencing on the Illumina MiSeq platform. Genomic functional annotation revealed a vast array of similar central networks (metabolic, cellular, and biochemical). The pan-genome analysis showed that the isolates formed a total of 4349 orthologous gene clusters, 4296 of which were shared; no unique clusters were observed. All the isolates had similar resistance phenotypes, which corroborated their chromosomally mediated resistome (bla and bla) and belonged to a novel sequence type, ST657 (a satellite clone). Isolates in the same sub-clades clustered according to their clonal lineages and host. Mobilome analysis revealed the presence of chromosome-borne insertion sequence families. The estimated pathogenicity score (P ≈ 0.60) indicated their potential pathogenicity in humans. Furthermore, these isolates carried several virulence factors (adherence factors, toxins, and immune evasion), in different permutations and combinations, indicating a differential ability to establish infection. Phylogenomic and metadata analyses revealed a predilection for water environments and aquatic animals, with more recent reports in humans and food animals across geographies, making a potential One Health indicator bacterium.
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http://dx.doi.org/10.3390/microorganisms8122008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765573PMC
December 2020

Antibiotic Susceptibility and Molecular Characterization of Uropathogenic Associated with Community-Acquired Urinary Tract Infections in Urban and Rural Settings in South Africa.

Trop Med Infect Dis 2020 Nov 27;5(4). Epub 2020 Nov 27.

Antimicrobial Research Unit, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.

We investigated the phenotypic and genotypic antibiotic resistance, and clonality of uropathogenic (UPEC) implicated in community-acquired urinary tract infections (CA-UTIs) in KwaZulu-Natal, South Africa. Mid-stream urine samples ( = 143) were cultured on selective media. Isolates were identified using the API 20E kit and their susceptibility to 17 antibiotics tested using the disk diffusion method. Extended-spectrum β-lactamases (ESBLs) were detected using ROSCO kits. Polymerase chain reaction (PCR) was used to detect uropathogenic (targeting the C gene), and β-lactam (-like and ) and fluoroquinolone (qA, qB, qS, A, C, a, and qA) resistance genes. Clonality was ascertained using ERIC-PCR. The prevalence of UTIs of Gram-negative etiology among adults 18-60 years of age in the uMgungundlovu District was 19.6%. Twenty-six isolates were obtained from 28 positive UTI samples. All isolates were C-positive. The highest resistance was to ampicillin (76.9%) and the lowest (7.7%) to amoxicillin/clavulanic acid and gentamycin. Four isolates were multidrug-resistant and three were ESBL-positive, all being -positive but -negative. The a and A were the most detected fluoroquinolone resistance genes (75%). Isolates were clonally distinct, suggesting the spread of genetically diverse UPEC clones within the three communities. This study highlights the spread of genetically diverse antibiotic-resistant CA-UTI aetiologic agents, including multidrug-resistant ones, and suggests a revision of current treatment options for CA-UTIs in rural and urban settings.
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http://dx.doi.org/10.3390/tropicalmed5040176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709581PMC
November 2020

High incidence and persistence of hepatitis B virus infection in individuals receiving HIV care in KwaZulu-Natal, South Africa.

BMC Infect Dis 2020 Nov 16;20(1):847. Epub 2020 Nov 16.

National Health Laboratory Service and School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.

Background: Hepatitis B virus (HBV), Human Immunodeficiency virus (HIV) and Tuberculosis (TB) are common infections in South Africa. We utilized the opportunity of care provision for HIV-TB co-infected patients to better understand the relationship between these coinfections, determine the magnitude of the problem, and identify risk factors for HBV infection in HIV infected patients with and without TB in KwaZulu-Natal, South Africa.

Methods: This retrospective cohort analysis was undertaken in 2018. In-care HIV infected patients were included in the analysis. Results from clinical records were analysed to determine the prevalence, incidence, persistence and factors associated with HBsAg positivity in HIV-infected patients with or without TB co-infection.

Results: A total of 4292 HIV-infected patients with a mean age of 34.7 years (SD: 8.8) were included. Based on HBsAg positivity, the prevalence of HBV was 8.5% (363/4292) [95% confidence interval (CI): 7.7-9.3] at baseline and 9.4% (95%CI: 8.6-10.3%) at end of follow-up. The HBV incidence rate was 2.1/100 person-years (p-y). Risk of incident HBV infection was two-fold higher among male patients (HR 2.11; 95% CI: 1.14-3.92), while severe immunosuppression was associated with a greater than two-fold higher risk of persistent infection (adjusted risk ratio (RR) 2.54; 95% CI 1.06-6.14; p = 0.004. Additionally, active TB at enrolment was associated with a two-fold higher risk of incident HBV infection (aHR 2.38; 95% CI: 0.77-7.35).

Conclusion: The provision of HIV care and treatment in high HBV burden settings provide a missed opportunity for HBV screening, immunization and care provision.
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http://dx.doi.org/10.1186/s12879-020-05575-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670610PMC
November 2020

A genomics network established to respond rapidly to public health threats in South Africa.

Lancet Microbe 2020 Oct 18;1(6):e229-e230. Epub 2020 Aug 18.

KwaZulu-Natal Research Innovation and Sequencing Platform, University of KwaZulu-Natal, Durban, South Africa.

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http://dx.doi.org/10.1016/S2666-5247(20)30116-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434425PMC
October 2020

Discordant line probe genotypic testing vs culture-based drug susceptibility phenotypic testing in TB endemic KwaZulu-Natal: Impact on bedside clinical decision making.

J Clin Tuberc Other Mycobact Dis 2020 Aug 1;20:100176. Epub 2020 Aug 1.

Medical Research Council-CAPRISA HIV-TB Pathogenesis and Treatment Research Unit, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.

The recommendations for drug susceptibility testing include both phenotypic and genotypic methods. This concurrent use of differing testing platforms has created an emerging challenge of discordant results, creating a diagnostic dilemma for the laboratorians as well as attending clinicians. We undertook a retrospective study to determine the prevalence of discordant results between the MTBDR line probe assay and solid culture-based drug susceptibility testing for rifampicin and isoniazid. The analysis was conducted for the period January 2013 and December 2015 at the Inkosi Albert Luthuli Central Hospital. Rifampicin and isoniazid resistance testing data were "paired" on 8273 isolates for culture-based drug susceptibility testing and line probe assay. The latter method showed high sensitivity and specificity of 93% and 95% respectively for isoniazid testing. For rifampicin testing, sensitivity and specificity were 95% and 75%. Overall, discordance was 14.6% for rifampicin and 7.2% for isoniazid. This report is not intended to determine superiority of one method over another. It is merely to show that discordance does exist between different methods of testing. Given the burden of HIV and Tuberculosis in Sub-Saharan Africa, these findings have clinical significance and huge public health implications. Clinicians should understand the limitations of phenotypic testing methods.
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http://dx.doi.org/10.1016/j.jctube.2020.100176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414011PMC
August 2020

Testing the regulatory framework in South Africa - a single-blind randomized pilot trial of commercial probiotic supplementation to standard therapy in women with bacterial vaginosis.

BMC Infect Dis 2020 Jul 10;20(1):491. Epub 2020 Jul 10.

Division of Medical Virology, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, Cape Town, 7925, South Africa.

Background: Bacterial vaginosis (BV) increases HIV risk and adverse reproductive outcomes. Standard-of-care (SOC) for BV are antibiotics; however, cure rates are low. Probiotics for vaginal health may be useful in improving cure and recurrence although the regulatory framework governing probiotics and the conduct of randomized clinical trials to evaluate these has not been established in South Africa. We performed an exploratory single-blind trial evaluating a commercial oral-vaginal-combination probiotic as adjunct to SOC for BV treatment.

Methods: Women with symptomatic vaginal discharge were screened for BV and common sexually transmitted infections (STIs). BV+ (Nugent 7-10) but STI- women were randomized to vaginal metronidazole alone (n = 12) or to metronidazole followed by a commercial oral/vaginal probiotic (n = 18). The primary qualitative outcome was to test the regulatory landscape for conducting randomized probiotic trials in South Africa; and acceptability of vaginal application by women. BV cure at 1 month (Nugent≤3) was the primary quantitative endpoint. Secondary quantitative endpoints were BV recurrence, symptoms, vaginal microbiota and genital cytokine changes over 5 months post-treatment.

Results: The  South African Health Products Regulatory Authority (SAHPRA) reviewed and approved this trial. As probiotics continue to be regulated as health supplements in South Africa, SAHPRA required a notification application for this trial. Acceptability and adherence to the oral and vaginal application of the probiotic were high, although women reported a preference for oral capsules. 44.8% of women cleared BV one-month post-treatment, and no significant differences in BV cure (RR = 0.52, 95% CI = 0.24-1.16), recurrence, vaginal pH, symptoms, microbiota or vaginal IL-1α concentrations were found between SOC and intervention groups in this pilot study with an over-the-counter product.

Conclusion: Navigation of the SAHPRA registration process for evaluating a commercial probiotic in a randomised trial laid the foundation for planned larger trials of improved probiotic products for vaginal health in South Africa. Although adherence to the vaginally delivered probiotic was high, women preferred oral application and we recommend that improvements in the content and method of application for future probiotics for vaginal health should be considered.

Trial Registration: This trial was registered on 17 October 2017 with the South African National Clinical Trial Register ( http://www.sanctr.gov.za/ ; BV-trial1; DOH-27-1117-5579 ).
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http://dx.doi.org/10.1186/s12879-020-05210-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350581PMC
July 2020

Impact of Viral Load Monitoring on Retention and Viral Suppression: A Regression Discontinuity Analysis of South Africa's National Laboratory Cohort.

Am J Epidemiol 2020 12;189(12):1492-1501

South African guidelines recommend repeat viral load testing within 6 months when human immunodeficiency virus (HIV) viral loads exceed 1,000 copies/mL. We assessed whether South African facilities follow viral load monitoring guidelines and whether guidelines improve HIV-related outcomes, using a regression discontinuity design in a national HIV cohort of 174,574 patients (2013-2015). We assessed whether patients with viral loads just above versus just below 1,000 copies/mL were more likely to receive repeat testing in 6 months, and we compared differences in clinic transfers, retention, and viral suppression. The majority (67%) of patients with viral loads of >1,000 copies/mL did not receive repeat testing within 6 months, and these patients were 8.0% (95% confidence interval (CI): 6.2, 9.7) more likely to receive repeat testing compared with ≤1,000 copies/mL. Eligibility for repeat testing (>1,000 copies/mL) was associated with greater 12-month retention (risk difference = 2.9%, 95% CI: 0.6, 5.2) and combined suppression and retention (risk difference = 5.8%, 95% CI: 3.0, 8.6). Patients with viral loads of >1,000 copies/mL who actually received repeat testing were 85.2% more likely to be both retained and virally suppressed at 12 months (95% CI: 35.9, 100.0). Viral load monitoring might improve patient outcomes, but most patients with elevated viral loads do not receive monitoring within recommended timelines.
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http://dx.doi.org/10.1093/aje/kwaa140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705603PMC
December 2020

Delays in repeat HIV viral load testing for those with elevated viral loads: a national perspective from South Africa.

J Int AIDS Soc 2020 07;23(7):e25542

Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

Introduction: In South Africa, HIV patients with an elevated viral load (VL) should receive repeat VL testing after adherence counselling. We set out to use a national HIV Cohort to describe time to repeat viral load testing across South Africa and identify predictors of time to repeat testing.

Methods: We conducted a cohort study of prospectively collected laboratory data. HIV treatment guidelines have changed over time in South Africa, but call for repeat VL testing within six months if 400 to 1000 copies/mL and two to three months if >1000 copies/mL. We included patients with suppressed viral loads (indicating they are on ART) and a first elevated VL (>400 copies/mL) between April 2004 and December 2014. Follow-up began at first elevated VL and continued until repeat testing, loss to follow-up or December 2016. We calculated adjusted hazard ratios (aHR) using Cox proportional hazard models.

Results: Of 371,648 patients with a VL > 400, 83.9% (311,790) had a repeat VL, in a median (IQR) of 7.0 (4.1 to 12.2) months. Of those with a first viral load 400 to 1000 copies/mL, 56.4% had a repeat VL within guideline recommended six months (defined as up to nine months), whereas among those >1000 copies/mL only 47.7% had a repeat viral load within guideline recommended two to three months (defined as up to six months). We found a small increase in repeat testing associated with higher VL value (aHR 1.11; 95% CI: 1.10 to 1.12 comparing >1000 vs 400 to 1000 copies/mL) and very low CD4 counts at first elevated VL (aHR 1.16; 95% CI: 1.13 to 1.19 comparing CD4 < 50 vs <500 cells/mm ). We also found strong variation in time to repeat VL testing by province.

Conclusions: Median time to repeat viral load testing for those with an elevated viral load was longer than guidelines recommend. Future work should identify whether delays are due to patient or provider factors.
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http://dx.doi.org/10.1002/jia2.25542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343337PMC
July 2020

HIV treatment outcomes among people with initiation CD4 counts >500 cells/µL after implementation of Treat All in South African public clinics: a retrospective cohort study.

J Int AIDS Soc 2020 04;23(4):e25479

Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa.

Introduction: The World Health Organisation recommends to Treat All people with HIV, irrespective of CD4 count. However, people with CD4 counts >500 cells/µL may be asymptomatic and therefore less motivated to adhere to antiretroviral therapy (ART). We aimed to assess whether people initiated with CD4 counts >500 cells/µL had worse treatment outcomes compared to those initiated at lower CD4 counts.

Methods: We performed a retrospective cohort study among non-pregnant adults initiating ART at eight public clinics in South Africa between September 2016, when Treat All was implemented, and August 2017. We assessed whether initiation CD4 count >500 cells/µL was associated with the outcomes of attrition (death, lost to follow-up or treatment interruption >180 days), and viraemia >1000 copies/mL, by twelve months using Cox proportional hazards and Poisson regression models.

Results And Discussion: Among 4952 patients initiating ART, the median age was 32.4 years (interquartile range (IQR) 27.2 to 39.7), 58.9% were women and 30.3% had an initiation CD4 count >500 cells/µL. After twelve months, 3382 (68.3%) were retained in care, 303 (6.1%) had transferred to another clinic, 1010 (20.4%) were lost to follow-up, 232 (4.7%) had a treatment interruption >180 days and 25 (0.5%) were known to have died. Overall, 1267 experienced attrition at a median time of 91 days (IQR 23 to 213), with 302 of these (23.8%) experiencing attrition immediately after their ART initiation visit. Among those in care at twelve months with viral load results, 4.6% had viraemia. In multivariable analysis, the hazard of attrition was similar between patients newly eligible for ART with CD4 counts >500 cells/µL compared to those with CD4 ≤500 cells/µL (adjusted hazard ratio 1.03, 95% confidence interval (CI) 0.90 to 1.17). The risk of viraemia was lower among patients with CD4 counts >500 cells/µL compared to those with CD4 ≤500 cells/µL (adjusted risk ratio 0.58, 95% CI 0.37 to 0.92).

Conclusions: After implementation of Treat All in South African public clinics, we found that patients newly eligible for ART with initiation CD4 counts >500 cells/µL had comparable or better outcomes compared to those with lower CD4 counts. These finding support ongoing implementation of Treat All in our setting.
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http://dx.doi.org/10.1002/jia2.25479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174836PMC
April 2020

Modeling Missing Cases and Transmission Links in Networks of Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

Am J Epidemiol 2020 07;189(7):735-745

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.

Patterns of transmission of drug-resistant tuberculosis (TB) remain poorly understood, despite over half a million incident cases worldwide in 2017. Modeling TB transmission networks can provide insight into drivers of transmission, but incomplete sampling of TB cases can pose challenges for inference from individual epidemiologic and molecular data. We assessed the effect of missing cases on a transmission network inferred from Mycobacterium tuberculosis sequencing data on extensively drug-resistant TB cases in KwaZulu-Natal, South Africa, diagnosed in 2011-2014. We tested scenarios in which cases were missing at random, missing differentially by clinical characteristics, or missing differentially by transmission (i.e., cases with many links were under- or oversampled). Under the assumption that cases were missing randomly, the mean number of transmissions per case in the complete network needed to be larger than 20, far higher than expected, to reproduce the observed network. Instead, the most likely scenario involved undersampling of high-transmitting cases, and models provided evidence for super-spreading. To our knowledge, this is the first analysis to have assessed support for different mechanisms of missingness in a TB transmission study, but our results are subject to the distributional assumptions of the network models we used. Transmission studies should consider the potential biases introduced by incomplete sampling and identify host, pathogen, or environmental factors driving super-spreading.
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http://dx.doi.org/10.1093/aje/kwaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443195PMC
July 2020

In silico Design and Synthesis of Tetrahydropyrimidinones and Tetrahydropyrimidinethiones as Potential Thymidylate Kinase Inhibitors Exerting Anti-TB Activity Against .

Drug Des Devel Ther 2020 9;14:1027-1039. Epub 2020 Mar 9.

Department of Microbiology, National Health Laboratory Services, KZN Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban 4001, South Africa.

Background And Purpose: Tuberculosis has been reported to be the worldwide leading cause of death resulting from a sole infectious agent. The emergence of multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis has made the battle against the infection more difficult since most currently available therapeutic options are ineffective against these resistant strains. Therefore, novel molecules need to be developed to effectively treat tuberculosis disease. Preliminary docking studies revealed that tetrahydropyrimidinone derivatives have favorable interactions with the thymidylate kinase receptor. In the present investigation, we report the synthesis and the mycobacterial activity of several pyrimidinones and pyrimidinethiones as potential thymidylate kinase inhibitors.

Methods: The title compounds () and () were synthesized by a one-pot three-component Biginelli reaction. They were subsequently characterized and used for whole-cell anti-TB screening against H37Rv and multidrug-resistant (MDR) strains of (MTB) by the resazurin microplate assay (REMA) plate method. Molecular modeling was conducted using the Accelry's Discovery Studio 4.0 client program to explain the observed bioactivity of the compounds. The pharmacokinetic properties of the synthesized compounds were predicted and analyzed.

Results: Of the compounds tested for anti-TB activity, pyrimidinone and pyrimidinethione displayed moderate activity against susceptible MTB H37Rv strains at 16 and 32 µg/mL, respectively. Only compound was observed to exert modest activity at 128 µg/mL against MTB strains with cross-resistance to rifampicin and isoniazid. The presence of the trifluoromethyl group was essential to retain the inhibitory activity of compounds and . Molecular modeling studies of these compounds against thymidylate kinase targets demonstrated a positive correlation between the bioactivity and structure of the compounds. The in-silico ADME (absorption, distribution, metabolism, and excretion) prediction indicated favorable pharmacokinetic and drug-like properties for most compounds.

Conclusion: Pyrimidinone and pyrimidinethione were identified as the leading compounds and can serve as a starting point to develop novel anti-TB therapeutic agents.
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http://dx.doi.org/10.2147/DDDT.S228381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082623PMC
February 2021

Assessing a diagnosis tool for bacterial vaginosis.

Eur J Clin Microbiol Infect Dis 2020 Aug 20;39(8):1481-1485. Epub 2020 Mar 20.

Department of Microbiology, National Health Laboratory Services, KwaZulu-Natal Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban, South Africa.

Diagnosis of bacterial vaginosis (BV) in resource-poor settings relies on semiquantitative microscopy algorithm such as the Nugent score (NS). We evaluated a quantitative real-time PCR (qPCR) assay to detect and quantify individual BV-associated bacterial communities. Vaginal swabs from 247 South African women attending an STI clinic were evaluated for BV using NS. We used qPCR to analyze DNA from vaginal swabs for eight BV-associated bacteria, Gardnerella vaginalis (GV), Prevotella bivia (PB), BV-associated bacteria 2 (BVAB2), Megasphaera-1 (M-1), Atopobium vaginae (AV), Lactobacillus crispatus (LC), Lactobacillus jensenii (LJ), and Lactobacillus iners (LI). Sensitivities and specificities were generated for each qPCR assay. Using a ROC analysis, cutoffs were calculated for each bacterial species. A logistic regression model was used to determine the strongest predictors of BV status. Nugent scores indicated 35.6% of patients harbor BV-associated flora (NS 7-10). AV, GV, GAMB (GV + AV + M-1 + BVAB2), and LC + LJ showed the highest AUC, sensitivities, and specificities (listed respectively): AV (0.96; 96%; 93%), GV (0.88; 78%; 79%), GAMB (0.9; 87%; 82%), and LC + LJ (0.84; 82%; 72%) (all p < 0.05). Increased GAMB copies (effect = 0.15, p = 0.01) and decreased LC + LJ copies (effect = - 0.26, p < 0.0001) demonstrated the strongest association with higher BV scoring. Scoring of BV did not differ across our qPCR assay when compared to the commercial BD MAX® and the gold standard Nugent scores. We developed an accurate assay, which has the potential to be used as a BV diagnosis tool that is cost-effective and has the potential to be utilized in a resource limited setting.
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http://dx.doi.org/10.1007/s10096-020-03862-3DOI Listing
August 2020

Synthesis and Biological Evaluation of Novel Carbazole Hybrids as Promising Antimicrobial Agents.

Chem Biodivers 2020 May 15;17(5):e1900550. Epub 2020 Apr 15.

Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (Westville), Durban, 4000, South Africa.

Two series of carbazole analogs of 8-methoxy-N-substituted-9H-carbazole-3-carboxamides (series 1) and carbazolyl substituted rhodanines (series 2) were synthesized through facile synthetic routes. All the final compounds from these two series were evaluated for their preliminary in vitro antifungal and antibacterial activity against four fungal (Candida albicans, Cryptococcus neoformans, Cryptococcus tropicalis and Aspergillus niger) and four bacterial (Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa) strains, respectively. Among the tested compounds, three compounds of series 1 displayed promising antifungal and antibacterial activity, especially against C. neoformans and S. aureus. In addition, one compound of series 1 displayed notable antimicrobial activity (MIC: 6.25 μg/mL) against clinical isolates of C. albicans and C. neoformans (MIC: 12.5 μg/mL). From the second series, four compounds exhibited significant antifungal and antibacterial activity, especially against C. neoformans and S. aureus. The most active compound of series 2 displayed a prominent antimicrobial activity against C. neoformans (MIC: 3.125 μg/mL) and S. aureus (MIC: 1.56 μg/mL), respectively.
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http://dx.doi.org/10.1002/cbdv.201900550DOI Listing
May 2020

Point-of-care HIV viral load testing combined with task shifting to improve treatment outcomes (STREAM): findings from an open-label, non-inferiority, randomised controlled trial.

Lancet HIV 2020 04 24;7(4):e229-e237. Epub 2020 Feb 24.

Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa; School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.

Background: Monitoring HIV treatment with laboratory testing introduces delays for providing appropriate care in resource-limited settings. The aim of our study was to determine whether point-of-care HIV viral load testing with task shifting changed treatment and care outcomes for adults on antiretroviral therapy (ART) when compared with standard laboratory viral load testing.

Methods: We did an open-label, non-inferiority, randomised controlled trial in a public clinic in Durban, South Africa. We enrolled HIV-positive adults (aged ≥18 years) who presented for their first routine HIV viral load test 6 months after ART initiation. Individuals were randomly assigned by a random number allocation sequence to receive either point-of-care viral load testing at enrolment and after 6 months with task shifting to enrolled nurses (intervention group), or laboratory viral load testing (standard-of-care group). The primary outcome was combined viral suppression (<200 copies per mL) and retention at 12 months after enrolment. A non-inferiority margin of 10% was used. Analysis was done by intention to treat. This study was registered with ClinicalTrials.gov, NCT03066128.

Findings: Between Feb 24, 2017, and Aug 23, 2017, we screened 657 participants, and 390 were enrolled and randomly assigned to either the intervention group (n=195) or standard-of-care group (n=195). 175 (90%) individuals in the intervention group and 148 (76%) individuals in the standard-of-care group had the primary outcome of retention with viral suppression, a difference of 13·9% (95% CI 6·4-21·2; p<0·00040). 182 participants (93%) in the intervention group had viral suppression compared with 162 (83%) in the standard-of-care group (difference 10·3%, 3·9-16·8; p=0·0025); 180 (92%) and 162 (85%) were retained in care (7·7%, 1·3-14·2; p=0·026). There were no adverse events related to point-of-care HIV viral load testing or task shifting.

Interpretation: Point-of-care viral load testing combined with task shifting significantly improved viral suppression and retention in HIV care. Point-of-care testing can simplify treatment and improve outcomes for HIV-positive adults receiving ART in resource-limited settings.

Funding: National Institute of Allergy and Infectious Diseases.
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http://dx.doi.org/10.1016/S2352-3018(19)30402-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183312PMC
April 2020

Pathogenomic Analysis of a Novel Extensively Drug-Resistant Isolate Carrying a bla Carbapenemase in South Africa.

Pathogens 2020 Jan 31;9(2). Epub 2020 Jan 31.

Antimicrobial Research Unit, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.

Pathogenomic analysis was performed on a novel carbapenem-resistant isolate (H2730R) from a rectal swab of an adult male patient admitted to a tertiary hospital, Durban, South Africa. H2730R was identified using selective media and API 20e kit. Confirmatory identification and antibiotic susceptibility testing were performed using the VITEK II. H2730R was whole-genome sequenced on the Illumina MiSeq platform. H2730R was resistant to all tested antibiotics except tigecycline and was defined as ST498 by the multilocus sequence typing (MLST) database. The estimated pathogenic potential predicted a higher probability (P ≈ 0.875), supporting H2730R as a human pathogen. H2730R harbored 25 putative acquired resistance genes, 4 plasmid replicons, 4 intact prophages, a class 1 integron (IntI1), 2 predominant insertion sequences (IS3 and IS5), numerous efflux genes, and virulome. BLASTn analysis of the bla encoding contig (00022) and its flanking sequences revealed the bla was located on a plasmid similar to the multireplicon p18-43_01 plasmid reported for the spread of carbapenem resistance in South Africa. Phylogenomic analysis showed clustering of H2730R with CF003/CF004 strains in the same clade, suggesting a possible association between C. freundii strains/clones. Acquiring the p18-43_01 plasmid containing bla, the diversity, and complex resistome, virulome, and mobilome of this pathogen makes its incidence very worrying regarding mobilized resistance. This study presents the background genomic information for future surveillance and tracking of the spread of carbapenem-resistant in South Africa.
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http://dx.doi.org/10.3390/pathogens9020089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168644PMC
January 2020

Effect of HIV Envelope Vaccination on the Subsequent Antibody Response to HIV Infection.

mSphere 2020 Jan 29;5(1). Epub 2020 Jan 29.

National Institute for Communicable Diseases of the National Health Laboratory Service (NHLS), Johannesburg, South Africa

Analysis of breakthrough HIV-1 infections could elucidate whether prior vaccination primes relevant immune responses. Here, we measured HIV-specific antibody responses in 14 South African volunteers who acquired HIV infection after participating in phase 1/2 trials of envelope-containing immunogens. Serum samples were collected annually following HIV-1 infection from participants in trials HVTN 073 (subtype C, DNA/MVA, phase 1 trial,  = 1), HVTN 086 (subtype C, DNA/MVA/gp140 protein, phase 1 trial,  = 2), and HVTN 204 (multisubtype, DNA/adenovirus serotype 5 [Ad5], phase 2 trial,  = 7) and 4 placebo recipients. Binding and neutralizing antibody responses to Env proteins and peptides were determined pre- and post-HIV infection using an enzyme-linked immunosorbent assay and the TZM-bl cell neutralization assay, respectively. HIV-infected South African individuals served as unvaccinated controls. Binding antibodies to gp41, V3, V2, the membrane-proximal external region (MPER), and the CD4 binding site were detected from the first year of HIV-1 subtype C infection, and the levels were similar in vaccinated and placebo recipients. Neutralizing antibody responses against tier 1A viruses were detected in all participants, with the highest titers being to a subtype C virus, MW965.26. No responses were observed just prior to infection, indicating that vaccine-primed HIV-specific antibodies had waned. Sporadic neutralization activity against tier 2 isolates was observed after 2 to 3 years of HIV infection, but these responses were similar in the vaccinated and placebo groups as well as the unvaccinated controls. Our data suggest that prior vaccination with these immunogens did not alter the antibody responses to HIV-1 infection, nor did it accelerate the development of HIV neutralization breadth. There is a wealth of information on HIV-specific vaccine-induced immune responses among HIV-uninfected participants; however, data on immune responses among participants who acquire HIV after vaccination are limited. Here we show that HIV-specific binding antibody responses in individuals with breakthrough HIV infections were not affected by prior vaccination with HIV envelope-containing immunogens. We also found that these vectored vaccines did not prime tier 2 virus-neutralizing antibody responses, which are thought to be required for prevention against HIV acquisition, or accelerate the development of neutralization breadth. Although this study is limited, such studies can provide insights into whether vaccine-elicited antibody responses are boosted by HIV infection to acquire broader neutralizing activity, which may help to identify antigens relevant to the design of more effective vaccines.
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http://dx.doi.org/10.1128/mSphere.00738-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992371PMC
January 2020

Genomic Analysis of CarbapenemaseProducing Extensively Drug-Resistant Isolates Reveals the Horizontal Spread of p18-43_01 Plasmid Encoding in South Africa.

Microorganisms 2020 Jan 17;8(1). Epub 2020 Jan 17.

Antimicrobial Research Unit, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.

Whole-genome sequence (WGS) analyses were employed to investigate the genomic epidemiology of extensively drug-resistant strains, focusing on the carbapenem resistance-encoding determinants, mobile genetic support, clonal and epidemiological relationships. A total of ten isolates were obtained from patients admitted to the intensive care unit (ICU) in a public hospital in South Africa. Five isolates were from rectal swabs of colonized patients and five from blood cultures of patients with invasive carbapenem-resistant infections. Following microbial identification and antibiotic susceptibility tests, the isolates were subjected to WGS on the Illumina MiSeq platform. All the isolates showed genotypic resistance to tested β-lactams (NDM-1, OXA-1, CTX-M-15, TEM-1B, SHV-1) and other antibiotics. All but one isolate belonged to the ST152 with a novel sequence type, ST3136, differing by a single-locus variant. The isolates had the same plasmid multilocus sequence type (IncF[K12:A-:B36]) and capsular serotype (), supporting the epidemiological linkage between the clones. Resistance to carbapenems in the 10 isolates was conferred by the mediated by the acquisition of multi-replicon [ColRNAI, IncFIB(pB171), Col440I, IncFII, IncFIB(K) and IncFII(Yp)] p18-43_01 plasmid. These findings suggest that the acquisition of bla-bearing plasmid structure (p18-43_01), horizontal transfer and clonal dissemination facilitate the spread of carbapenemases in South Africa. This emphasizes the importance of targeted infection control measures to prevent dissemination.
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http://dx.doi.org/10.3390/microorganisms8010137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023316PMC
January 2020

Resazurin microtitre plate assay and Sensititre® MycoTB for detection of resistance in a high tuberculosis resistance setting.

Afr J Lab Med 2019 13;8(1):840. Epub 2019 Dec 13.

Department of Medical Microbiology, National Health Laboratory Services, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban, South Africa.

Background: Rapid diagnosis of drug-resistant is a challenge in low-income countries. Phenotypic drug susceptibility testing using Sensititre MycoTB assay and the resazurin microtitre plate assay (REMA) are relatively new innovative methods to determine drug susceptibility.

Objectives: This study aimed to determine the performance of the Sensititre and REMA for drug susceptibility testing in a high-volume tuberculosis reference laboratory.

Methods: A laboratory-based study was performed at the Inkosi Albert Luthuli Central Hospital Tuberculosis Laboratory from January 2014 to June 2015. The Sensititre MycoTB plate and REMA were compared to the gold standard agar proportion method (APM) using 134 stored isolates.

Results: Agreement between the Sensititre MycoTB plate and APM was observed with 98% sensitivity, 82% specificity, 94% positive and 93% negative predictive values of the Sensititre MycoTB assay for the detection of rifampicin resistance and 97%, 96%, 99% and 88% for isoniazid resistance. Good categorical agreement between the REMA and the APM was observed among isolates with 89% sensitivity, 68% specificity, 89% positive and 68% negative predictive value for the detection of rifampicin resistance and 95%, 96%, 99% and 81% for isoniazid resistance. Results for the second-line drugs showed elevated minimum inhibitory concentrations for multidrug-resistant and extensively drug-resistant tuberculosis isolates.

Conclusion: The REMA and Sensititre MycoTB plate are attractive alternatives to the gold standard APM for the phenotypic detection of drug resistance.
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http://dx.doi.org/10.4102/ajlm.v8i1.840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956686PMC
December 2019

The Impact of Concurrent Antiretroviral Therapy and MDR-TB Treatment on Adverse Events.

J Acquir Immune Defic Syndr 2020 01;83(1):47-55

Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.

Background: South Africa has among the highest incidence of multidrug-resistant tuberculosis (MDR-TB) and more than 70% of patients are HIV co-infected. MDR-TB treatment is associated with frequent adverse events (AEs). Although guidelines recommend concurrent treatment of MDR-TB and HIV, safety data on concurrent therapy are limited.

Methods: We conducted a prospective observational study of MDR-TB patients with and without HIV-coinfection in South Africa between 2011 and 2015. Participants received standardized MDR-TB and HIV regimens. Participants were followed monthly for the duration of MDR-TB therapy and screened for clinical and laboratory AEs. Audiometry was performed monthly during the intensive phase; color discrimination testing was performed every 2 months.

Results: We enrolled 150 HIV-infected and 56 HIV-uninfected participants. Nearly all experienced at least one clinical (93%) or laboratory (96%) AE. The most common clinical AEs were peripheral neuropathy (50%) and difficulty sleeping (48%); the most common laboratory AEs were hypokalemia (47%) and decreased creatinine clearance (46%). Among 19 clinical and lab AEs examined, there were no differences by HIV status, except for diarrhea (27% HIV-infected vs. 13% HIV-uninfected, P = 0.03). Hearing loss was experienced by 72% of participants (8% severe loss). Fourteen percent experienced color discrimination loss (4% severe loss). There were no differences in frequency or severity of hearing or vision loss by HIV status.

Conclusions: AEs were common, but not more frequent or severe among MDR-TB/HIV co-infected participants receiving concurrent antiretroviral therapy. Given the favorable treatment outcomes associated with concurrent treatment, antiretroviral therapy initiation should not be delayed in MDR-TB patients with HIV-coinfection.
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http://dx.doi.org/10.1097/QAI.0000000000002190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903405PMC
January 2020