Long Term Nationwide Analysis of HIV and AIDS in Iceland, 1983-2012.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.Introduction: Iceland is well suited for epidemiological research due to well-kept patient records, easy followup of patients and nation-wide health care databases. This study provides a nationwide 30-year epidemiological overview of the HIV epidemic in the country. Materials and methods: Retrospective study on all HIV positive individuals in Iceland, 1983-2012. Clinical data, CD4+ T-cell counts, plasma HIV RNA, proportion of late presenters and effectiveness of combined antiretroviral therapy (cART) were compared by different time intervals. Results: In total, 313 were diagnosed with HIV in 1983-2012, thereof 222 (71%) men and 91 (29%) women. Most infections (65%) were acquired outside the country. Mean incidence of HIV was 3.7/100,000 inhabitants/year, with a significant increase in 2010-2012 (p=0.0113), related to misuse of the prescription drug methylphenidate among intravenous drug users. Official prescriptions for this drug increased from 3.5 in 2002 to 17.4 defined daily doses/ 1,000 inhabitants/day in 2012. Mortality decreased by 70% during the study period (p=0.0275). Proportion of late presenters decreased from 74% in the first decade to 36% during the third (p=0.0001). After 6 months of ART, CD4+ T-cells increased by only 26 cells/µl on average during the monotherapy era (1987-1995; p=0,174), by 107 cells/µl during the early-cART era (1996-2004; p<0.0001) and by 159 cells/µl during the late-cART era (2005-2012; p<0,0001). Similarly, progressively greater reductions in plasma HIV RNA were observed from 1996-2004 to 2005-2012 (p<0.0001). Conclusions: HIV incidence remained relatively low in Iceland until 2010, when it increased significantly due to spread among IDUs. The majority of HIV infections diagnosed in Iceland were imported. With ever more effective drug treatments on CD4+ T-cells and plasma HIV RNA, the number of AIDS diagnoses and deaths has decreased dramatically.University of Iceland Research Fund, Gilead Nordic fellowshi

Utility of oropharyngeal real-time PCR for S. pneumoniae and H. influenzae for diagnosis of pneumonia in adults.

Efst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn To access publisher's full text version of this article click on the hyperlink at the bottom of the pageor click on the hyperlink at the To access publisher's full text version of this article, please click on the hyperlink in Additional Links field top of the page marked FilesA lack of sensitive tests and difficulties obtaining representative samples contribute to the challenge in identifying etiology in pneumonia. Upper respiratory tract swabs can be easily collected and analyzed with real-time PCR (rtPCR). Common pathogens such as S. pneumoniae and H. influenzae can both colonize and infect the respiratory tract, complicating the interpretation of positive results. Oropharyngeal swabs were collected (n = 239) prospectively from adults admitted to hospital with pneumonia. Analysis with rtPCR targeting S. pneumoniae and H. influenzae was performed and results compared with sputum cultures, blood cultures, and urine antigen testing for S. pneumoniae. Different Ct cutoff values were applied to positive tests to discern colonization from infection. Comparing rtPCR with conventional testing for S. pneumoniae in patients with all tests available (n = 57) resulted in: sensitivity 87 %, specificity 79 %, PPV 59 % and NPV 94 %, and for H. influenzae (n = 67): sensitivity 75 %, specificity 80 %, PPV 45 % and NPV 94 %. When patients with prior antimicrobial exposure were excluded sensitivity improved: 92 % for S. pneumoniae and 80 % for H. influenzae. Receiver operating characteristic curve analysis demonstrated for S. pneumoniae: AUC = 0.65 (95 % CI 0.51-0.80) and for H. influenzae: AUC = 0.86 (95 % CI 0.72-1.00). Analysis of oropharyngeal swabs using rtPCR proved both reasonably sensitive and specific for diagnosing pneumonia caused by S. pneumoniae and H. influenzae. This method may be a useful diagnostic adjunct to other methods and of special value in patients unable to provide representative lower airway samples.Icelandic Center for Research Rannis Landspitali University Hospital Science Fund University of Iceland Research Fun

Invasive infections due to Streptococcus pyogenes: seasonal variation of severity and clinical characteristics, Iceland, 1975 to 2012.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageEpidemiology and clinical characteristics of invasive Group A streptococcal infections (IGASI) are highly variable. Long-term studies are needed to understand the interplay between epidemiology and virulence. In a population-based study of IGASI in Iceland from 1975 to 2012, 288 cases were identified by positive cultures from normally sterile body sites. Charts were reviewed retrospectively and emm-types of viable Streptococcus pyogenes isolates (n=226) determined. Comparing the first and last decade of the study period, IGASI incidence increased from 1.09 to 3.96 cases per 100,000 inhabitants per year. The most common were emm types 1 (25%), 28 (11%) and 89 (11%); emm1 strains were most likely to cause severe infections. Infections in adults were significantly more likely to be severe during the seasonal peak from January to April (risk ratio: 2.36, 95% confidence interval: 1.34–4.15). Significant seasonal variability in severity was noted among patients with diagnosis of sepsis, respiratory infection and cellulitis, with 38% of severe infections in January to April compared with 16% in other months (p<0.01). A seasonal increase in severity of IGASI suggested that generalised seasonal increase in host susceptibility, rather than introduction of more virulent strains may play a role in the pathogenesis of these potentially fatal infections.Icelandic Center for Research, Rannis/100436021 Landspitali University Hospital Science Fun

Treatment as Prevention for Hepatitis C (TraP Hep C) - a nationwide elimination programme in Iceland using direct-acting antiviral agents

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesA nationwide programme for the treatment of all patients infected with hepatitis C virus (HCV) was launched in Iceland in January 2016. By providing universal access to direct-acting antiviral agents to the entire patient population, the two key aims of the project were to (i) offer a cure to patients and thus reduce the long-term sequelae of chronic hepatitis C, and (ii) to reduce domestic incidence of HCV in the population by 80% prior to the WHO goal of HCV elimination by the year 2030. An important part of the programme is that vast majority of cases will be treated within 36 months from the launch of the project, during 2016-2018. Emphasis is placed on early case finding and treatment of patients at high risk for transmitting HCV, that is people who inject drugs (PWID), as well as patients with advanced liver disease. In addition to treatment scale-up, the project also entails intensification of harm reduction efforts, improved access to diagnostic tests, as well as educational campaigns to curtail spread, facilitate early detection and improve linkage to care. With these efforts, Iceland is anticipated to achieve the WHO hepatitis C elimination goals well before 2030. This article describes the background and organization of this project. Clinical trial number: NCT02647879.Merck Astellas Gilead Gilead Sciences AbbVie BM

Prevalence and Outcomes for Heavily Treatment-Experienced (HTE) Individuals Living with Human Immunodeficiency Virus in a European Cohort

BACKGROUND: Although antiretroviral treatments have improved survival of persons living with HIV, their long-term use may limit available drug options. We estimated the prevalence of heavily treatment-experienced (HTE) status and the potential clinical consequences of becoming HTE. SETTING: EuroSIDA, a European multicentre prospective cohort study. METHODS: A composite definition for HTE was developed, based on estimates of antiretroviral resistance and prior exposure to specific antiretroviral regimens. Risks of progressing to clinical outcomes were assessed by Poisson regression, comparing every HTE individual with three randomly-selected controls who never became HTE. RESULTS: Of 15,570 individuals under follow-up in 2010-2016, 1617 (10.4%, 95% CI 9.9-10.9%) were classified as HTE. 1093 individuals became HTE during prospective follow-up (HTE incidence rate 1.76, CI 1.66-1.87 per 100 person-years of follow-up). The number of HTE individuals was highest in West/Central Europe (636/4019 persons, 15.7%) and lowest in East Europe (26/2279 persons, 1.1%). Although most HTE individuals maintained controlled viral loads (<400 copies/ml), many had low CD4 counts (≤350 cells/µl). After controlling for age, immunological parameters and pre-existing comorbidities, HTE status was not associated with the risk of new AIDS (adjusted incidence rate ratio, aIRR 1.44, CI 0.86-2.40, p = 0.16) or non-AIDS clinical events (aIRR 0.96, CI 0.74-1.25, p = 0.77). CONCLUSIONS: HTE prevalence increased with time. After adjusting for key confounding factors, there was no evidence for an increased risk of new AIDS or non-AIDS clinical events in HTE. Additional therapeutic options and effective management of comorbidities remain important to reduce clinical complications in HTE individuals

Comparative Long-term Adverse Effects Elicited by Invasive Group B and C Meningococcal Infections

No vaccine is universally active against serogroup B meningococci. A theoretical concern that serogroup B capsular polysaccharide may induce autoimmunity hampers vaccine development. We studied long-term complications in 120 survivors of meningococcal disease. No evidence of increased autoimmune, neurological, or psychiatric disease was noted

Phage-Antibiotic Synergy (PAS): β-Lactam and Quinolone Antibiotics Stimulate Virulent Phage Growth

Although the multiplication of bacteriophages (phages) has a substantial impact on the biosphere, comparatively little is known about how the external environment affects phage production. Here we report that sub-lethal concentrations of certain antibiotics can substantially stimulate the host bacterial cell's production of some virulent phage. For example, a low dosage of cefotaxime, a cephalosporin, increased an uropathogenic Escherichia coli strain's production of the phage ΦMFP by more than 7-fold. We name this phenomenon Phage-Antibiotic Synergy (PAS). A related effect was observed in diverse host-phage systems, including the T4-like phages, with β-lactam and quinolone antibiotics, as well as mitomycin C. A common characteristic of these antibiotics is that they inhibit bacterial cell division and trigger the SOS system. We therefore examined the PAS effect within the context of the bacterial SOS and filamentation responses. We found that the PAS effect appears SOS-independent and is primarily a consequence of cellular filamentation; it is mimicked by cells that constitutively filament. The fact that completely unrelated phages manifest this phenomenon suggests that it confers an important and general advantage to the phages

Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.We sequenced the genomes of 3,615 strains of serotype Emm protein 1 (M1) group A Streptococcus to unravel the nature and timing of molecular events contributing to the emergence, dissemination, and genetic diversification of an unusually virulent clone that now causes epidemic human infections worldwide. We discovered that the contemporary epidemic clone emerged in stepwise fashion from a precursor cell that first contained the phage encoding an extracellular DNase virulence factor (streptococcal DNase D2, SdaD2) and subsequently acquired the phage encoding the SpeA1 variant of the streptococcal pyrogenic exotoxin A superantigen. The SpeA2 toxin variant evolved from SpeA1 by a single-nucleotide change in the M1 progenitor strain before acquisition by horizontal gene transfer of a large chromosomal region encoding secreted toxins NAD(+)-glycohydrolase and streptolysin O. Acquisition of this 36-kb region in the early 1980s into just one cell containing the phage-encoded sdaD2 and speA2 genes was the final major molecular event preceding the emergence and rapid intercontinental spread of the contemporary epidemic clone. Thus, we resolve a decades-old controversy about the type and sequence of genomic alterations that produced this explosive epidemic. Analysis of comprehensive, population-based contemporary invasive strains from seven countries identified strong patterns of temporal population structure. Compared with a preepidemic reference strain, the contemporary clone is significantly more virulent in nonhuman primate models of pharyngitis and necrotizing fasciitis. A key finding is that the molecular evolutionary events transpiring in just one bacterial cell ultimately have produced millions of human infections worldwide.Knut and Alice Wallenberg Foundation Swedish Research Council Houston Methodist Hospital Fondren Foundatio

Transcriptome Remodeling Contributes to Epidemic Disease Caused by the Human Pathogen Streptococcus pyogenes

For over a century, a fundamental objective in infection biology research has been to understand the molecular processes contributing to the origin and perpetuation of epidemics. Divergent hypotheses have emerged concerning the extent to which environmental events or pathogen evolution dominates in these processes. Remarkably few studies bear on this important issue. Based on population pathogenomic analysis of 1,200 Streptococcus pyogenes type emm89 infection isolates, we report that a series of horizontal gene transfer events produced a new pathogenic genotype with increased ability to cause infection, leading to an epidemic wave of disease on at least two continents. In the aggregate, these and other genetic changes substantially remodeled the transcriptomes of the evolved progeny, causing extensive differential expression of virulence genes and altered pathogen-host interaction, including enhanced immune evasion. Our findings delineate the precise molecular genetic changes that occurred and enhance our understanding of the evolutionary processes that contribute to the emergence and persistence of epidemically successful pathogen clones. The data have significant implications for understanding bacterial epidemics and for translational research efforts to blunt their detrimental effects. IMPORTANCE The confluence of studies of molecular events underlying pathogen strain emergence, evolutionary genetic processes mediating altered virulence, and epidemics is in its infancy. Although understanding these events is necessary to develop new or improved strategies to protect health, surprisingly few studies have addressed this issue, in particular, at the comprehensive population genomic level. Herein we establish that substantial remodeling of the transcriptome of the human-specific pathogen Streptococcus pyogenes by horizontal gene flow and other evolutionary genetic changes is a central factor in precipitating and perpetuating epidemic disease. The data unambiguously show that the key outcome of these molecular events is evolution of a new, more virulent pathogenic genotype. Our findings provide new understanding of epidemic disease.Peer reviewe

Treatment as Prevention for Hepatitis C (TraP Hep C) - a nationwide elimination programme in Iceland using direct-acting antiviral agents

Publisher's version (útgefin grein)A nationwide programme for the treatment of all patients infected with hepatitis C virus (HCV) was launched in Iceland in January 2016. By providing universal access to direct‐acting antiviral agents to the entire patient population, the two key aims of the project were to (i) offer a cure to patients and thus reduce the long‐term sequelae of chronic hepatitis C, and (ii) to reduce domestic incidence of HCV in the population by 80% prior to the WHO goal of HCV elimination by the year 2030. An important part of the programme is that vast majority of cases will be treated within 36 months from the launch of the project, during 2016–2018. Emphasis is placed on early case finding and treatment of patients at high risk for transmitting HCV, that is people who inject drugs (PWID), as well as patients with advanced liver disease. In addition to treatment scale‐up, the project also entails intensification of harm reduction efforts, improved access to diagnostic tests, as well as educational campaigns to curtail spread, facilitate early detection and improve linkage to care. With these efforts, Iceland is anticipated to achieve the WHO hepatitis C elimination goals well before 2030. This article describes the background and organization of this project. Clinical trial number: NCT02647879.Sigurdur Olafsson: Speaker's fee from Merck. Magnus Gottfredsson: Speaker's fee from Astellas and Gilead. MH and the Burnet Institute receive investigator‐initiated research funding from Gilead Sciences, AbbVie and BMS.Peer Reviewe