Browsing by Department "Division of Infectious Disease and HIV Med"

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    Acute generalised exanthematous pustulosis secondary to cotrimoxazole or tenofovir
    (2012) Black, J; Kruger, R; Roberts, R; Lehloenya, R; Mendelson, M
    Cutaneous adverse drug reactions are a common complication of antiretroviral therapy and of drugs used to treat opportunistic infections. We present a rare case of acute generalised exanthematous pustulosis secondary to cotrimoxazole or tenofovir.
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    Atypical pneumonia in adults in southern Africa
    (South African Academy of Family Physicians, 2012) Dlamini, S K; Mendelson, M
    The true incidence of Legionella pneumophilia, Mycoplasma pneumoniae, Chlamydophila pneumoniae and Coxiella burnetti, the so-called atypical pathogens that cause adult community-acquired pneumonia in southern Africa, is unknown. Although there are a lack of community-based studies, hospital-based studies suggest that the incidence may be as high as 30% in patients admitted to, but not requiring, an intensive care unit. A lack of specific clinical features that differentiate atypical pathogens, plus the lack of reliable, simple diagnostics, compound the uncertainty regarding the contribution of atypical pathogens to the sum total of community-acquired pneumonia in southern Africa. Without reliable diagnostic tests, macrolide or azalide antibiotics are widely used for in-patients with pneumonia, potentially fuelling the rise of antibiotic resistance to macrolides in other bacteria.
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    Beware of 'normal' creatine kinase levels in HIV-associated polmyositis
    (2010) Heckmann, Janine; Pillay, Komala; Kenyon, Christopher R
    Generalised weakness may be a common complaint of persons infected with HIV, but the development of significant proximal weakness requires specific attention. Polymyositis may occur in HIV infection and is readily treatable with prednisone. Elevated creatine kinase (CK) levels have been regarded as an important criterion for diagnosing polymyositis. A study of HIV-associated polymyositis reported similarly elevated CK levels to those observed in non-HIV settings.1 However, muscle inflammation can be associated with normal or near-normal CK levels. We report 4 cases of HIV-associated polymyositis in which the diagnosis was almost missed owing to the absence of raised CK levels.
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    Burden of pneumocystis pneumonia in HIV-infected adults in sub-Saharan Africa: a systematic review and meta-analysis
    (BioMed Central, 2016-09-09) Wasserman, Sean; Engel, Mark E; Griesel, Rulan; Mendelson, Marc
    Abstract Background Seroprevalence data and clinical studies in children suggest that the burden of pneumocystis pneumonia (PCP) in Africa may be underestimated. We performed a systematic review to determine the prevalence and attributable mortality of PCP amongst HIV-infected adults in sub-Saharan Africa. Methods We searched Pubmed, Web of Science, Africa-Wide: NiPAD and CINAHL, from Jan 1 1995 to June 1 2015, for studies that reported the prevalence, mortality or case fatality of PCP in HIV-infected adults living in sub-Saharan African countries. Prevalence data from individual studies were combined by random-effects meta-analysis according to the Mantel-Haenszel method. Data were stratified by clinical setting, diagnostic method, and study year. Results We included 48 unique study populations comprising 6884 individuals from 18 countries in sub-Saharan Africa. The pooled prevalence of PCP among 6018 patients from all clinical settings was 15 · 4 % (95 % CI 12 · 9–18 · 0), and was highest amongst inpatients, 22 · 4 % (95 % CI 17 · 2–27 · 7). More cases were identified by bronchoalveolar lavage, 21 · 0 % (15 · 0–27 · 0), compared with expectorated, 7 · 7 % (4 · 4–11 · 1), or induced sputum, 11 · 7 % (4 · 9–18 · 4). Polymerase chain reaction (PCR) was used in 14 studies (n = 1686). There was a trend of decreasing PCP prevalence amongst inpatients over time, from 28 % (21–34) in the 1990s to 9 % (8–10) after 2005. The case fatality rate was 18 · 8 % (11 · 0–26 · 5), and PCP accounted for 6 · 5 % (3 · 7–9 · 3) of study deaths. Conclusions PCP is an important opportunistic infection amongst HIV-infected adults in sub-Saharan Africa, particularly amongst patients admitted to hospital. Although prevalence appears to be decreasing, improved access to antiretroviral therapy and non-invasive diagnostics, such as PCR, are needed.
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    Clinical Antibiotic Stewardship in South Africa
    (2015) Boyles, Tom
    This course on clinical antibiotic stewardship consists of 22 lectures split into 2 sections. Section 1 covers the background to the problem of antibiotic resistance and teaches principles of antibiotic prescribing and infection control. Section 2 covers specific clinical conditions in turn and explains the clinical approach to managing these problems.
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    The clinical features and estimated incidence of MIS-C in Cape Town, South Africa
    (2022-05-02) Butters, Claire; Abraham, Deepthi R; Stander, Raphaella; Facey-Thomas, Heidi; Abrahams, Debbie; Faleye, Ayodele; Allie, Nazneen; Soni, Khushbu; Rabie, Helena; Scott, Christiaan; Zühlke, Liesl; Webb, Kate
    Background Multisystem inflammatory syndrome is a severe manifestation of SARS-CoV-2 in children. The incidence of MIS-C after infection is poorly understood. There are very few cohorts describing MIS-C in Africa despite MIS-C being more common in Black children worldwide. Methods A cohort of children with MIS-C and healthy children was recruited from May 2020 until May 2021 from the two main paediatric hospitals in Cape Town, South Africa. Clinical and demographic data were collected, and serum was tested for SARS-CoV-2 antibodies. The incidence of MIS-C was calculated using an estimation of population exposure from seroprevalence in the healthy group. Summary data, non-parametric comparisons and logistic regression analyses were performed. Results Sixty eight children with MIS-C were recruited with a median age of 7 years (3.6, 9.9). Ninety seven healthy children were recruited with a 30% seroprevalence. The estimated incidence of MIS-C was 22/100 000 exposures in the city in this time. Black children were over-represented in the MIS-C group (62% vs 37%, p = 0.002). The most common clinical features in MIS-C were fever (100%), tachycardia (98.5%), rash (85.3%), conjunctivitis (77.9%), abdominal pain (60.3%) and hypotension (60.3%). The median haemoglobin, sodium, neutrophil count, white cell count, CRP, ferritin, cardiac (pro-BNP, trop-T) and coagulation markers (D-dimer and fibrinogen) were markedly deranged in MIS-C. Cardiac, pulmonary, central nervous and renal organ systems were involved in 71%, 29.4%, 27.9% and 27.9% respectively. Ninety four percent received intravenous immune globulin, 64.7% received methylprednisolone and 61.7% received both. Forty percent required ICU admission, 38.2% required inotropic support, 38.2% required oxygen therapy, 11.8% required invasive ventilation and 6% required peritoneal dialysis. Older age was an independent predictor for the requirement for ionotropic support (OR = 1.523, CI 1.074, 2.16, p = 0.018). The median hospital stay duration was 7 days with no deaths. Conclusion The lack of reports from Southern Africa does not reflect a lack of cases of MIS-C. MIS-C poses a significant burden to children in the region as long as the pandemic continues. MIS-C disproportionately affects black children. The clinical manifestations and outcomes of MIS-C in this region highlight the need for improved surveillance, reporting and data to inform diagnosis and treatment.
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    Cognitive dissonance as an explanation of the genesis, evolution and persistence of Thabo Mbeki's HIV denialism
    (2008) Kenyon, Chris
    The ongoing damage that the newer forms of HIV denialism are visiting upon our country is evidenced by the recent firing of Nozizwe Madlala-Routledge, the South African Deputy Minister of Health. It is widely believed that the underlying reason for her dismissal was her support of orthodox HIV treatment and prevention strategies and her disdain for HIV denialism. This paper seeks to understand the origins, spread and metamorphosis of President Thabo Mbeki's HIV denialism in South Africa. Using the theory of cognitive dissonance, I argue that, given the structural beliefs of the African National Congress (ANC) and the pattern of emergence of HIV in the 1980s, a degree of scepticism around the putative science of HIV was probable in ANC circles. On assuming the Presidency in 1999, Mbeki tapped into this scepticism to formulate his initial biological version of HIV denialism, which claimed that 'a virus can't cause a syndrome.' The steady erosion of support for this flagrant HIV denialism, together with the rise of neoliberal thinking in the ANC, would lead to the evolution of this biological denialism into a form of treatment denialism. This ideology argued against the widespread provision and use of antiretroviral treatment. Empirical evidence is presented to demonstrate the extent to which ongoing HIV denial in the general population is continuing to fuel the spread of HIV.
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    The Community PrEP Study: a randomized control trial leveraging community-based platforms to improve access and adherence to pre-exposure prophylaxis to prevent HIV among adolescent girls and young women in South Africa—study protocol
    (2021-07-26) Medina-Marino, Andrew; Bezuidenhout, Dana; Hosek, Sybil; Barnabas, Ruanne V.; Atujuna, Millicent; Bezuidenhout, Charl; Ngwepe, Phuti; Peters, Remco P H; Little, Francesca; Celum, Connie L; Daniels, Joseph; Bekker, Linda-Gail
    Background HIV incidence among South African adolescent girls and young women (AGYW) remains high, but could be reduced by highly effective pre-exposure prophylaxis (PrEP). Unfortunately, AGYW report significant barriers to clinic-based sexual and reproductive health services. Even when AGYW access PrEP as an HIV prevention method, poor prevention-effective use was a serious barrier to achieving its optimal HIV prevention benefits. Determining the acceptability and feasibility of community-based platforms to increase AGYW’s access to PrEP, and evaluating behavioural interventions to improve prevention-effective use of PrEP are needed. Methods We propose a mixed-methods study among AGYW aged 16–25 years in Eastern Cape Province, South Africa. In the first component, a cross-sectional study will assess the acceptability and feasibility of leveraging community-based HIV counselling and testing (CBCT) platforms to refer HIV-negative, at-risk AGYW to non-clinic-based, same-day PrEP initiation services. In the second component, we will enrol 480 AGYW initiating PrEP via our CBCT platforms into a three-armed (1:1:1) randomized control trial (RCT) that will evaluate the effectiveness of adherence support interventions to improve the prevention-effective use of PrEP. Adherence will be measured over 24 months via tenofovir-diphosphate blood concentration levels. Qualitative investigations will explore participant, staff, and community experiences associated with community-based PrEP services, adherence support activities, study implementation, and community awareness. Costs and scalability of service platforms and interventions will be evaluated. Discussion This will be the first study to assess the acceptability and feasibility of leveraging CBCT platforms to identify and refer at-risk AGYW to community-based, same-day PrEP initiation services. It will also provide quantitative and qualitative results to inform adherence support activities and services that promote the prevention-effective use of PrEP among AGYW. By applying principles of implementation science, behavioural science, and health economics research, we aim to inform strategies to improve access to and prevention-effective use of PrEP by AGYW. Trial registration ClinicalTrials.gov NCT03977181 . Registered on 6 June 2019—retrospectively registered.
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    Determinants and reasons for switching anti-retroviral regimen among HIV-infected youth in a large township of South Africa (2002–2019)
    (2022-06-28) Kabarambi, Anita; Balinda, Sheila; Abaasa, Andrew; Cogill, Dolphina; Orrell, Catherine
    Background There are limited data exploring antiretroviral therapy (ART) changes and time to change among South Africa young people living with HIV/AIDS. Objective We describe the time to first drug switch, which includes ART regimen change (three drug switch) and substitutions (single drug switch). We describe common reasons for ART switch among young people aged 10 to 24 years in South Africa. Methods We conducted a retrospective cohort study at a primary health care clinic in Cape Town, South Africa, providing ART to HIV-infected adolescents and adults since 2002. Those aged 10 to 24 years at ART initiation, who accessed care clinic between September 2002 and April 2019. Data was retrieved from electronic information systems: ART regimens, ART changes, dates for initiation or stop of each drug/regimen, laboratory results (viral loads, haemoglobin, liver enzyme results, and creatinine to support the reason for ART switch. From written records, we abstracted reason for single drug switch or regimen change, as well as socio demographic and clinical data. We fitted cox regression models to determine factors associated with ART switch (Having a change in one or more drugs in ART combination) and the rate of occurrence. Results Of 2601 adolescents included, 605 (24.9%) adolescents switched ART over 5090.5 person years at risk (PYAR), a rate of 11.9 /100PYAR. Median follow-up time was 4.4 (± 3.2) years. At multivariable analysis, the older age group was protective of the risk of ART switch: adjusted Hazard Ratio [aHR] 0.78, 95% CI 0.62–0.98, transfer status [transferred out 1.42 [1.11–1.82]. The hazard of ART switch increased with more severe HIV-disease at ART start, as observed by increasing WHO clinical stage or reduced CD4 count at baseline. The primary reasons for ART switch were side effects (20.0%), virological failure (17.9%) and formulation switch (27.8%). Others reasons included pregnancy, Hepatitis B, tuberculosis and psychosis. Conclusion ART switches are frequent and occur at a consistent rate across 7.5 years from initiation. The main reasons for ART switch were virological failure and drug side effects.
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    Differences in access and patient outcomes across antiretroviral treatment clinics in the Free State province: A prospective cohorot study
    (2010) Ingle, Suzanne M; May, Margaret; Uebel, Kerry; Timmerman, Venessa; Kotze, Eduan; Bachmann, Max; Sterne, Jonathan A C; Egger, Matthias; Fairall, Lara
    Objective. To assess differences in access to antiretroviral treatment (ART) and patient outcomes across public sector treatment facilities in the Free State province, South Africa. Design. Prospective cohort study with retrospective database linkage. We analysed data on patients enrolled in the treatment programme across 36 facilities between May 2004 and December 2007, and assessed percentage initiating ART and percentage dead at 1 year after enrolment. Multivariable logistic regression was used to estimate associations of facility-level and patient-level characteristics with both mortality and treatment status. Results. Of 44 866 patients enrolled, 15 219 initiated treatment within 1 year; 8 778 died within 1 year, 7 286 before accessing ART. Outcomes at 1 year varied greatly across facilities and more variability was explained by facility-level factors than by patient-level factors. The odds of starting treatment within 1 year improved over calendar time. Patients enrolled in facilities with treatment initiation available on site had higher odds of starting treatment and lower odds of death at 1 year compared with those enrolled in facilities that did not offer treatment initiation. Patients were less likely to start treatment if they were male, severely immunosuppressed (CD4 count ≤50 cells/μl), or underweight (<50 kg). Men were also more likely to die in the first year after enrolment. Conclusions. Although increasing numbers of patients started ART between 2004 and 2007, many patients died before accessing ART. Patient outcomes could be improved by decentralisation of treatment services, fast-tracking the most immunodeficient patients and improving access, especially for men.
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    Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis
    (BioMed Central, 2018-05-16) Houston, Simon; Lithgow, Karen V; Osbak, Kara K; Kenyon, Chris R; Cameron, Caroline E
    Background Syphilis continues to be a major global health threat with 11 million new infections each year, and a global burden of 36 million cases. The causative agent of syphilis, Treponema pallidum subspecies pallidum, is a highly virulent bacterium, however the molecular mechanisms underlying T. pallidum pathogenesis remain to be definitively identified. This is due to the fact that T. pallidum is currently uncultivatable, inherently fragile and thus difficult to work with, and phylogenetically distinct with no conventional virulence factor homologs found in other pathogens. In fact, approximately 30% of its predicted protein-coding genes have no known orthologs or assigned functions. Here we employed a structural bioinformatics approach using Phyre2-based tertiary structure modeling to improve our understanding of T. pallidum protein function on a proteome-wide scale. Results Phyre2-based tertiary structure modeling generated high-confidence predictions for 80% of the T. pallidum proteome (780/978 predicted proteins). Tertiary structure modeling also inferred the same function as primary structure-based annotations from genome sequencing pipelines for 525/605 proteins (87%), which represents 54% (525/978) of all T. pallidum proteins. Of the 175 T. pallidum proteins modeled with high confidence that were not assigned functions in the previously annotated published proteome, 167 (95%) were able to be assigned predicted functions. Twenty-one of the 175 hypothetical proteins modeled with high confidence were also predicted to exhibit significant structural similarity with proteins experimentally confirmed to be required for virulence in other pathogens. Conclusions Phyre2-based structural modeling is a powerful bioinformatics tool that has provided insight into the potential structure and function of the majority of T. pallidum proteins and helped validate the primary structure-based annotation of more than 50% of all T. pallidum proteins with high confidence. This work represents the first T. pallidum proteome-wide structural modeling study and is one of few studies to apply this approach for the functional annotation of a whole proteome.
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    Genome-wide profiling of transcribed enhancers during macrophage activation
    (BioMed Central, 2017-10-23) Denisenko, Elena; Guler, Reto; Mhlanga, Musa M; Suzuki, Harukazu; Brombacher, Frank; Schmeier, Sebastian
    Background: Macrophages are sentinel cells essential for tissue homeostasis and host defence. Owing to their plasticity, macrophages acquire a range of functional phenotypes in response to microenvironmental stimuli, of which M(IFN-γ) and M(IL-4/IL-13) are well known for their opposing pro- and anti-inflammatory roles. Enhancers have emerged as regulatory DNA elements crucial for transcriptional activation of gene expression. Results: Using cap analysis of gene expression and epigenetic data, we identify on large-scale transcribed enhancers in bone marrow-derived mouse macrophages, their time kinetics, and target protein-coding genes. We observe an increase in target gene expression, concomitant with increasing numbers of associated enhancers, and find that genes associated with many enhancers show a shift towards stronger enrichment for macrophage-specific biological processes. We infer enhancers that drive transcriptional responses of genes upon M(IFN-γ) and M(IL-4/IL-13) macrophage activation and demonstrate stimuli specificity of regulatory associations. Finally, we show that enhancer regions are enriched for binding sites of inflammation-related transcription factors, suggesting a link between stimuli response and enhancer transcriptional control. Conclusions: Our study provides new insights into genome-wide enhancer-mediated transcriptional control of macrophage genes, including those implicated in macrophage activation, and offers a detailed genome-wide catalogue of transcribed enhancers in bone marrow-derived mouse macrophages.
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    Gonococcal resistance can be viewed productively as part of a syndemic of antimicrobial resistance: an ecological analysis of 30 European countries
    (2020-06-30) Kenyon, Chris; Manoharan-Basil, Sheeba S; Van Dijck, Christophe
    Background It is unclear how important bystander selection is in the genesis of antimicrobial resistance (AMR) in Neisseria gonorrhoeae. Methods We assessed bystander selection in a novel way. Mixed-effects linear regression was used to assess if country-level prevalence of gonococcal AMR in 30 European countries predicts homologous AMR in other bacteria. The data used was from the European Antimicrobial Resistance Surveillance Network. Results The prevalence of gonococcal ciprofloxacin resistance was found to be positively associated with AMR prevalence in E. coli (coef. 0.52; P = 0.007), Acinetobacter spp. (coef. 0.13; P = 0.044) and Pseudomonas aeruginosa (coef. 0.36; P = 0.020) but not Klebsiella pneumoniae. Azithromycin resistance in N. gonorrhoeae was positively associated with macrolide resistance in Streptococcus pneumoniae (coef. 0.01; P = 0.018). No association was found for cephalosporins. Conclusions Gonococcal AMR is linked to that in other bacteria. This finding is likely explained by high antimicrobial consumption in affected populations and provides additional motivation for strengthening antimicrobial stewardship programs.
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    Government policy interventions to reduce human antimicrobial use: protocol for a systematic review and meta-analysis
    (BioMed Central, 2017-12-13) Rogers Van Katwyk, Susan; Grimshaw, Jeremy M; Mendelson, Marc; Taljaard, Monica; Hoffman, Steven J
    Background: Antimicrobial resistance (AMR) is a recognized threat to global public health. Increasing AMR and a dry pipeline of novel antimicrobial drugs have put AMR in the international spotlight. One strategy to combat AMR is to reduce antimicrobial drug consumption. Governments around the world have been experimenting with different policy interventions, such as regulating where antimicrobials can be sold, restricting the use of last-resort antimicrobials, funding AMR stewardship programs, and launching public awareness campaigns. To inform future action, governments should have access to synthesized data on the effectiveness of large-scale AMR interventions. This planned systematic review will (1) identify and describe previously evaluated government policy interventions to reduce human antimicrobial use and (2) estimate the effectiveness of these different strategies. Methods: An electronic search strategy has been developed in consultation with two research librarians. Seven databases (MEDLINE, CINAHL, EMBASE, CENTRAL, PAIS Index, Web of Science, and PubMed excluding MEDLINE) will be searched, and additional studies will be identified using several gray literature search strategies. To be included, a study must (1) clearly describe the government policy and (2) use a rigorous design to quantitatively measure the impact of the policy on human antibiotic use. The intervention of interest is any policy intervention enacted by a government or government agency in any country to change human antimicrobial use. Two independent reviewers will screen for eligibility using criteria defined a priori. Data will be extracted with Covidence software using a customized extraction form. If sufficient data exists, a meta-analysis by intervention type will be conducted as part of the effectiveness review. However, if there are too few studies or if the interventions are too heterogeneous, data will be tabulated and a narrative synthesis strategy will be used. Discussion: This evidence synthesis is intended for use by policymakers, public health practitioners, and researchers to inform future government policies aiming to address antimicrobial resistance. This review will also identify gaps in the evidence about the effectiveness of different policy interventions to inform future research priorities. Systematic review registration: PROSPERO CRD42017067514.
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    Increases in condomless chemsex associated with HIV acquisition in MSM but not heterosexuals attending a HIV testing center in Antwerp, Belgium
    (BioMed Central, 2018-10-19) Kenyon, Chris; Wouters, Kristien; Platteau, Tom; Buyze, Jozefien; Florence, Eric
    Background It has been speculated that the prevalence of chemsex is increasing in men who have sex with men and that this may be playing a role in the spread of HIV. Methods We assessed if the prevalence of reported chemsex was increasing and if chemsex was associated with HIV infection in clients attending the ‘Helpcenter’, Antwerp, between 2011 and 2017. This is a HIV/STI testing center that offers HIV/STI testing to HIV-uninfected individuals from key populations including MSM. Results We found an increase in the reporting of condomless sex associated with the use of a number of drugs, including ecstasy, amphetamines, GHB and cocaine in MSM (from 8 to 17%) but not in heterosexuals. Reporting condomless chemsex was associated with HIV infection (adjusted odds ratio 5.7 [95% confidence interval 3.2–10.4]). Conclusions Our findings provide further evidence of the importance of asking MSM clients about the use of psychoactive substances during consultations and tailoring interventions such as pre exposure prophylaxis, more frequent STI screening and substance abuse counseling accordingly.
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    Management of cryptoccocal meningitis in resource-limited settings: A systematic review
    (2009) Sloan, Derek; Dlamini, Sipho; Dedicoat, Martin
    Cryptococcal meningitis (CM) remains a serious cause of mortality and morbidity in individuals infected with the human immunodeficiency virus (HIV). The optimal treatment of CM is unknown. We conducted a systematic review to determine the best treatment for CM with an emphasis on resource-poor settings. Six studies met the inclusion criteria; none was found that compared amphotericin B with fluconazole. From the available evidence, it is not possible to determine which treatment is superior for CM.
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    Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1
    (2004) Van Leth, Frank; Phanuphak, Prahpan; Stroes, Erik; Gazzard, Brian; Cahn, Pedro; Raffi, François; Wood, Robin; Bloch, Mark; Katlama, Christine; Kastelein, John J P; Schechter, Mauro; Murphy, Robert L; Horban, Andrzej; Hall, David B; Lange, Joep M A; Reiss, Peter
    Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analyzed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV).
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    Outcomes of the South African National Antiretroviral Treatment Programme for children: The IeDEA Southern Africa collaboration
    (2009) Davies, M; Keiser, O; Technau, K; Eley, B; Rabie, H; Van Cutsem, G; Giddy, J; Wood, R; Boulle, A; Egger, M; Moultrie, H
    Objectives: To assess paediatric antiretroviral treatment (ART) outcomes and their associations from a collaborative cohort representing 20% of the South African national treatment programme. Design and setting: Multi-cohort study of 7 public sector paediatric ART programmes in Gauteng, Western Cape and KwaZulu-Natal provinces. Subjects: ART-naïve children (≤16 years) who commenced treatment with ≥3 antiretroviral drugs before March 2008. Outcome measures: Time to death or loss to follow-up were assessed using the Kaplan-Meier method. Associations between baseline characteristics and mortality were assessed with Cox-proportional hazards models stratified by site. Immune status, virologic suppression and growth were also described by duration on ART. Results: The median (IQR) age of 6078 children with 9368 child-years of follow-up was 43 (15 – 83) months, with 29% being <18 months. Most were severely ill at ART initiation. More than 75% of children were appropriately monitored at 6-monthly intervals with viral load suppression (<400 copies/ml) being 80% or above throughout 36 months of treatment. Mortality and retention in care at 3 years were 7.7% (95%CI: 7.0% – 8.6%) and 81.4% (80.1% - 82.6%) respectively. Together with young age, all markers of disease severity (low weight-for-age z-score; high viral load; severe immune suppression, stage 3/4 disease and anaemia) were independently associated with mortality. Conclusions: Dramatic clinical benefit for children accessing the national ART programme is demonstrated. Higher mortality in infants and those with advanced disease highlights the need for early diagnosis of HIV infection and commencement of ART.
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    Presence and Persistence of Putative Lytic and Temperate Bacteriophages in Vaginal Metagenomes from South African Adolescents
    (2021-11-23) Happel, Anna-Ursula; Balle, Christina; Maust, Brandon S; Konstantinus, Iyaloo N; Gill, Katherine; Bekker, Linda-Gail; Froissart, Rémy; Passmore, Jo-Ann; Karaoz, Ulas; Varsani, Arvind; Jaspan, Heather
    The interaction between gut bacterial and viral microbiota is thought to be important in human health. While fluctuations in female genital tract (FGT) bacterial microbiota similarly determine sexual health, little is known about the presence, persistence, and function of vaginal bacteriophages. We conducted shotgun metagenome sequencing of cervicovaginal samples from South African adolescents collected longitudinally, who received no antibiotics. We annotated viral reads and circular bacteriophages, identified CRISPR loci and putative prophages, and assessed their diversity, persistence, and associations with bacterial microbiota composition. Siphoviridae was the most prevalent bacteriophage family, followed by Myoviridae, Podoviridae, Herelleviridae, and Inoviridae. Full-length siphoviruses targeting bacterial vaginosis (BV)-associated bacteria were identified, suggesting their presence in vivo. CRISPR loci and prophage-like elements were common, and genomic analysis suggested higher diversity among Gardnerella than Lactobacillus prophages. We found that some prophages were highly persistent within participants, and identical prophages were present in cervicovaginal secretions of multiple participants, suggesting that prophages, and thus bacterial strains, are shared between adolescents. The number of CRISPR loci and prophages were associated with vaginal microbiota stability and absence of BV. Our analysis suggests that (pro)phages are common in the FGT and vaginal bacteria and (pro)phages may interact.
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    Pretreatment chest x-ray severity and its relation to bacterial burden in smear positive pulmonary tuberculosis
    (BioMed Central, 2018-05-21) Murthy, S E; Chatterjee, F; Crook, A; Dawson, R; Mendel, C; Murphy, M E; Murray, S R; Nunn, A J; Phillips, P P J; Singh, Kasha P; McHugh, T D; Gillespie, S H
    Background Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. Methods Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577–87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. Results For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16–30, p < 0.001) in patients without cavitation compared to those with cavitation. The median percentage of lung-field affected was 18.1% (IQR 11.3–28.8%). For every 10-fold increase in TTP, the area of lung field affected decreased by 11.4%. Multivariable models showed that serum albumin decreased significantly as the percentage of lung field area increased in both those with and without cavitation. In addition, BMI and logged TTP had a small but significant effect in those with cavitation and the number of severe TB symptoms in the non-cavitation group also had a small effect, whilst other factors found to be significant on univariable analysis lost this effect in the model. Conclusions The radiological severity of disease on chest x-ray prior to treatment in smear positive pulmonary TB patients is weakly associated with the bacterial burden. When compared against other variables at diagnosis, this effect is lost in those without cavitation. Radiological severity does reflect the overall disease severity in smear positive pulmonary TB, but we suggest that clinicians should be cautious in over-interpreting the significance of radiological disease extent at diagnosis.