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Besides the significant benefits of vaccination against COVID-19, the risk of severe disease and death from COVID-19 among highly vulnerable populations remains of concern. Implementation of oral antiviral treatment has shown significant benefits for outpatients with high risk for severe disease, however, their effectiveness remains to be evaluated in real-life settings and in the presence of new Omicron subvariants. We aimed to investigate the effectiveness of molnupiravir and nirmatrelvir/ritonavir using a retrospective cohort design with outcomes hospital admission and death from COVID-19, in Greece. The effectiveness of each drug was estimated through a comparison of the antiviral’s recipients with an age-matched control group of non-recipients, adjusted for age, previous SARS-CoV-2 infection, vaccination status, and vaccination recency. Our analysis showed that molnupiravir significantly reduced the risk for hospitalization (OR = 0.40, p < 0.001) and death from COVID-19 (OR = 0.31, p < 0.001), with the effect being more intense among elderly patients (≥75 years old). The effectiveness was higher among those with full adherence. Nirmatrelvir/ritonavir was found also to significantly reduce the risk of hospital admission (OR = 0.31, p < 0.001) and death (OR = 0.28, p < 0.001) and, similarly to molnupiravir, effectiveness was stronger among elderly patients and those with the highest levels of adherence. Analysis of the relative effectiveness of nirmatrelvir/ritonavir versus molnupiravir suggested that nirmatrelvir/ritonavir was associated with a reduced risk for hospital admission (OR = 0.58, p < 0.001) compared to molnupiravir, adjusted for age, previous SARS-CoV-2 infection, vaccination status, and co-morbidities. Our real-world study provides evidence about the reduced risk of hospitalization and death in highly vaccinated patients with a high risk for severe disease in Greece. These findings highlight that although the hospitalization and mortality risk has been reduced mainly due to vaccination and the emergence of Omicron variants, antivirals provide significant additional benefits in highly vulnerable patients and therefore their use is documented and strongly indicated.

The new global pandemic of COVID-19 declared on March 11, 2020, by the World Health Organization, has already caused unprecedented health and socio-economic impacts, worldwide. The second wave of the COVID-19 pandemic has been sweeping the Unites States of America and Europe since late September 2020. The northern countries of Europe (Germany, France, Austria, Finland, Sweden) faced this second wave of the pandemic earlier in September 2020 against other southern countries, such as Greece, where there was a significant increase in cases in late October 2020. To understand the spread of COVID-19 in Greece, from the environmental perspective, we try to examine the effect of air temperature, humidity and wind on the emergence of COVID-19. More specifically, we concern whether warm and wet conditions have a positive effect by decreasing the number of COVID-19 cases, while on the contrary, cold and dry conditions are associated with increasing cases. We apply Pearson correlation analysis and Generalized Linear Models taking as dependent variable the confirmed admissions in intensive care units (ICU) of COVID-19 from the National Public Health Organization and the corresponding air temperature, humidity and wind speed from the Hellenic National Meteorological Service, as independent variables. The analysis concerns Athens and Thessaloniki, the two largest cities in Greece.

Background and AimsThe HIV outbreak among People Who Inject Drugs (PWID) in Athens, Greece in 2011-2013 was the largest recent epidemic in Europe and North America. We aim to assess trends in HIV prevalence, drug use and access to prevention among PWID in Athens, to estimate HIV incidence and identify risk factors and to explore HIV-1 dispersal using molecular methods during 2014-2020.MethodsTwo community-based HIV/hepatitis C programs on PWID were implemented in 2012-2013 (N=3,320) and 2018-2020 (N=1,635) through consecutive Respondent-Driven Sampling (RDS) rounds. PWID were uniquely identified across rounds/programs. We obtained RDS-weighted HIV prevalence estimates per round for 2018-2020 and compared them to 2012-2013. We assessed changes in HIV status, behaviours, and access to prevention in PWID participating in both periods. We estimated HIV incidence in a cohort of seronegative PWID as the number of HIV seroconversions/100 persons-years during 2014-2020 and used Cox regression to identify associated risk factors. Molecular sequencing and phylogenetic analysis were performed in HIV seroconverters.ResultsHIV prevalence per round ranged between 12.0%-16.2% in 2012-2013 and 10.7%-11.3% in 2018-2020 with overlapping 95% Confidence Intervals (95% CI). Among PWID participating in both programs, HIV prevalence[95% CI] increased from 14.2%[11.7%-17.1%] in 2012-2013 to 22.0%[19.0%-25.3%] in 2018-2020 (pConclusionsThe ongoing HIV transmission among PWID in Athens provides empirical evidence that the current levels of prevention and treatment are inadequate to control the epidemic. Re-evaluation of prevention programs is urgently needed.

Background: TRIP (Transmission Reduction Intervention Project) was a network-based, contact tracing approach to locate and link to care, mostly people who inject drugs (PWID) with recent HIV infection.Objective: We investigated whether sequences from HIV-infected participants with high viral load cluster together more frequently than what is expected by chance. Methods: Paired end reads were generated for 104 samples using Illumina MiSeq next-generation sequencing. Results: 63 sequences belonged to previously identified local transmission networks of PWID (LTNs) of an HIV outbreak in Athens, Greece. For two HIV-RNA cut-offs (105 and 106 IU/mL), HIV transmissions were more likely between PWID with similar levels of HIV-RNA (p106 IU/mL were clustered in 5 pairs. For 4 of these clusters (80%), there was in each one of them at least one sequence from a recently HIV-infected PWID. Conclusion: We showed that transmissions are more likely among PWID with high viremia. © 2018 Bentham Science Publishers.

Integrase strand transfer inhibitors (INSTIs) belong to a novel class of antiretroviral agents that have emerged as the new first-line treatments. Three such compounds are currently available, raltegravir, elvitegravir, dolutegravir and two more under development, bictegravir and cabotegravir. These compounds share the same mode of action but exhibit different pharmacokinetic/ pharmacodynamic properties, and drug-drug interactions. A series of studies in the past decade have established their efficacy compared to previous regimens, both in treatment-naïve and experienced patients. INSTIs have demonstrated a favorable safety profile with fewer adverse events and low rates of virological failure. Emergence of resistance to these agents, however, is a worrying concern, particularly for elvitegravir and raltegravir that display a lower genetic barrier than dolutegravir. On-going trials aim at establishing INSTIs as part of dual-drug HIV treatments or even monotherapy. New long-acting, injectable formulations are under investigation for treatment or prevention. © 2017 Bentham Science Publishers.

Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected. © The Author 2015.

Objectives: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. Methods: This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score=10 to at least one InSTI. To rule out circulation of minority InSTIresistant HIV, 65 samples were selected for 454 integrase sequencing. Results: For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIswere detected. Eleven (4%) subjects hadmutations at resistance-associated positions with an HIVdb score =10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutationsweredetected, whereas integrase substitutionswithanHIVdbscore=10were found in8(14.3%) individuals. Conclusions:No signature InSTI-resistant variantswere circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistancewere not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Motivation: Genetic analysis of HIV-1 is important not only for vaccine development, but also to guide treatment strategies, track the emergence of new viral variants and ensure that diagnostic assays are contemporary and fully optimized. However, most genotyping methods are laborious and complex, and involve the use of multiple software applications. Here, we describe the development of an automated genotyping system that can be easily applied to HIV-1 and other rapidly evolving viral pathogens. Results: The new REGA subtyping tool, developed using Java programming and PERL scripts, combines phylogenetic analyses with bootscanning methods for the genetic subtyping of full-length and subgenomic fragments of HIV-1. When used to investigate the subtype of previously published reference datasets that were analysed using manual phylogenetic methods, the automated method correctly identified 97.5--100% of non-recombinant and circulating recombinant forms of HIV-1, including 108 full-length, 108 gag and 221 env sequences downloaded from the Los Alamos database. Availability: The tool, which can be easily downloaded and installed on either a UNIX or Linux-based computer system, is available at http://www.bioafrica.net/subtypetool/html/ Contact: tulio.deoliveira@zoology.oxford.ac.uk

Duality between N=1 supersymmetric gauge theories(Seiberg's duality) isgeometrized, in the framework of AdS/CFT correspodences. It is shown thatSeiberg's duality corresponds to monodromy of wrapped D5 branes on the homologycycles of a generalized conifold where D3 branes are located. The celebrated\tilde{N}_c=N_f-N_c, \tilde{N}_f=N_f rule is reproduced and a braid groupstructure in a sequence of dualities, is found.

Circulating recombinant form (CRF) 01_AE caused an extensive HIV-1 epidemic in Thailand and Southeast Asia. Reanalysis of the recombination pattern of CRF01_AE suggested a more complicated pattern of mosaicism consisting of subtypes A, G, and E. These findings provide evidence that CRF01_AE originated from recombination between at least three different subtypes.

The widespread use of antiviral drugs against HIV has increased the prevalence of HIV-1 resistant strains among naïve individuals due to transmission of resistant strains. The purpose of this study was to investigate the presence of HIV-1 strains harboring resistance mutations in naïve patients in Greece. Blood samples were collected from 25 individuals. The DNA sequence of protease and partial reverse transcriptase regions (codons 41-223) were obtained by direct sequencing. Our results showed the absence of any primary resistance mutations in the study population. However, we were able to identify high prevalence of sequence polymorphisms at positions in reverse transcriptase region associated mainly with resistance to NNRTIs. Moreover, in protease region several secondary mutations were detected, suggesting the higher genetic variability of this region. The clinical significance of the polymorphisms associated with reduced susceptibility to NNRTIs remains to be clarified.

Background: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.Methods: Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy.Results: The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained constant at 5%, a significant decline in protease inhibitors resistance mutations was observed, from 3.9% in 2002 to 1.6% in 2007 (p = 0.001). In contrast, resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) doubled from 2.0% in 2002 to 4.1% in 2007 (p = 0.004) with 58% of viral strains carrying a K103N mutation. Phylogenetic analysis showed that these temporal changes could not be explained by large clusters of TDRM.Conclusion: During the years 2002 to 2007 transmitted resistance to NNRTI has doubled to 4% in Europe. The frequent use of NNRTI in first-line regimens and the clinical impact of NNRTI mutations warrants continued monitoring. © 2014 Frentz et al.; licensee BioMed Central Ltd.

To evaluate the safety and antiviral action of interferon-alpha (IFN-alpha) in HIV-1 infection, we undertook a proof of concept study in 27 treatment-naive patients. Eligible patients comprised two groups: the IFN-alphaT group (n = 17), which received 5 MIU IFN-alpha s.c. daily for 32 consecutive days, and the IFN-alphaNT group (n = 10), which did not receive IFN-alpha prior to highly active antiretroviral therapy (HAART), which was commenced on day 28 in both groups. IFN-alphaTreatment was well tolerated in 14 of the 17 patients of the IFN-alphaT group who completed the study. The mean HIV RNA reduction in the IFN-alphaT group on day 14 was 1.1 log(10). Viral load suppression was inversely associated with baseline viral load (p = 0.031). Four weeks after initiation of HAART, IFN-alphaT and IFN-alphaNT group patients had 2.40 and 1.82 log(10) HIV RNA reduction from baseline, respectively (p0.001). There was no evidence of cross-resistance with existing antiretrovirals in patients with HIV-RNA rebound after initial plasma viral load declineor = 1 log(10) during IFN-alpha monotherapy. Thus, low daily IFN-alpha exhibits potent anti-HIV-1 activity in vivo without serious adverse effects. These properties render IFN-alpha an attractive candidate for further assessment as a constituent of HAART.

A simple, safe and cost-effective treatment protocol in ovarian stimulation is of great importance in IVF practice, especially in the case of previous unsuccessful attempts. hCG has been used as a substitute of LH because of the degree of homology between the two hormones. The main aim of this prospective randomized study was to determine, for the first time, whether low dose hCG added to rFSH for ovarian stimulation could produce better results compared to the addition of rLH in women entering IVF-ET, especially in those women that had previous IVF failures. An additional aim was to find an indicator that would allow us to follow-up ovarian stimulation and, possibly, modify it in order to achieve a better IVF outcome; and that indicator may be the cDNA copies of the LH/hCG receptor. Group A patients (n = 58) were administered hCG and Group B rLH (n = 56) in addition to rFSH in the first days of ovarian stimulation. The number of follicles and oocytes and, most importantly, implantation and pregnancy rates were shown to be statistically significantly higher in the hCG group. This study has also determined, for the first time to our best knowledge, m-RNA for LH/hCG receptors in the lymphocytes of peripheral blood 40 h before ovum pick-up. cDNA levels of the hCG receptor after ovarian stimulation were significantly higher among women receiving hCG compared to those receiving LH. In addition, higher levels were encountered among women with pregnancy compared to those without, although this was not statistically significant due to the small number of pregnancies. It seems that hCG permits a highly effective and more stable occupancy of rLH/hCG receptors and gives more follicles and more oocytes. The determination of cDNA copies could be, in the future, a marker during ovulation induction protocols and of course a predictor for the outcome of ART in the special subgroup of patients with previous failures.

BackgroundInfection with drug-resistant human immunodeficiency virus type 1 (HIV-1) can impair the response to combination therapy. Widespread transmission of drug-resistant variants has the disturbing potential of limiting future therapy options and affecting the efficacy of postexposure prophylaxis penta increase-spacing 1>MethodsWe determined the baseline rate of drug resistance in 2208 therapy-naive patients recently and chronically infected with HIV-1 from 19 European countries during 1996-2002 ResultsIn Europe, 1 of 10 antiretroviral-naive patients carried viruses with ⩾1 drug-resistance mutation. Recently infected patients harbored resistant variants more often than did chronically infected patients (13.5% vs. 8.7%; P=.006). Non-B viruses (30%) less frequently carried resistance mutations than did subtype B viruses (4.8% vs. 12.9%; P

The relevance of GB virus C/hepatitis G virus (GBV-C/HGV) infections in liver pathology remains unclear. To investigate the epidemiology of GBV-C/HGV in Athens, Greece, sera from 512 subjects were screened for present and past markers of GBV-C/HGV infection using a reverse transcription-polymerase chain reaction (RT-PCR) and a serological assay, respectively. GBV-C/HGV RNA was detected in 18/56 (32.1%), 12/42 (28.6%), and 16/55 (29.1%) patients with acute hepatitis B, C, or non-A-E, and in 5/58 (8.6%) and 18/68 (26.5%) patients with chronic hepatitis B or C, respectively, as well as in 50/133 (37.6%) hemodialysis patients and 10/100 (10%) healthy individuals. The data indicated that GBV-C/HGV seroprevalence is age-dependent; thus, GBV-C/HGV RNA and anti-E2 positivity were shown to be associated with younger age [odds ratio 0.98, 95% confidence interval (CI) 0. 97-1.00, P = 0.017] and older age (odds ratio 1.03, 95% CI 1.01-1.05, P = 0.002), respectively. No significant associations were identified between GBV-C/HGV RNA status and alanine aminotransferase (ALT) levels in either hepatitis or hemodialysis patients. Nevertheless, GBV-C/HGV RNA-positive acute non-A-E hepatitis patients were more likely to manifest a more severe clinical form of acute hepatitis (P = 0.024). Phylogenetic analysis of partial 5'-untranslated region sequences isolated from 18 viremic individuals showed that most GBV-C/HGV strains circulating in the greater metropolitan area of Athens belong to the 2a subgroup. A genetically diverse type 2 sequence that may represent a novel subtype within group 2 was also characterized.

Haemodialysis patients are at high risk of infection by hepatitis C virus. The aim of this study was to investigate a hepatitis C virus outbreak which occurred in a haemodialysis unit, using epidemiological and molecular methods.Five seroconversions to hepatitis C virus antibody (anti-HCV) were observed over a 6 month period and these were added to the four previously recorded anti-HCV-positive patients. All nine patients involved in the outbreak were tested for HCV RNA by reverse transcription-polymerase chain reaction and hepatitis C genotype determination was accomplished by a reverse hybridization assay. Furthermore, part of the NS5 region of hepatitis C genome (nucleotide positions 7904-8304) was amplified and sequenced in all HCV RNA-positive patients. Then, phylogenetic analysis of the nucleotide sequences obtained was carried out in order to investigate any possible epidemiological linkage among patients. Detailed epidemiological records were also available for all haemodialysis patients.Samples from all five incident cases and three out of four prevalent HCV infections were found positive for HCV RNA. HCV genotyping studies revealed that all incident cases were classified as 4c/d, whereas one and two prevalent cases were 1a and 4c/d respectively. Sequence comparisons and phylogenetic tree analysis revealed that six of the patients harboured very similar strains and clustered together, including all incident and one prevalent case, which was implicated as index case. Further epidemiological analysis was consistent with patient to patient transmission.Molecular and epidemiological analysis suggested that horizontal nosocomial patient to patient transmission was the most likely explanation for the virus spread within the haemodialysis unit under study.

The HIV-1 subtype distribution in 83 HIV-1-seropositive individuals living in Greece was investigated by using the heteroduplex mobility assay (HMA), DNA sequencing, and phylogenetic analysis. The results revealed that partial HIV-1 gp120 sequences from 71 (86%) patients were subtype B, 5 (6%) were subtype A, 4 were subtype D (5%), 2 (2%) were subtype C, and 1 (1%) was subtype I. The subtype I isolate was documented in an intravenous drug user. A high prevalence (90-100%) of B isolates among intravenous drug users, hemophiliacs, and homosexual men was observed, in contrast to heterosexuals, among whom non-B subtypes seemed to be common (42.9%, p0.001). Among the Greek population subtype B is the most frequent (94%), in contrast to the high prevalence (57%) of non-B isolates found in emigrants living in Greece (p0.001). A heterosexual transmission case of subtype D in a Greek individual not traveling abroad was also documented. The broad HIV-1 diversity in Greece may be explained by population movements, such as migration and traveling.

D. Paraskevis , C. Haida , N. Tassopoulos , M. Raptopoulou , D. Tsantoulas , H. Papachristou , V. Sypsa , A. Hatzakis * a Department of Hygiene and Epidemiology, Athens University Medical School, M. Asias 75, GR-115 27, Athens, Greece b Western Attika General Hospital, Athens, Greece c Fourth Medical Department, University of Thessaloniki, Thessaloniki, Greece d ‘‘Sismanogleion’’ Hospital, Athens, Greece

Recombination is one of several factors that contribute to the great genetic diversity of human immunodeficiency virus type 1 (HIV-1). In the current study, analysis of the full-length genome of a novel complex mosaic HIV-1 isolate (99GR303) from a Greek sailor who was possibly infected in Sierra Leone, Africa is presented. The 99GR303 isolate was found to comprise genomic regions belonging to subtypes A, G, J and K as well as of regions of a subtype that remains unclassified. For a partial region of env as well as vpr, no apparent similarity to the known HIV-1 subtypes or to any of the circulating recombinant forms was found. In fact, in the partial env gene, including the C2-V3 region, the 99GR303 isolate formed a new clade, suggesting the existence of an additional HIV-1 subtype. Thus, novel recombinants embody partial genomic regions which may have originated either from subtypes that existed in the past and became extinct or from contemporary subtypes that are extremely rare.

Human immunodeficiency virus type 1 (HIV-1) has been classified into three main groups and 11 distinct subtypes. Moreover, several circulating recombinant forms (CRFs) of HIV-1 have been recently documented to have spread widely causing extensive HIV-1 epidemics. A subtype, initially designated I (CRF04_cpx), was documented in Cyprus and Greece and was found to comprise regions of sequence derived from subtypes A and G as well as regions of unclassified sequence. Re-analysis of the three full-length CRF04_cpx sequences that were available revealed a mosaic genomic organization of unique complexity comprising regions of sequence from at least five distinct subtypes, A, G, H, K and unclassified regions. These strains account for approximately 2% of the total HIV-1-infected population in Greece, thus providing evidence of the great capability of HIV-1 to recombine and produce highly divergent strains which can be spread successfully through different infection routes.

Inclusion of darunavir and etravirine significantly increased the percentage of patients having at least one fully-active drug from two or three different drug categories. Specifically, this percentage changed from 21% to 44% (two categories) and from 15% to 31% (three categories) (p < 0.001). Interestingly, in the study population, 81 (58%) individuals had no options in the N(t)RTI class. Concerning the other drug classes, 33 (41%) individuals had no available NNRTIs, while 58 (72%) of them had less than two options among the PIs.