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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.

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.

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.govNCT03977181. Registered on 6 June 2019—retrospectively registered.

Objectives The aim of the RAAS-COVID-19 randomized control trial is to evaluate whether an upfront strategy of temporary discontinuation of renin angiotensin aldosterone system (RAAS) inhibition versus continuation of RAAS inhibition among patients admitted with established COVID-19 infection has an impact on short term clinical and biomarker outcomes. We hypothesize that continuation of RAAS inhibition will be superior to temporary discontinuation with regards to the primary endpoint of a global rank sum score. The global rank sum score has been successfully used in previous cardiovascular clinical trials. Trial design This is an open label parallel two arm (1,1 ratio) randomized control superiority trial of approximately 40 COVID-19 patients who are on chronic RAAS inhibitor therapy. Participants Adults who are admitted to hospital within the McGill University Health Centre systems (MUHC) including Royal Victoria Hospital (RVH), Montreal General Hospital (MGH) and Jewish General Hospital (JGH) and who are within 96 hours of COVID-19 diagnosis (confirmed via PCR on any biological sample) will be considered for the trial. Of note, the initial protocol to screen and enrol within 48 hours of COVID-19 diagnosis was extended through an amendment, to 96 hours to increase feasibility. Participants have to be 18 years or older and would have to be on RAAS inhibitors for at least a month to be considered eligible for the study. Additionally, RAAS inhibitors should not have been held for more than 48 hours before randomization. A list of inclusion and exclusion criteria can be found in the full protocol document. In order to prevent heart failure exacerbation, patients with reduced ejection fraction were excluded from the trial. Once a patient is admitted on the ward with a diagnosis of COVID-19, we will confirm with the treating physician if the participant is suitable for the RAAS-COVID trial and meets all the inclusion and exclusion criteria. If the patient is eligible and informed consent has been obtained we will collect data on sex, age, ethnicity, past medical history and list of medications (e.g. other anti-hypertensives or anticoagulants), for further analysis. Intervention and comparator All the study participants will be randomized to a strategy of temporarily holding the RAAS inhibitor [intervention] versus continuing the RAAS inhibitor [continued standard of care]. Among participants who are randomized to the intervention arm, alternative guide-line directed anti-hypertensive medication will be provided to the treating physician team (detail in study protocol). In the intervention arm RAAS inhibitor will be withheld for a total of 7 days with the possibility of the withdrawn medication being initiated at any point after day 7 or on the day of discharge. The recommendation for re-initiating the withdrawn medication will be made to the treating physician. The re-initiation of these therapies are according to standard convention and follow-up as per Canadian guidelines. Additionally, the date of restarting the withdrawn medication or whether the medication was re-prescribed on discharge or not, will be collected. This will be used to conduct a sensitivity analysis. Furthermore, biomarkers such as troponin, c-reactive protein (CRP) and lymphocyte count will be assessed during the same time period. Samples will be collected on randomization, day 4 and day 7. Main outcomes Primary endpoint In this study the primary end point is a global rank score calculated for all participants, regardless of treatment assignment ( score from 0 to 7). Please refer to table 4 in the full protocol. In the context of the current trial, it is estimated that death is the most meaningful endpoint, and therefore has the highest score ( score of 7). This is followed by admission to ICU, the need for mechanical ventilation etc. The lowest scores ( score of 1) are assigned to biomarker changes (e.g. change in troponin, change in CRP). This strategy has been used successfully in cardiovascular disease trials and therefore is applicable to the current trial. The primary endpoint for the present trial is assessed from baseline to day 7 (or discharge). Participants are ranked across the clinical and biomarker domains. Lower values indicate better health (or stability). Participants who died during the 7th day of the study will be ranked based on all events occurring before their death and also including the fatal event in the score. Next, participants who did not die but were transferred to ICU for invasive ventilation will be ranked based on all the events occurring before the ICU entry and also including the ICU admission in the score. Those participants who did not die were not transferred to ICU for invasive ventilation, will be ranked based on the subsequent outcomes. The mean rank score will then be compared between groups. In this scheme, a lower mean rank score indicates greater overall stability for participants. Secondary endpoints : The key secondary endpoints are the individual components of the primary components and include the following: death, transfer to ICU primarily for invasive ventilation, transfer to ICU for other indication, non-fatal MACE ( any of following, MI, stroke, acute HF, new onset Afib), length of stay > 4 days, development of acute kidney injury ( > 40% decline in eGFR or doubling of serum creatinine), urgent intravenous treatment for high blood pressure, 30% increase in baseline high sensitivity troponin, 30% increase in baseline BNP, increase in CRP to > 30% in 48 hours and lymphocyte count drop> 30%. We will also look at the World Health Organization (WHO) ordinal scale for clinical improvement (in COVID-19) in our data. In this scale death will be assigned the highest score of 8. Patients with no limitation of activity will be assigned a score of 1 which indicates overall more stability (3). Additionally, we will evaluate the potential effects of discontinuing RAAS inhibition on alternative schedules (longer/shorter than 7 days, intermittent discontinuation) using a mechanistic mathematical model of COVID-19 immunopathology calibrated to data collected from our patient cohort. In particular, we will assess the impact of alternative schedules on primary and secondary endpoints including increases to baseline CRP and lymphocyte counts. Randomization Participants will be randomized in a 1:1 ratio. Randomization will be performed within an electronic database system at the time of enrolment using a random number generator, an approach that has been successfully used in other clinical trials. Neither participant, study team, or treating team will be blinded to the intervention arm. Blinding This is an open label study with no blinding. Numbers to be randomised (sample size) The approximate number of participants required for this trial is 40 patients (randomized 1:1 to continuation versus discontinuation of RAAS inhibitors). This number was calculated based on previous rates of outcomes for COVID-19 in the literature (e.g. death, ICU transfer) and statistical power calculations. Trial Status Protocol number: MP-37-2021-6641, Version 4: 01-10-2020. Trial start date September 1st 2020 and currently enrolling participants. Estimated end date for recruitment of participants : July 2021. Estimated end date for study completion: September 1st 2021. Trial registration Trial registration: ClincalTrials.gov: NCT04508985, date of registration: August 11th , 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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.

International audience

Background In 2011, a decision was made to scale up a pilot innovation involving ‘adherence clubs’ as a form of differentiated care for HIV positive people in the public sector antiretroviral therapy programme in the Western Cape Province of South Africa. In 2016 we were involved in the qualitative aspect of an evaluation of the adherence club model, the overall objective of which was to assess the health outcomes for patients accessing clubs through epidemiological analysis, and to conduct a health systems analysis to evaluate how the model of care performed at scale. In this paper we adopt a complex adaptive systems lens to analyse planned organisational change through intervention in a state health system. We explore the challenges associated with taking to scale a pilot that began as a relatively simple innovation by a non-governmental organisation. Results Our analysis reveals how a programme initially representing a simple, unitary system in terms of management and clinical governance had evolved into a complex, differentiated care system. An innovation that was assessed as an excellent idea and received political backing, worked well whilst supported on a small scale. However, as scaling up progressed, challenges have emerged at the same time as support has waned. We identified a ‘tipping point’ at which the system was more likely to fail, as vulnerabilities magnified and the capacity for adaptation was exceeded. Yet the study also revealed the impressive capacity that a health system can have for catalysing novel approaches. Conclusions We argue that innovation in largescale, complex programmes in health systems is a continuous process that requires ongoing support and attention to new innovation as challenges emerge. Rapid scaling up is also likely to require recourse to further resources, and a culture of iterative learning to address emerging challenges and mitigate complex system errors. These are necessary steps to the future success of adherence clubs as a cornerstone of differentiated care. Further research is needed to assess the equity and quality outcomes of a differentiated care model and to ensure the inclusive distribution of the benefits to all categories of people living with HIV.

SETTING: Xpert® MTB/RIF is the most widely used molecular assay for rapid diagnosis of tuberculosis (TB). The number of polymerase chain reaction cycles after which detectable product is generated (cycle threshold value, CT) correlates with the bacillary burden. OBJECTIVE : To investigate the association between Xpert CT values and smear status through a systematic review and individual-level data meta-analysis. DESIGN: Studies on the association between CT values and smear status were included in a descriptive systematic review. Authors of studies including smear, culture and Xpert results were asked for individual-level data, and receiver operating characteristic curves were calculated. RESULTS : Of 918 citations, 10 were included in the descriptive systematic review. Fifteen data sets from studies potentially relevant for individual-level data meta-analysis provided individual-level data (7511 samples from 4447 patients); 1212 patients had positive Xpert results for at least one respiratory sample (1859 samples overall). ROC analysis revealed an area under the curve (AUC) of 0.85 (95%CI 0.82-0.87). Cut-off CT values of 27.7 and 31.8 yielded sensitivities of 85% (95%CI 83-87) and 95% (95%CI 94-96) and specificities of 67% (95%CI 66-77) and 35% (95%CI 30-41) for smear-positive samples. CONCLUSION: Xpert CT values and smear status were strongly associated. However, diagnostic accuracy at set cut-off CT values of 27.7 or 31.8 would not replace smear microscopy. How CT values compare with smear microscopy in predicting infectiousness remains to be seen. © 2017 The Union.

Background Unstable settings present challenges for the effective provision of antiretroviral treatment (ART). In this paper, we summarize the experience and results of providing ART and implementing contingency plans during acute instability in the Central African Republic (CAR) and Yemen. Case presentation In CAR, MSF has provided HIV care in three conflict-affected rural regions; these were put on hold throughout the acute phase of violence. “Run-away bags” containing 3 or 4 months of ART were distributed to patients at MSF facilities. Among 1820 HIV patients enrolled into care, 1440 (79%) initiated ART. By December 2016, 782 (54%) patients were still under ART, 354 (25%) have been lost to follow up and 182 (13%) had died. In 2013, when violence disrupted services, 683 patients were receiving ART. Between September–December 2013, 594 (87%) patients received runaway bags and by February 2014, 313 (53%) of these patients returned to the clinic. In Yemen, when violence erupted, patients received a health card that included a helpline to call in case of drug shortages in admission to emergency stocks; this was not possible in CAR due to lack of a functioning telephone network. One thousand six hundred fifty-five PLWHA have been enrolled in care and 1470 (89%) initiated ART; 1056 (72%) are still followed on ART, 126 (9%) were lost to follow up, and 288 (20%) died. In January 2011 clashes began and by April 2011 MSF medical activities were interrupted. Of the 363 patients receiving ART, 363 (100%) received emergency bags to cover 9 months and by February 2012, 354 (98%) patients returned to care. In March 2015 a new wave of conflict affected Yemen, forcing HIV activities to revert to contingency planning. Conclusions This experience provides further evidence that provision of HIV treatment and emergency drug stocks can be successfully provided to most patients in both conflict-affected settings.

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

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. Electronic supplementary material The online version of this article (10.1186/s12900-018-0086-3) contains supplementary material, which is available to authorized users.

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.

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. Electronic supplementary material The online version of this article (10.1186/s13643-017-0640-2) contains supplementary material, which is available to authorized users.

© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated., 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., This work was supported by grants from the South African National Research Foundation (NRF) and from the Department of Science and Technology, South African Research Chair Initiative (SARCHi) and South Africa Medical Research Council (SAMRC) to FB, grant from the Japan Society for the Promotion of Science (JSPS) and National Research Foundation of South Africa to FB and HS, and grants from the South African National Research Foundation (NRF) Competitive Programme for Unrated Researchers (CSUR) to RG.

Background If national peak Human Immunodeficiency Virus (HIV) prevalence is positively associated with the prevalence of other sexually transmitted infections (STIs) from before or early on in the HIV epidemics this would suggest common underlying drivers. Methods Pearson’s correlations were calculated between the prevalence of seven STIs at a country-level: chlamydia, gonorrhoea, trichomoniasis, syphilis, bacterial vaginosis, herpes simplex virus-2 (HSV-2) and HIV. Results The prevalence of all the STIs was highest in the sub-Saharan African region excluding chlamydia. The prevalence of all seven STIs were positively correlated excluding chlamydia. The correlations were strongest for HIV-HSV-2 (r = 0.85, P

Background It is not known if there is a difference in the immune response to syphilis between HIV-infected and uninfected individuals. Methods We prospectively recruited all patients with a new diagnosis of syphilis and tested their plasma for IFNα, IFNγ, IL-1β, IL-12p40, IL-12p70, IP-10, MCP-1, MIP-1α, MIP-1β, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10 and IL-17A at baseline pre-treatment and 6 months following therapy. Results A total of 79 HIV-infected [44 primary/secondary syphilis (PSS) and 35 latent syphilis (LS)] and 12 HIV-uninfected (10 PSS and 2 LS) cases of syphilis and 30 HIV-infected controls were included in the study. At the baseline visit, compared to the control group, concentrations of IL-10 were significantly elevated in the HIV-infected and uninfected groups. The level of IL-10 was significantly higher in the HIV-infected compared to the HIV-uninfected PSS group (25.3 pg/mL (IQR, 4.56–41.76) vs 2.73 pg/mL (IQR, 1.55–9.02), P = 0.0192). In the HIV-infected PSS group (but not the HIV-infected LS or HIV-uninfected PSS groups) the IP-10, MIP-1b, IL-6 and IL-8 were raised compared to the controls. IL-10 levels decreased but did not return to control baseline values by 6 months in HIV infected PSS and LS and HIV uninfected PSS. Conclusion PSS and LS in HIV-infected individuals is characterized by an increase in inflammatory and anti-inflammatory cytokines such as IL-10. The increase of IL-10 is greater in HIV-infected than uninfected individuals. Further work is required to ascertain if this is part of an immunological profile that correlates with adverse outcomes such as serofast syphilis and neurosyphilis, in HIV-infected individuals. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2201-7) contains supplementary material, which is available to authorized users.

Background HIV-1 infection impairs tuberculosis (TB) specific immune responses affecting the diagnosis of latent TB. We aimed to (1) determine the proportion of HIV-1-infected adults with a negative QuantiFERON®-TB Gold in-tube (QFT-GIT) and Tuberculin skin testing (TST) that convert to QFT-GIT positive following TST, and (2) evaluate the relationship between conversion and baseline QFT-GIT results. Methods HIV-1 infected adults being screened for a TB vaccine study in South Africa underwent QFT-GIT followed by TST. As per protocol, QFT-GIT was repeated if randomization was delayed allowing for evaluation of TST boosting in a proportion of participants. Results Of the 22 HIV-1 infected, TST and QFT-GIT negative adults (median CD4 477/mm3 IQR 439–621) who had QFT-GIT repeated after median 62 days (IQR 49–70), 40.9 % (95 % CI 18.6–63.2 %) converted. Converters had a significantly greater increase in the background subtracted TB antigen response (TBAg-Nil – all units IU/mL) following TST, 0.82 (IQR 0.39–1.28) vs 0.03 (IQR −0.05–0.06), p = 0.0001. Those who converted also had a significantly higher baseline TBAg-Nil 0.21(IQR 0.17–0.26) vs 0.02(IQR 0.01–0.07), p = 0.002. Converters did not differ with regard to CD4 count or ART status. ROC analysis showed a baseline cut off of 0.15 correctly classified 86.4 % of converters with 88.9 % sensitivity. Conclusions Our findings support the possibility that there are 2 distinct groups in an HIV-1 infected population with negative QFT-GIT and TST; a true negative group and a group showing evidence of a weak Mtb specific immune response that boosts significantly following TST resulting in conversion of the test result that may represent false negatives. Further evaluation of whether a lower cut off may improve sensitivity of QFT-GIT in this population is warranted. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1875-6) contains supplementary material, which is available to authorized users.

Background: In a proportion of patients with HIV-associated tuberculosis who develop paradoxical immune reconstitution inflammatory syndrome (IRIS), the clinical course of IRIS is prolonged necessitating substantial health care utilization for diagnostic and therapeutic interventions. Prolonged TB-IRIS has not been prospectively studied to date. We aimed to determine the proportion of patients with prolonged TB-IRIS, as well as the clinical characteristics and risk factors for prolonged TB-IRIS. Methods: We pooled data from two prospective observational studies and a randomized controlled trial conducted in Cape Town, South Africa, that enrolled patients with paradoxical TB-IRIS. We used the same diagnostic approach and clinical case definitions for TB-IRIS in the 3 studies. Prolonged TB-IRIS was defined as TB-IRIS symptoms lasting > 90 days. Risk factors for prolonged TB-IRIS were analysed using Wilcoxon rank sum test, Fisher’s exact test, multivariate logistic regression and Cox proportional hazards models. Results: Two-hundred and sixteen patients with TB-IRIS were included. The median duration of TB-IRIS symptoms was 71.0 days (IQR 41.0–113.2). In 73/181 patients (40.3 %) with adequate follow-up data, IRIS duration was > 90 days. Six patients (3.3 %), mainly with lymph node involvement, had IRIS duration > 1 year. In univariate logistic regression analysis the following were significantly associated with IRIS duration > 90 days: lymph node involvement at initial TB diagnosis, drug-resistant TB, lymph node TB-IRIS, and not being hospitalised at time of TB-IRIS diagnosis. In our multivariate logistic regression model lymph node TB-IRIS (aOR 2.27, 95 % CI 1.13–4.59) and not being hospitalised at time of TB-IRIS diagnosis (aOR for being hospitalised 0.5, 95 % CI 0.25-0.99) remained significantly associated with prolonged TB-IRIS, and drug-resistant TB was of borderline significance (aOR 3.26, 95 % CI 0.97–12.99). The association of not being hospitalised with longer duration of IRIS might be related to 1 of the 3 cohorts in which all patients were hospitalised at ART initiation with close inpatient follow-up. This could have resulted in diagnosis of milder cases and earlier IRIS treatment potentially resulting in shorter TB-IRIS duration in these hospitalised patients. Conclusions: Around 40 % of patients with TB-IRIS have symptoms for more than 90 days. Involvement of lymph nodes at time of TB-IRIS is an independent risk factor for prolonged TB-IRIS. Future studies should address whether more prompt anti-inflammatory treatment of lymph node TB-IRIS reduces the risk of prolonged TB-IRIS. Trial registration: The randomized controlled trial was registered with Current Controlled Trials ISRCTN21322548 on 17 August 2005.

International audience; Protozoan parasites of the genus Leishmania adapt to their arthropod and vertebrate hosts through the development of defined life cycle stages. Stage differentiation is triggered by environmental stress factors and has been linked to parasite chaperone activities. Using a null mutant approach we previously revealed important, nonredundant functions of the cochaperone cyclophilin 40 in L. donovani-infected macrophages. Here, we characterized in more detail the virulence defect of cyp40-/- null mutants. In vitro viability assays, infection tests using macrophages, and mixed infection experiments ruled out a defect of cyp40-/- parasites in resistance to oxidative and hydrolytic stresses encountered inside the host cell phagolysosome. Investigation of the CyP40-dependent proteome by quantitative 2D-DiGE analysis revealed up regulation of various stress proteins in the null mutant, presumably a response to compensate for the lack of CyP40. Applying transmission electron microscopy we showed accumulation of vesicular structures in the flagellar pocket of cyp40-/- parasites that we related to a significant increase in exosome production, a phenomenon previously linked to the parasite stress response. Together these data suggest that cyp40-/- parasites experience important intrinsic homeostatic stress that likely abrogates parasite viability during intracellular infection.

Background The durability of isoniazid preventive therapy (IPT) in preventing tuberculosis (TB) is limited in high-prevalence settings. The underlying mechanism (reactivation of persistent latent TB or reinfection) is not known. We aimed to investigate the timing of TB incidence during and after IPT and associated risk factors in a very high TB and HIV-prevalence setting, and to compare the observed rate with a modelled estimate of TB incidence rate after IPT due to reinfection. Methods In a post-hoc analysis of a cluster-randomized trial of community-wide IPT among South African gold miners, all intervention arm participants that were dispensed IPT for at least one of the intended 9 months were included. An incident TB case was defined as any participant with a positive sputum smear or culture, or with a clinical TB diagnosis assigned by a senior study clinician. Crude TB incidence rates were calculated during and after IPT, overall and by follow-up time. HIV status was not available. Multivariable Cox regression was used to analyse risk factors by follow-up time after IPT. Estimates from a published mathematical model of trial data were used to calculate the average reinfection TB incidence in the first year after IPT. Results Among 18,520 participants (96 % male, mean age 41 years, median follow-up 2.1 years), 708 developed TB. The TB incidence rate during the intended IPT period was 1.3/100 person-years (pyrs; 95 % confidence interval (CI), 1.0–1.6) and afterwards 2.3/100 pyrs (95 % CI, 1.9–2.7). TB incidence increased within 6 months followed by a stable rate over time. There was no evidence for changing risk factors for TB disease over time after miners stopped IPT. The average TB incidence rate attributable to reinfection in the first year was estimated at 1.3/100 pyrs, compared to an observed rate of 2.2/100 pyrs (95 % CI, 1.8–2.7). Conclusions The durability of protection by IPT was lost within 6–12 months in this setting with a high HIV prevalence and a high annual risk of M. tuberculosis infection. The observed rate was higher than the modelled rate, suggesting that reactivation of persistent latent infection played a role in the rapid return to baseline TB incidence. Electronic supplementary material The online version of this article (doi:10.1186/s12916-016-0589-3) contains supplementary material, which is available to authorized users.

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. Keywords: antiretrovirals, causes, HIV/AIDS, neoliberalism, policy, political aspects, South Africa, treatmentAfrican Journal of AIDS Research 2008, 7(1): 29–35

Two case reports have recently been published describing possible immune reconstitution inflammatory syndrome (IRIS) to Strongyloides infection [1,2]; however, there is debate as to whether the presentations may alternatively be caused by Strongyloides hyperinfection [3]. We report, we believe for the first time, a case that fulfils the criteria for Strongyloides IRIS with no evidence of hyperinfection syndrome.

Background Postnatal transmission of HIV-1 through breast milk remains an unsolved challenge in many resource-poor settings where replacement feeding is not a safe alternative. WHO now recommends breastfeeding of infants born to HIV-infected mothers until 12 months of age, with either maternal highly active antiretroviral therapy (HAART) or peri-exposure prophylaxis (PEP) in infants using nevirapine. As PEP, lamivudine showed a similar efficacy and safety as nevirapine, but with an expected lower rate of resistant HIV strains emerging in infants who fail PEP, and lower restrictions for future HIV treatment. Lopinavir/ritonavir (LPV/r) is an attractive PEP candidate with presumably higher efficacy against HIV than nevirapine or lamivudine, and a higher genetic barrier to resistance selection. It showed an acceptable safety profile for the treatment of very young HIV-infected infants. The ANRS 12174 study aims to compare the risk of HIV-1 transmission during and safety of prolonged infant PEP with LPV/r (40/10 mg twice daily if 2-4 kg and 80/20 mg twice daily if >4 kg) versus Lamivudine (7,5 mg twice daily if 2-4 kg, 25 mg twice daily if 4-8 kg and 50 mg twice daily if >8 kg) from day 7 until one week after cessation of BF (maximum 50 weeks of prophylaxis) to prevent postnatal HIV-1 acquisition between 7 days and 50 weeks of age. Methods The ANRS 12174 study is a multinational, randomised controlled clinical trial conducted on 1,500 mother-infant pairs in Burkina Faso, South Africa, Uganda and Zambia. We will recommend exclusive breastfeeding (EBF) until 26th week of life and cessation of breastfeeding at a maximum of 49 weeks in both trial arms. HIV-uninfected infants at day 7 (± 2 days) born to HIV-1 infected mothers not eligible for HAART who choose to breastfeed their infants. The primary endpoint is the acquisition of HIV-1 (as assessed by HIV-1 DNA PCR) between day 7 and 50 weeks of age. Secondary endpoints are safety (including resistance, adverse events and growth) until 50 weeks and HIV-1-free survival until 50 weeks. Discussion This study will provide a new evidence-based intervention to support HIV-1-infected women not eligible for HAART to safely breastfeed their babies. Trial registration number (http://www.clinicaltrials.gov) NCT00640263

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.

The prevalence of hepatitis B virus (HBV) infection in 1 765 HIVpositive patients in rural Eastern Cape was 7.1%. This is lower than the previously reported rural prevalence and is similar to urban prevalence. Male sex and baseline alanine aminotransferase (ALT) were significant predictors of HBV status. Most HBV-positive patients had normal baseline ALT, making ALT an insensitive screening test for HBV status.

International audience; ABSTRACT: Early infant diagnosis (EID) of HIV-1 infection confers substantial benefits to HIV-infected and HIV-uninfected infants, to their families, and to programs providing prevention of mother-to-child transmission (PMTCT) services, but has been challenging to implement in resource-limited settings. In order to correctly inform parents/caregivers of infant infection status and link HIV-infected infants to care and treatment, a "cascade" of events must successfully occur. A frequently-cited barrier to expansion of EID programs is the cost of the required laboratory assays. However, substantial implementation barriers, as well as personnel and infrastructure requirements, exist at each step in the cascade. In this update, we review challenges to uptake at each step in the EID cascade, highlighting that even with the highest reported levels of uptake, nearly half of HIV-infected infants may not complete the cascade successfully. We next synthesize the available literature about the costs and cost-effectiveness of EID programs; identify areas for future research; and place these findings within the context of the benefits and challenges to EID implementation in resource-limited settings.

Rochelle Walensky and colleagues use a model-based analysis to examine which of the 2010 WHO antiretroviral therapy guidelines should be implemented first in resource-limited settings by ranking them according to survival, cost-effectiveness, and equity., Background The new 2010 World Health Organization (WHO) HIV treatment guidelines recommend earlier antiretroviral therapy (ART) initiation (CD4, Editors' Summary Background Since 1981, acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people, and about 33 million people (30 million of them in low- and middle-income countries) are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections (so-called opportunistic infections). Early in the AIDS epidemic, most people with HIV died within 10 years of infection. Then, in 1996, highly active antiretroviral therapy (ART)—a combination of several powerful antiretroviral drugs—was developed. Now, in resource-rich countries, clinicians care for people with HIV by prescribing ART regimens tailored to each individual's needs. They also regularly measure the amount of virus in their patients' blood, test for antiretroviral-resistant viruses, and monitor the health of their patients' immune systems through regular CD4 cell counts. As a result, the life expectancy of patients with HIV in developed countries has dramatically improved. Why Was This Study Done? Initially, resource-limited countries could not afford to provide ART for their populations, and the life expectancy of HIV-positive people remained low. Now, through the concerted efforts of governments, the World Health Organization (WHO), and other international agencies, more than a third of the people in low- and middle-income countries who need ART are receiving it. However, many without access are still in need of ART, and ART programs in developing countries follow a public-health approach rather than an individualized approach. That is, drug regimens, clinical decision-making, and disease monitoring are all standardized and follow recommendations in the 2006 WHO ART guidelines. This year (2010), these guidelines were revised. The guidelines now recommend the following: earlier ART initiation—when the CD4 count falls below 350/µl of blood, instead of below 200/µl as in the 2006 guidelines; the provision of sequential ART regimens instead of a single regimen; and the replacement of the antiretroviral drug stavudine with tenofovir, a less toxic but more expensive drug, in first-line ART regimens. However, many resource-limited countries are still struggling to implement the 2006 guidelines, so which of these new recommendations should be prioritized? Here, the researchers use a mathematical model to address this question. What Did the Researchers Do and Find? The Cost Effectiveness of AIDS Complications (CEPAC)–International model simulates the natural history and treatment of HIV disease. The researchers entered South African clinical and cost data for HIV treatment into this model and then used it to project survival and costs in a hypothetical group of South African HIV-positive patients under alternative guideline prioritization scenarios. The reference strategy for the simulations (denoted as “stavudine/WHO/one-line”) assumed that patients (with a mean CD4 count of 375/µl) began a single stavudine-based ART regimen when they developed WHO stage III/IV HIV disease (i.e., when patients develop multiple opportunistic infections such as tuberculosis and pneumonia). When the new guideline recommendations were considered separately, ART initiation at CD4

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.

OBJECTIVES: 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

Based on data from West Africa, Elena Losina and colleagues predict that interventions to reduce dropout rates from HIV treatment programs (such as eliminating copayments) will be cost-effective., Background Data from HIV treatment programs in resource-limited settings show extensive rates of loss to follow-up (LTFU) ranging from 5% to 40% within 6 mo of antiretroviral therapy (ART) initiation. Our objective was to project the clinical impact and cost-effectiveness of interventions to prevent LTFU from HIV care in West Africa. Methods and Findings We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) International model to project the clinical benefits and cost-effectiveness of LTFU-prevention programs from a payer perspective. These programs include components such as eliminating ART co-payments, eliminating charges to patients for opportunistic infection-related drugs, improving personnel training, and providing meals and reimbursing for transportation for participants. The efficacies and costs of these interventions were extensively varied in sensitivity analyses. We used World Health Organization criteria of, Editors' Summary Background Acquired immunodeficiency syndrome (AIDS) has killed more than 25 million people since the first reported case in 1981. Currently, about 33 million people are infected with the human immunodeficiency virus (HIV), which causes AIDS. Two-thirds of people infected with HIV live in sub-Saharan Africa. HIV infects and destroys immune system cells, thereby weakening the immune system and rendering infected individuals susceptible to infection. There is no cure for HIV/AIDS. Combination antiretroviral therapy (ART), a mixture of antiretroviral drugs that suppress the replication of the virus in the body, is used to treat and prevent HIV infection. ART is expensive but major international efforts by governments, international organizations, and funding bodies have increased ART availability. According to World Health Organization (WHO) estimates, at least 9.7 million people in low- and middle-income countries need ART and as of 2007, 3 million of those people had reliable access to the drugs. Why Was This Study Done? Although ART is an effective treatment for HIV, a large number of individuals who initiate ART do not receive long-term follow-up care. These patients are generally sicker and have a worse long-term outcome than those who receive follow-up care. Loss to follow up (LTFU) is a significant problem that can undermine the benefits of expanding ART availability. Strategies to improve follow up concentrate on bringing lost patients back into the health care system, but such patients often die before they can be contacted. Prevention of LTFU might be a better strategy to improve HIV care after ART initiation, but there is little information available on which specific interventions might best accomplish this goal. What Did the Researchers Do and Find? Given the lack of reported data on the actual costs and effectiveness of LTFU prevention, the researchers used a model to estimate the clinical impact and cost-effectiveness of several possible strategies to prevent LTFU in HIV-infected persons receiving ART in Côte d'Ivoire, West Africa. The researchers used the previously developed Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model and combined it with data from a program of ART delivery in Abidjan, Côte d'Ivoire. They then projected the clinical benefits and the cost required to attain a given level of benefit (cost-effectiveness ratio) of different LTFU-prevention strategies from the perspective of the payer (the organization that pays all the medical costs to provide care). Several interventions were considered, including reducing costs to patients (eliminating patient co-payments and paying for transportation) and increasing services to patients at their visits (improving staff training in HIV care, and providing meals at clinic times). LTFU was predicted to cause a 54.3%–58.3% reduction in the estimated life expectancy beyond age 37; patients continuing HIV care were predicted to live a further 144.7 months whie those lost to follow up by 1 year after ART initiation were predicted to live only for a further 73.9–80.7 months. LTFU-prevention strategies in the Côte d'Ivoire were deemed to be cost-effective if they cost less than $2,823 (which is 3× gross domestic product per capita) per year of life saved. The efficacy and cost of the different LTFU-prevention strategies varied in the analyses; stopping ART co-payment alone would be cost-effective at a cost of $22/person/year if it reduced LTFU rates by 12%, while including all the LTFU-prevention strategies described would be cost-effective at $77/person/year if they reduced LTFU-rates by 41%. What Do These Findings Mean? The findings suggest that moderately effective strategies for preventing LTFU in resource-limited settings would improve survival, provide good value for money, and should be used to improve HIV treatment programs. Although modeling is valuable to explore the costs and effectiveness of LTFU-prevention strategies it cannot replace the need for more reported data to shed light on problems leading to LTFU and the prevention strategies required to combat it. Also, Côte d'Ivoire might not be representative of all West African countries or resource-limited settings. A similar analysis using data from other ART programs in different countries would be useful to provide better understanding of the impact of LTFU in HIV treatment programs. Finally, the research highlights the cost of second-line ART (a new antiretroviral drug combination for patients in whom first-line treatment fails) as a crucial issue. It is estimated that 5% of all people receiving ART in low- and middle-income countries receive second-line ART and these numbers are expected to increase. Second-line ART had major effects on cost-effectiveness, and a reduction in the cost of this treatment is critical in order to guarantee continued access to HIV treatment. Additional Information Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000173. This study is further discussed in a PLoS Medicine Perspective by Gregory Bisson and Jeffrey Stringer WHO provides information on disease prevention, treatment, and HIV/AIDS programs and projects The UN Millennium Development Goals project site contains information on worldwide efforts to halt the spread of HIV/AIDS aidsmap, a nonprofit, nongovernmental organization, provides information on HIV and supporting those living with HIV

International audience; Leptospirosis is a zoonotic disease that has emerged as an important cause of morbidity and mortality among impoverished populations. One hundred years after the discovery of the causative spirochaetal agent, little is understood about Leptospira spp. pathogenesis, which in turn has hampered the development of new intervention strategies to address this neglected disease. However, the recent availability of complete genome sequences for Leptospira spp. and the discovery of genetic tools for their transformation have led to important insights into the biology of these pathogens and their pathogenesis. We discuss the life cycle of the bacterium, the recent advances in our understanding and the implications for the future prevention of leptospirosis.

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.

International audience; OBJECTIVE: To determine whether differences in short-term virologic failure among commonly used antiretroviral therapy (ART) regimens translate to differences in clinical events in antiretroviral-na? patients initiating ART. DESIGN: Observational cohort study of patients initiating ART between January 2000 and December 2005. SETTING: The Antiretroviral Therapy Cohort Collaboration (ART-CC) is a collaboration of 15 HIV cohort studies from Canada, Europe, and the United States. STUDY PARTICIPANTS: A total of 13 546 antiretroviral-na? HIV-positive patients initiating ART with efavirenz, nevirapine, lopinavir/ritonavir, nelfinavir, or abacavir as third drugs in combination with a zidovudine and lamivudine nucleoside reverse transcriptase inhibitor backbone. MAIN OUTCOME MEASURES: Short-term (24-week) virologic failure (>500 copies/ml) and clinical events within 2 years of ART initiation (incident AIDS-defining event, death, and a composite measure of these two outcomes). RESULTS: Compared with efavirenz as initial third drug, short-term virologic failure was more common with all other third drugs evaluated; nevirapine (adjusted odds ratio = 1.87, 95% confidence interval (CI) = 1.58-2.22), lopinavir/ritonavir (1.32, 95% CI = 1.12-1.57), nelfinavir (3.20, 95% CI = 2.74-3.74), and abacavir (2.13, 95% CI = 1.82-2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with nevirapine (adjusted hazard ratio for composite outcome measure 1.27, 95% CI = 1.04-1.56) and abacavir (1.22, 95% CI = 1.00-1.48). CONCLUSION: Among antiretroviral-na? patients initiating therapy, between-ART regimen, differences in short-term virologic failure do not necessarily translate to differences in clinical outcomes. Our results should be interpreted with caution because of the possibility of residual confounding by indication.

lIgObjectives.l/Ig To describe the incidence, spectrum and prognosis of AIDS-defining illnesses (ADI) in patients without access to antiretroviral therapy (ART). lBRglIgDesign.l/Ig Prospective cohort study. lBRglIgSubjects.l/Ig 1 215 HIV-infected patients attending adult HIV clinics affiliated to the University of Cape Town in the New Somerset and Groote Schuur Hospitals from 1992 to 2000. Main outcome measures.l/Ig Incidence rate (IR) of ADIs and survival after the development of ADI. lBRglIgResults.l/Ig During follow-up, 430 ADIs occurred (IR = 21.3 cases per 100 patient-years (PYs)). IR varied according to CD4 count, with 38.8, 17.0 and 8.52 cases/100 PYs in patients with CD4 counts 350 cells/µl, respectively. Tuberculosis (TB) was the commonest ADI, followed by candidiasis of the oesophagus/trachea/bronchi. IRs for chronic herpes simplex ulcers, HIV wasting, Pneumocystis cariniil/Ig pneumonia and Kaposi's sarcoma were > 1.00 cases/100 PYs. TB was diagnosed in all CD4 strata, and was the only illness to occur commonly above 200 cells/µl. The median CD4 counts within 6 months of diagnosis of ADI ranged from 138 cells/µl for TB to 17 cells/µl for cryptococcosis. Overall, median time to death from date of diagnosis was 18 months, and ranged from 24.1 months for patients diagnosed with TB to 6 months for those diagnosed with cytomegalovirus. lBRglIgConclusions.l/Ig HIV-infected patients with no access to ART in Cape Town are at high risk of AIDS-defining illnesses. This study provides useful data for designing therapeutic interventions for preventing these infections.

Background 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 analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV). Methods and Findings Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417), or EFV (n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (−4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. Conclusion NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease., Comparison of two commonly prescribed non-nucleoside reverse transcriptase inhibitors shows that patients on nevirapine have better blood lipid profiles

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.

OBJECTIVES: Cryptococcal meningitis is the commonest cause of adult meningitis in Southern Africa. A sizeable proportion of this disease burden is thought to be due to symptomatic relapse of previously treated infection. We carried out a study to examine the contribution of inadequate secondary fluconazole prophylaxis to symptomatic relapses of cryptococcal meningitis. DESIGN: A prospective observational study of patients presenting with laboratory-confirmed symptomatic relapse of HIV-associated cryptococcal meningitis between January 2007 and December 2008 at GF Jooste Hospital, a public sector adult referral hospital in Cape Town. OUTCOME MEASURES: Relapse episodes were categorized into 1) patients not taking fluconazole prophylaxis, 2) immune reconstitution inflammatory syndrome (IRIS) and 3) relapses occurring prior to ART in patients taking fluconazole. In-hospital mortality was recorded. RESULTS: There were 69 relapse episodes, accounting for 23% of all cases of cryptococcal meningitis. 43%(n=30) of relapse episodes were in patients not taking fluconazole prophylaxis, 45%(31) were due to IRIS and 12%(8) were in patients pre-ART taking fluconazole. Patients developing relapse due to inadequate secondary prophylaxis had severe disease and high in-hospital mortality (33%). Of the 30 patients not taking fluconazole, 47% (14) had not been prescribed secondary prophylaxis by their healthcare providers. Importantly, we documented no relapses due to fluconazole resistance in this cohort of patients who has received amphotericin B as initial therapy. CONCLUSIONS: Large numbers of relapses of cryptococcal meningitis are due to failed prescription, dispensing, referral for or adherence to secondary fluconazole prophylaxis. Interventions to improve the use of secondary fluconazole prophylaxis are essential.

Background We investigated the prevalence of human papillomavirus (HPV) infection and associated behavioural risk factors in men-who-have-sex-with-men (MSM) attending a clinical service in Cape Town, South Africa. Methods MSM were enrolled at the Ivan Toms Centre for Men’s Health in Cape Town. A psychosocial and sexual behavioral risk questionnaire was completed for each participant and urine, oro-pharyngeal and anal swabs were collected for HPV testing using the Linear Array HPV Genotyping Test. Logistic regression analyses were performed to determine sexual risk factors associated with HPV infection at the three anatomical sites. Results The median age of all 200 participants was 32 years (IQR 26-39.5), of which 31.0 % were black, 31.5 % mixed race/coloured and 35.5 % white. The majority of the participants (73.0 %) had completed high school, 42.0 % had a tertiary level qualification and 69.0 % were employed. HPV genotypes were detected in 72.8 % [95 % CI: 65.9–79.0 %], 11.5 % [95 % CI: 7.4–16.8 %] and 15.3 % [95 % CI: 10.5–21.2 %] of anal, oro-pharyngeal and urine specimens, respectively. Prevalence of high-risk (HR)-HPV types was 57.6 % [95 % CI: 50.3–64.7 %] in anal samples, 7.5 % [95 % CI: 4.3–12.1 %] in oro-pharyngeal samples and 7.9 % [95 % CI: 4.5–12.7 %] in urine, with HPV-16 being the most common HR-HPV type detected at all sites. HPV-6/11/16/18 was detected in 40.3 % [95 % CI: 33.3–47.6 %], 4.5 % [95 % CI: 2.1–8.4 %] and 3.2 % [95 % CI: 1.2–6.8 %] of anal, oro-pharyngeal and urine samples, respectively. Multiple HPV types were more common in the anal canal of MSM while single HPV types constituted the majority of HPV infections in the oropharynx and urine. Among the 88 MSM (44.0 %) that were HIV positive, 91.8 % [95 % CI: 83.8–96.6 %] had an anal HPV infection, 81.2 % [95 % CI: 71.2–88.8 %] had anal HR-HPV and 85.9 % [95 % CI: 76.6–92.5 %] had multiple anal HPV types. Having sex with men only, engaging in group sex in lifetime, living with HIV and practising receptive anal intercourse were the only factors independently associated with having any anal HPV infection. Conclusions Anal HPV infections were common among MSM in Cape Town with the highest HPV burden among HIV co-infected MSM, men who have sex with men only and those that practiced receptive anal intercourse. Behavioural intervention strategies and the possible roll-out of HPV vaccines among all boys are urgently needed to address the high prevalence of HPV and HIV co-infections among MSM in South Africa.

International audience; BACKGROUND: School closure is a non-pharmaceutical intervention that was considered in many national pandemic plans developed prior to the start of the influenza A(H1N1)pdm09 pandemic, and received considerable attention during the event. Here, we retrospectively review and compare national and local experiences with school closures in several countries during the A(H1N1)pdm09 pandemic. Our intention is not to make a systematic review of country experiences; rather, it is to present the diversity of school closure experiences and provide examples from national and local perspectives. METHODS: Data were gathered during and following a meeting, organized by the European Centres for Disease Control, on school closures held in October 2010 in Stockholm, Sweden. A standard data collection form was developed and sent to all participants. The twelve participating countries and administrative regions (Bulgaria, China, France, Hong Kong Special Administrative Region (SAR), Italy, Japan, New Zealand, Serbia, South Africa, Thailand, United Kingdom, and United States) provided data. RESULTS: Our review highlights the very diverse national and local experiences on school closures during the A(H1N1)pdm09 pandemic. The processes including who was in charge of making recommendations and who was in charge of making the decision to close, the school-based control strategies, the extent of school closures, the public health tradition of responses and expectations on school closure varied greatly between countries. Our review also discusses the many challenges associated with the implementation of this intervention and makes recommendations for further practical work in this area. CONCLUSIONS: The single most important factor to explain differences observed between countries may have been the different public health practises and public expectations concerning school closures and influenza in the selected countries.

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-naive children (< or = 16 years) who commenced treatment with > or = 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, virological suppression and growth were described in relation to duration of ART. RESULTS: The median (interquartile range) age of 6 078 children with 9 368 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% confidence interval 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.