Search

BackgroundNeisseria gonorrhoeae is a major public health problem due to increasing incidence and antimicrobial resistance. Genetic markers of reduced susceptibility have been identified; the extent to which those are representative of global antimicrobial resistance is unknown. We evaluated the performance of whole-genome sequencing (WGS) used to predict susceptibility to ciprofloxacin and other antimicrobials using a global collection of N. gonorrhoeae isolates.MethodsSusceptibility testing of common antimicrobials and the recently developed zolifodacin was performed using agar dilution to determine minimum inhibitory concentrations (MICs). We identified resistance alleles at loci known to contribute to antimicrobial resistance in N. gonorrhoeae from WGS data. We tested the ability of each locus to predict antimicrobial susceptibility.ResultsA total of 481 N. gonorrhoeae isolates, collected between 2004 and 2019 and making up 457 unique genomes, were sourced from 5 countries. All isolates with demonstrated susceptibility to ciprofloxacin (MIC ≤0.06 μg/mL) had a wild-type gyrA codon 91. Multilocus approaches were needed to predict susceptibility to other antimicrobials. All isolates were susceptible to zoliflodacin, defined by an MIC ≤0.25 μg/mL.ConclusionsSingle marker prediction can be used to inform ciprofloxacin treatment of N. gonorrhoeae infection. A combination of molecular markers may be needed to determine susceptibility for other antimicrobials.

BackgroundSexually transmitted infections (STIs) during pregnancy are associated with adverse birth outcomes, including preterm birth, low birth weight, perinatal death, and congenital infections such as increased mother-to-child HIV transmission. Prevalence of STIs among pregnant women in South Africa remains high, with most women being asymptomatic for their infection(s). Unfortunately, most STIs remain undetected and untreated due to standard practice syndromic management in accordance with World Health Organization (WHO) guidelines. Although lab-based and point-of-care molecular tests are available, optimal screening strategies during pregnancy, their health impact, and cost-effectiveness are unknown.MethodsWe will implement a 3-arm (1:1:1) type-1 hybrid effectiveness-implementation randomized-controlled trial (RCT). We will enroll 2500 pregnant women attending their first antenatal care (ANC) visit for their current pregnancy at participating health facilities in Buffalo City Metro District, Eastern Cape Province, South Africa. Participants allocated to arms 1 and 2 (intervention) will receive GeneXpert® point-of-care diagnostic testing for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, with same-day treatment for detected infection(s). Arm 1 will additionally receive a test-of-cure 3 weeks post-treatment, while Arm 2 will receive a repeat test at 30-34 weeks' gestation. Those allocated to Arm 3 will receive syndromic management (standard-of-care). The RE-AIM framework will be used to guide collection of implementation indicators to inform potential future scale up. Primary outcome measures include (1) frequency of adverse birth outcomes among study arms, defined by a composite measure of low birth weight and pre-term delivery, and (2) change in STI prevalence between baseline and birth outcome among intervention arms and compared to standard-of-care. Estimates and comparative costs of the different screening strategies relative to standard-of-care and the costs of managing adverse birth outcomes will be calculated. Cost-effectiveness will be assessed per STI and disability-adjusted life year averted.DiscussionThis trial is the first RCT designed to identify optimal, cost-effective screening strategies that decrease the burden of STIs during pregnancy and reduce adverse birth outcomes. Demonstrating the impact of diagnostic screening and treatment, compared to syndromic management, on birth outcomes will provide critical evidence to inform changes to WHO guidelines for syndromic management of STIs during pregnancy.Trial registrationClinicalTrials.gov NCT04446611 . Registered on 25 June 2020.

Humanity is currently facing the challenge of two devastating pandemics caused by two very different RNA viruses: HIV-1, which has been with us for decades, and SARS-CoV-2, which has swept the world in the course of a single year. The same evolutionary strategies that drive HIV-1 evolution are at play in SARS-CoV-2. Single nucleotide mutations, multi-base insertions and deletions, recombination, and variation in surface glycans all generate the variability that, guided by natural selection, enables both HIV-1's extraordinary diversity and SARS-CoV-2's slower pace of mutation accumulation. Even though SARS-CoV-2 diversity is more limited, recently emergent SARS-CoV-2 variants carry Spike mutations that have important phenotypic consequences in terms of both antibody resistance and enhanced infectivity. We review and compare how these mutational patterns manifest in these two distinct viruses to provide the variability that fuels their evolution by natural selection.

Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus.sup.1,2. 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.sup.3-5. 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.sup.6-8. The 501Y.V2 variant of SARS-CoV-2 in South Africa became dominant over other variants within weeks of its emergence, suggesting that this variant is linked to increased transmissibility or immune escape., Author(s): Houriiyah Tegally [sup.1] , Eduan Wilkinson [sup.1] , Marta Giovanetti [sup.2] [sup.3] , Arash Iranzadeh [sup.4] , Vagner Fonseca [sup.1] [sup.3] , Jennifer Giandhari [sup.1] , Deelan Doolabh [sup.5] [...]

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).sup.1. 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.sup.2. 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. .sup.3), 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. .sup.4), 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. .sup.5). Interrogation of 1,365 near whole-genome sequences of SARS-CoV-2 variants isolated in South Africa during the first 6 months of the global pandemic reveals three major monophyletic lineages responsible for more than half of the infections in the country and underscores the value of integrating genomic surveillance methods to inform the national pandemic response., Author(s): Houriiyah Tegally [sup.1] , Eduan Wilkinson [sup.1] , Richard J. Lessells [sup.1] , Jennifer Giandhari [sup.1] , Sureshnee Pillay [sup.1] , Nokukhanya Msomi [sup.2] , Koleka Mlisana [sup.3] , [...]

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 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. Keywords: viral load; viral suppression; monitoring; retention; laboratory testing; cohort; HIV, 1 | INTRODUCTION After patients initiate antiretroviral therapy (ART) for treatment of HIV, laboratory monitoring of patient progress is critical to ensuring treatment success. For individual patients, this means reaching [...]

Introduction: The World Health Organisation recommends to Treat All people with HIV, irrespective of CD4 count. However, people with CD4 counts >500 cells/[micro]L 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/[micro]L 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/[micro]L 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/[micro]L. 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/[micro]L compared to those with CD4 [less than or equal to]500 cells/[micro]L (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/[micro]L compared to those with CD4 [less than or equal to]500 cells/[micro]L (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/[micro]L had comparable or better outcomes compared to those with lower CD4 counts. These finding support ongoing implementation of Treat All in our setting. Keywords: HIV; Treat All; viral load; CD4; antiretroviral therapy; universal test and treat, 1 | INTRODUCTION In 2015 the World Health Organization (WHO) introduced its Treat All guidelines, which recommend antiretroviral therapy (ART) for all people living with HIV (PLHIV), including those with [...]

By comparing younger to older participants enrolled in a HIV vaccine efficacy trial, we aimed to gain insights into the inclusion of adolescents in future trials. This was a sub-analysis of a multisite HIV vaccine randomized clinical trial in South Africa, conducted January-September 2007. Motivations for trial enrolment, social harms, adverse events and loss to follow-up were compared between younger (18-20 years old) and older participants (21-35 years old). Both younger (n = 238) and older participants (n = 563) were equally likely to report enrolling for altruistic reasons. Younger females were less likely than older participants to join for trial reimbursement (p = 0.005), while younger males were more likely to enrol because the vaccine may provide protection from HIV-acquisition (p < 0.001). There were no significant differences in the number of social harms reported. Compared to males over 20 years old, 18-20-year-old females were less likely to experience adverse events (OR = 0.1, CI 0.01-0.80) and no more likely to be lost to follow-up (OR = 0.7, CI 0.39-1.25), while 18-20-year-old males were no more likely to experience adverse events (OR = 1.3, CI 0.58-2.83) or loss to follow-up (OR = 0.8, CI 0.51-1.41). Our data support the inclusion of younger participants who are at risk for HIV in future HIV vaccine efficacy trials.

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., Author(s): Jacob Bor 1,2,3,*, Anna Gage 4, Dorina Onoya 2, Mhairi Maskew 2, Yorghos Tripodis 5, Matthew P. Fox 1,2,3, Adrian Puren 6, Sergio Carmona 6, Koleka Mlisana 6, William [...]

Respiratory diphtheria, caused by toxigenic strains of the gram-positive bacillus Corynebacterium diphtheriae, is an upper respiratory tract disease characterized by a sore throat; mild fever; and gray-white pseudomembrane on the [...]

Drug-resistant tuberculosis (TB) poses a significant threat to global health, with an estimated 480,000 new cases of multidrug-resistant tuberculosis (MDR TB) in 2014; 10% of these cases were classified as [...]