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M184V is a single-base mutation in the YMDD domain of reverse transcriptase (RT). The M184V resistance-associated mutation (RAM) is related to virological unresponsiveness to lamivudine (3TC) and emtricitabine (FTC) and induces high-level resistance to these two antiretroviral agents. M184V is rapidly selected in the setting of non-suppressive antiretroviral therapy (ART) and accumulates in the HIV reservoir. There were continuous efforts to evaluate the impact of the M184V mutation on the treatment outcomes in people living with HIV (PLWH). Since 3TC remains an extensively used part of recommended antiretroviral combinations, M184V is commonly detected in patients with virological failure (VF). ART guidelines do not recommend the use of drugs impacted by RAMs as they have been confirmed to comprise a risk factor for VF. However, there is evidence that 3TC/FTC can remain active even in the presence of M184V. Given the potential benefits of 3TC in ART combinations, the investigation of M184V remains of high interest to clinicians and researchers, especially in certain regions with limited resources, and especially for its unusual effects. This is a review of the literature on the challenges in treating both naïve and experienced individuals carrying the M184V mutation, including virological failure, virological suppression, and resistance to ART.

Our aim was to estimate the date of the origin and the transmission rates of the major local clusters of subtypes A1 and B in Greece. Phylodynamic analyses were conducted in 14 subtype A1 and 31 subtype B clusters. The earliest dates of origin for subtypes A1 and B were in 1982.6 and in 1985.5, respectively. The transmission rate for the subtype A1 clusters ranged between 7.54 and 39.61 infections/100 person years (IQR: 9.39, 15.88), and for subtype B clusters between 4.42 and 36.44 infections/100 person years (IQR: 7.38, 15.04). Statistical analysis revealed that the average difference in the transmission rate between the PWID and the MSM clusters was 6.73 (95% CI: 0.86 to 12.60; p = 0.026). Our study provides evidence that the date of introduction of subtype A1 in Greece was the earliest in Europe. Transmission rates were significantly higher for PWID than MSM clusters due to the conditions that gave rise to an extensive PWID HIV-1 outbreak ten years ago in Athens, Greece. Transmission rate can be considered as a valuable measure for public health since it provides a proxy of the rate of epidemic growth within a cluster and, therefore, it can be useful for targeted HIV prevention programs.

Our aim was to investigate the dispersal patterns and parameters associated with local molecular transmission clusters (MTCs) of subtypes A1 and B in Greece (predominant HIV-1 subtypes). The analysis focused on 1751 (28.4%) and 2575 (41.8%) sequences of subtype A1 and B, respectively. Identification of MTCs was based on phylogenetic analysis. The analyses identified 38 MTCs including 2-1518 subtype A1 sequences and 168 MTCs in the range of 2-218 subtype B sequences. The proportion of sequences within MTCs was 93.8% (1642/1751) and 77.0% (1982/2575) for subtype A1 and B, respectively. Transmissions within MTCs for subtype A1 were associated with risk group (Men having Sex with Men vs. heterosexuals, OR = 5.34, p < 0.001) and Greek origin (Greek vs. non-Greek origin, OR = 6.05, p < 0.001) and for subtype B, they were associated with Greek origin (Greek vs. non-Greek origin, OR = 1.57, p = 0.019), younger age (OR = 0.96, p < 0.001), and more recent sampling (time period: 2011-2015 vs. 1999-2005, OR = 3.83, p < 0.001). Our findings about the patterns of across and within country dispersal as well as the parameters associated with transmission within MTCs provide a framework for the application of the study of molecular clusters for HIV prevention.

Background: Aiming to eliminate HIV infection, UNAIDS has set a global "90-90-90" target by 2020. We sought to construct a 6-stages HIV Cascade of Care (CoC) in Greece, overall and by risk group, to assess risk-group and stage-specific progress in achieving the UNAIDS target., Patients and Methods: Combining data from the HIV/AIDS surveillance system and a population-based HIV cohort study, the CoC included: i) number of people living with HIV (PLHIV) by end of 2013; ii) proportion of PLHIV ever diagnosed; iii) proportion of diagnosed linked-to-care iv) proportion of linked-to-care ever initiating antiretroviral therapy (ART); v) proportion of treated who retained-in-care vi) proportion of those retained-in-care who were virally suppressed (≤200 copies/mL) at their last visit (01/07/2012-31/12/2013)., Results: In 2013, 14147 PLHIV were in Greece. Overall, proportions of each stage in the cascade were: 78.4% diagnosed; 86% linked-to-care; 78.5% initiated ART; 86.4% retained-in-care, and 87.1% virally suppressed. Totally, 42.6% of all PLHIV were virally suppressed. The percentage diagnosed was lower among heterosexual men and women (heterosexuals) than in MSM (men who have sex with men) or PWID (people who inject drugs). Most MSM were linked to care (97.2% of diagnosed) while a substantial proportion of PWID were not (80.8% of diagnosed). Once treated, PWID remained in care in similar proportions to MSM. Unlike PWID, a high proportion of the retained in care MSM and heterosexuals achieved viral suppression., Conclusions: At the end of 2013, we identified gaps in the HIV CoC in Greece, which differed across risk groups. Targeted interventions are critical in optimizing early diagnosis and timely linkage. A 6-stage CoC, stratified by risk group, can inform strategic public health planning in improving HIV treatment outcomes., Competing Interests: GT has received grants unrelated to this study from Gilead Sciences Europe, UCL, ECDC and EU and National fund. NVS has received research and travel grants unrelated to this study from Gilead Sciences Greece, and GSK Greece. OK has received support unrelated to this study from Baxalta, Novonordisk, Bayer, Pfizer in the form of research grants, lecture fees, travel expenses, payment of registration fees. GV has received travel expenses unrelated to the submitted work from ECDC. PG has received grants unrelated to this study from Astellas, Gilead, Jansesen, MSD, ViiV. The rest of the authors have no funding relevant to this study to report. AMACS has received initial funding from the Hellenic Center of Disease Control and Prevention. Additional grants unrelated to this study were received by Gilead Sciences Europe. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Despite successful virological suppression, HIV transcription frequently persists intracellularly. In this study, we hypothesize that HIV persistent transcription(HIVpt) may affect to a different extent patients on stable efavirenz(EFV) versus atazanavir(ATV)-based regimens. The role of the expression of drug efflux transporters in HIVpt was also investigated., Methods: We prospectively enrolled 51 virologically suppressed patients on first-line treatment for one year with EFV or ATV combined with emtricitabine and tenofovir and followed them up for one year. Simultaneous ultrasensitive subpopulation staining/hybridization in situ(SUSHI) was performed to identify HIVpt in CD4+ T-cells and in the CD4+CD45RO+ T-cell subpopulation. The differential mRNA expression of P-glycoprotein(P-gp/ABCB1) and multidrug resistance-associated protein-1(MRP1/ABCC1) was also evaluated. Univariate logistic regression models were used to evaluate predictors of HIVpt., Results: In the CD4+ T-cell population, HIVpt affected 13/30 of patients on EFV versus 10/21 on ATV. In the CD4+CD45RO+ T-cell population, HIVpt was present in 14/30 of patients on EFV versus 15/21 on ATV. A trend for association was observed between the risk of HIVpt and ATV treatment in the CD4+CD45RO+ T-cell population (OR 2.86, 95% CI 0.87-9.37, p = 0.083). HIVpt status was not associated with loss of virological suppression or CD4 evolution. We found no evidence of differential expression of the drug efflux transporters P-gp and MRP1., Conclusions: Further study is required to evaluate whether the HIVpt profile in specific cell populations may differ across different antiretroviral regimens and to elucidate the potential clinical impact.

Viral load testing is a valuable tool in HIV clinical care and research. Discrepancies among diverse viral load assays, especially with regard to non-B HIV-1 subtypes have been reported. Our study aimed to explore the impact of HIV subtype (B versus non-B) on the agreement between CAP/CTM, v2.0 and m2000 RealTime in treated HIV patients, focusing on low viral loads (<200 copies/ml). Our findings indicate that there is a significant difference in the performance of the compared assays in the low-viremic range and non-B subtypes, suggesting that a single assay should be used for follow-up., (© 2015 Wiley Periodicals, Inc.)

Background: Chronic HIV infection leads to severe perturbations of the B cell populations and hypo-responsiveness to vaccines. The associations between circulating B cell subpopulations and the antibody response to pneumococcal polysaccharide vaccine in antiretroviral-naïve and treated patients were studied., Methods: Sixty-six HIV-infected adults were grouped according to antiretroviral therapy (ART) and CD4+ cell count; 31 were ART-naïve and 35 were ART-treated, and they were matched for age, CD4 cell count, and duration of HIV infection. All subjects were immunized with the 23-valent polysaccharide vaccine against Streptococcus pneumoniae. Pre- and post-vaccination B cell subpopulations were assessed by flow cytometry. Serum IgG concentrations for vaccine serotypes were quantified by ELISA at baseline and at 4 and 48 weeks post-vaccination., Results: Patients under highly active antiretroviral therapy (HAART) had significantly higher antibody levels against pneumococcal vaccine antigens, while an adequate number of patients responded to vaccination. Memory B cells were diminished over time, although treated patients maintained higher levels of all subsets studied, with the exception of activated memory and isotype-switched memory B cells., Conclusions: Low concentrations of total B cells and exhausted memory B cells was the strongest independent predictor of poor pneumococcal vaccine responsiveness, emphasizing that B cell subset disturbances are associated with a poor vaccine response among HIV-infected patients., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: This study sought to assess the West Nile Virus (WNV) seroprevalence and behavioral risk factors for WNV infection in HIV-1 infected individuals in Northern Greece in 2011., Methods: We prospectively enrolled 91 HIV-1 consecutive patients followed up in the HIV clinic of the AHEPA University Hospital in the period from November to December 2011. Serum samples were tested for the presence of WNV IgG antibodies. All subjects were administered a standardized questionnaire to evaluate for risk factors for WNV infection., Results: WNV IgG antibodies were detected in three subjects (3.3%, 95% CI 0.7-9.3%), two of whom were of African origin. The prevalence of WNV antibodies in HIV patients of Greek origin was 1.2% (95% CI: 0.03% - 6.3%). In the sample surveyed, 53.6% (95% CI: 42.4% to 64.5%) were aware of WNV prevention measures; 2.2% reported no implementation of prevention measures, whereas 46.1% implemented at least three measures. Approximately one half of the patients reported outdoor activities for more than two hours from dusk to dawn. None of the IgG-positive patients reported any symptoms compatible with WNV disease during the season at risk., Conclusions: Among native Greek HIV patients, the WNV seroprevalence is 1.2%. A considerable proportion of patients was aware of WNV prevention measures and implemented some of these. HIV patients and other categories of immunocompromised patients are at increased risk of neuroinvasive disease, and widespread implementation of prevention measures should be strongly encouraged in this patient population., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The emergence of resistance against current antiretroviral drugs to human immunodeficiency virus type 1 (HIV-1) is an increasingly important concern to the continuous success of antiretroviral therapy to HIV-1-infected patients. In the past decade, a number of studies reported that the prevalence of transmitted drug resistance among newly diagnosed patients has reached an overall 9% prevalence worldwide. Also, a number of studies using longitudinal HIV-1 patient study cohorts demonstrated that the cellular HIV-1 DNA level in peripheral blood mononuclear cells (PBMCs) has a prognostic value for the progression of HIV-1 disease independently of plasma HIV-1 RNA load and CD4 count. Using a previously established molecular-beacon-based real-time PCR methodology, cellular HIV-1 DNA levels were quantified in newly diagnosed and antiretroviral-naive patients in Northern Greece recruited between 2009 and 2010 using a predefined enrolling strategy, in an effort to investigate whether there is any relationship between cellular HIV-1 DNA levels and HIV-1 transmitted drug resistance. As part of the same study, DNA sequences encoding the env (C2-C5 region of gp120) were also amplified from PBMC-extracted DNA in order to determine the genotypic coreceptor tropism and genetic subtype. Cellular HIV-1 DNA levels had a median of 3.309 log10 HIV-1 copies per 10(6) PBMCs and demonstrated no correlation between cellular HIV-1 DNA levels and HIV-1 transmitted drug resistance. An absence of association between cellular HIV-1 DNA levels with plasma viral HIV-1 RNA load and CD4 levels was also found reconfirming the previously published study. Genotypic analysis of coreceptor tropism indicated that 96% of samples, independently of the presence or not of genotypic drug resistance, were CCR5-tropic. Overall, the findings reconfirmed the previously proposed proposition that transmitted drug resistance does not have an impact on disease progression in HIV-1-infected individuals. Also, CCR5 coreceptor tropism dominance suggests that both drug-resistant and drug-sensitive strains behave similarly in early infection in newly diagnosed patients.

A prospective molecular epidemiology study of HIV-1 infection was conducted in newly diagnosed and antiretroviral-naive patients in Northern Greece between 2009 and 2010 using a predefined enrolling strategy. Phylogenetic trees of the pol sequences obtained in this study with reference sequences indicated that subtypes B and A1 were the most common subtypes present and accounted for 44.9% and 42.9%, respectively, followed by subtype C (3.1%), CRF02&#95;AG (4.1%), CRF04&#95;cpx (2.0%), and subtypes CRF01&#95;01, F1, and G (1.0%). A high rate of clustered transmission of subtype A1-resistant strains to reverse transcriptase (RT) inhibitors was observed among men having sex with men. Indeed, 15 out of 17 study subjects (88.2%) infected with transmitted drug resistance (TDR) strains were implicated in transmission clusters, 10 of whom (66.7%) were men who have sex with men (MSM), and were also infected with subsubtype A1 strains. The main cluster within subtype A1 (I) included eight men reporting having sex with men from Thessaloniki infected with dual-class RT-resistant strains carrying both T215C and Y181C mutations.

Objectives: HIV prevalence among older people is on the increase. The aim of this study was to evaluate the epidemiological and clinical features at diagnosis and survival of older patients., Methods: This was a retrospective analysis of the data of 558 newly diagnosed antiretroviral-naïve patients between January 1998 and December 2008. Patients were divided into two groups according to their age at diagnosis: ≥50 years (n=103) and 18-49 years (n=455)., Results: The most common risk factor for older patients was heterosexual contact (p<0.013). Older patients were more likely to suffer from hypertension (33.0% vs. 5.1%, p<0.0005), cardiovascular disease (20.4% vs. 2.9%, p<0.0005), neurological disorders (11.7% vs. 5.5%, p=0.02), renal dysfunction (12.6% vs. 5.3%, p=0.01), and infections (66.0% vs. 49.7%, p=0.003) than their younger counterparts, and to have more hospital admissions during follow-up (47.5% vs. 19.6%, p<0.0005). Older patients had a shorter survival time (p<0.0005). A statistically significant increase in CD4+ cell number through time was observed in both groups (p<0.0005). Younger patients reached higher magnitudes of absolute numbers of CD4+ cells during follow-up (p<0.0005) after the initiation of antiretroviral therapy. The total number of patients with clinical AIDS from baseline throughout the study period was also higher in the older age group (35.9% vs. 25.0%)., Conclusions: HIV-infected people aged ≥50 years differ in epidemiological and clinical features to younger HIV-infected people. The issue of increasing prevalence of HIV infection is a matter of concern due to existing comorbidities, which probably lead to higher mortality rates and faster progression to clinical AIDS., (Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

We conducted a retrospective study on the prevalence and correlates of transmitted drug resistance among newly-diagnosed antiretroviral naive human immunodeficiency virus (HIV) patients in Northern Greece, during the period 2009-11. Transmitted drug resistance was documented in 21.8% of patients enrolled, affecting approximately 40% of subtype A HIV-1-infected individuals. Overcoming challenges due to the ongoing financial crisis, effective preventive measures should be implemented to control further dissemination of resistant HIV strains., (© 2012 The Authors Clinical Microbiology and Infection © 2012 European Society of Clinical Microbiology and Infectious Diseases.)

Objectives: To determine the contribution of transmission clusters to transmitted drug resistance (TDR) in newly diagnosed antiretroviral-naive HIV-1-infected patients in Northern Greece during 2000-07., Methods: The prevalence of TDR was estimated in 369 individuals who were diagnosed with HIV-1 infection in the period 2000-07 at the National AIDS Reference Laboratory of Northern Greece. Phylogenetic analysis was performed using a maximum likelihood method on partial pol sequences. TDR was defined in accordance with the surveillance drug resistance mutation list (2009 update)., Results: The overall prevalence of TDR in our population was 12.5% [46/369, 95% confidence interval (CI) 9.1%-15.8%], comprising 7.6% (28/369) resistant to nucleoside reverse transcriptase inhibitors, 5.4% (20/369) resistant to non-nucleoside reverse transcriptase inhibitors and 3.3% (12/369) resistant to protease inhibitors. Dual class resistance was identified in 3.8% (14/369). Infection with subtype A was the sole predictor associated with TDR in multivariate analysis (odds ratio 2.15, 95% CI 1.10-4.19, P = 0.025). Phylogenetic analyses revealed three statistically robust transmission clusters involving drug-resistant strains, including one cluster of 12 patients, 10 of whom were infected with a strain carrying both T215 revertants and Y181C mutations., Conclusions: Our findings underline the substantial impact of transmission networks on TDR in our population.

Acute renal failure is a rare complication following the administration of intravenous immunoglobulin (IVIG). Only 114 cases have been reported in the literature. The exact mechanism of IVIG-associated acute renal failure remains unclear. Hereby we describe the first case of ARF in a HIV-infected patient, who received IVIG stabilized with maltose for the treatment of HIV-related thrombocytopenic purpura.