A Phylogenetic Analysis of HIV-1 Sequences in Kiev: Findings among Key Populations

BACKGROUND: The HIV epidemic in Ukraine has been driven by a rapid rise among people who inject drugs, but recent studies have shown an increase through sexual transmission. METHODS: Protease and RT sequences from 876 new HIV diagnoses (April 2013 - March 2015) in Kiev were linked to demographic data. We constructed phylogenetic trees for 794 subtype A1 and 64 subtype B sequences and identified factors associated with transmission clustering. Clusters were defined as ≥ 2 sequences, ≥ 80% local branch support and maximum genetic distance of all sequence pairs in the cluster ≤ 2.5%. Recent infection was determined through the LAg avidity EIA assay. Sequences were analysed for transmitted drug resistance (TDR) mutations. RESULTS: 30% of subtype A1 and 66% of subtype B sequences clustered. Large clusters (maximum 11 sequences) contained mixed risk groups. In univariate analysis, clustering was significantly associated with subtype B compared to A1 (OR 4.38 [95% CI 2.56-7.50]), risk group (OR 5.65 [3.27-9.75]) for men who have sex with men compared to heterosexual males, recent, compared to long-standing, infection (OR 2.72 [1.64-4.52]), reported sex work contact (OR 1.93 [1.07-3.47]) and younger age groups compared to age ≥36 (OR 1.83 [1.10-3.05] for age ≤25). Females were associated with lower odds of clustering than heterosexual males (OR 0.49 [0.31-0.77]). In multivariate analysis, risk group, subtype and age group were independently associated with clustering (p<0.001, p=0.007 and p=0.033). 18 sequences (2.1%) indicated evidence of TDR. CONCLUSIONS: Our findings suggest high levels of transmission and bridging between risk groups

Model Kebijakan Penanggulangan Korupsi di Universitas Negeri YOGYAKARTA

Penelitian ini bertujuan untuk mengetahui kebijakan Universitas Negeri Yogyakarta dalam menanggulangi korupsi dan menemukan model kebijakan yang diinginkan Universitas Negeri Yogyakarta dalam menanggulangi korupsi. Penelitian ini adalah penelitian survei dengan pendekatan kuantitatif dan kualitatif. Sampel penelitian ditentukan secara multy stage sampling dengan teknik pengumpulan data dengan angket, dokumen dan diperkuat dengan pengumpulan data melalui Focus Group Discussion (FGD), dan validasi instrumen melalui validitas isi (content validity). Data dianalisis secara deskriptif. Hasil penelitian menunjukkan bahwa kebijakan penanggulangan korupsi di UNY tidak ada secara khusus dikeluarkan. Kebijakan yang ada mengikuti dan mempertahankan kebijakan yang lebih tinggi, yaitu dari Pemerintah. Model kebijakan penangggulangan korupsi di UNY yang digunakan adalah Model Rasional, yaitu kebijakan penanggulangan korupsi yang dikeluarkan merupakan aspirasi semua staf yang ada di unit kerja dan harus menekankan pada aspek efisiensi atas beban kerja pada unit kerja yang bersangkutan. Adapun kebijakan yang sudah ada yang berasal dari Pemerintah pusat dijadikan pedoman

Regulatory Polymorphisms in the Cyclophilin A Gene, PPIA, Accelerate Progression to AIDS

Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan-Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4+ T-cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein-binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5′ UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis

CASCADE protocol: exploring current viral and host characteristics, measuring clinical and patient-reported outcomes, and understanding the lived experiences and needs of individuals with recently acquired HIV infection through a multicentre mixed-methods observational study in Europe and Canada

Introduction: Despite the availability of pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART), 21 793 people were newly diagnosed with HIV in Europe in 2019. The Concerted action on seroconversion to AIDS and death in Europe study aims to understand current drivers of the HIV epidemic; factors associated with access to, and uptake of prevention methods and ART initiation; and the experiences, needs and outcomes of people with recently acquired HIV. / Methods and analysis: This longitudinal observational study is recruiting participants aged ≥16 years with documented laboratory evidence of HIV seroconversion from clinics in Canada and six European countries. We will analyse data from medical records, self-administered questionnaires, semistructured interviews and participatory photography. We will assess temporal trends in transmitted drug resistance and viral subtype and examine outcomes following early ART initiation. We will investigate patient-reported outcomes, well-being, and experiences of, knowledge of, and attitudes to HIV preventions, including PrEP. We will analyse qualitative data thematically and triangulate quantitative and qualitative findings. As patient public involvement is central to this work, we have convened a community advisory board (CAB) comprising people living with HIV. / Ethics and dissemination: All respective research ethics committees have approval for data to contribute to international collaborations. Written informed consent is required to take part. A dissemination strategy will be developed in collaboration with CAB and the scientific committee. It will include peer-reviewed publications, conference presentations and accessible summaries of findings on the study’s website, social media and via community organisations

Does rapid HIV disease progression prior to combination antiretroviral therapy hinder optimal CD4 + T-cell recovery once HIV-1 suppression is achieved?

This article compares trends in CD4 + T-cell recovery and proportions achieving optimal restoration (≥500 cells/μl) after viral suppression following combination antiretroviral therapy (cART) initiation between rapid and nonrapid progressors. We included HIV-1 seroconverters achieving viral suppression within 6 months of cART. Rapid progressors were individuals experiencing at least one CD4 + less than 200 cells/μl within 12 months of seroconverters before cART. We used piecewise linear mixed models and logistic regression for optimal restoration. Of 4024 individuals, 294 (7.3%) were classified as rapid progressors. At the same CD4 + T-cell count at cART start (baseline), rapid progressors experienced faster CD4 + T-cell increases than nonrapid progressors in first month [difference (95% confidence interval) in mean increase/month (square root scale): 1.82 (1.61; 2.04)], which reversed to slightly slower increases in months 1-18 [−0.05 (−0.06; −0.03)] and no significant differences in 18-60 months [−0.003 (−0.01; 0.01)]. Percentage achieving optimal restoration was significantly lower for rapid progressors than nonrapid progressors at months 12 (29.2 vs. 62.5%) and 36 (47.1 vs. 72.4%) but not at month 60 (70.4 vs. 71.8%). These differences disappeared after adjusting for baseline CD4 + T-cell count: odds ratio (95% confidence interval) 0.86 (0.61; 1.20), 0.90 (0.38; 2.17) and 1.56 (0.55; 4.46) at months 12, 36 and 60, respectively. Among people on suppressive antiretroviral therapy, rapid progressors experience faster initial increases of CD4 + T-cell counts than nonrapid progressors, but are less likely to achieve optimal restoration during the first 36 months after cART, mainly because of lower CD4 + T-cell counts at cART initiation

Conflicts of Interest and the Quality of Recommendations in Clinical Guidelines

Background: There is increasing concern that conflicts of interest affect the development process of clinical practice guidelines. We evaluated The American Psychiatric Association\u27s Practice Guideline for the Treatment of Patients with Major Depressive Disorder to determine the existence of financial and intellectual conflicts of interest and examine their possible effects. We selected this guideline because of its influence on clinical practice and because this guideline recommends pharmacotherapy for all levels of depression, despite controversies over the evidence base. Methods and Findings: We determined the number and type of financial conflicts of interest for members of the guideline development group as well as for the independent panel charged with mitigating any effect of these conflicts. We also quantified the potential for intellectual conflicts of interest. We examined the quality of references used to support recommendations, as well as the degree of congruence between the research results and the recommendations. Fewer than half (44.4%) of the studies supporting the recommendations met criteria for high quality. Over one-third (34.2%) of the cited research did not study outpatients with major depressive disorder, and 17.2% did not measure clinically relevant results. One-fifth (19.7%) of the references were not congruent with the recommendations. Financial ties to industry were disclosed by all members (100%) of the guideline development committee with members reporting a mean 20.5 relationships (range 9–33). The majority of the committee participated on pharmaceutical companies\u27 speakers\u27 bureaus. Members of the independent panel that reviewed the guidelines for bias had undeclared financial relationships. As a marker of intellectual conflict of interest, 9.1% of all cited research and 13% of references supporting the recommendations were co-authored by the six guideline developers. Conclusions: The prevalence of conflicts of interest among panel members was high. The quality of the evidence cited raises questions about the validity of the recommendations. Attention to the quality of cited studies and to the risk of bias resulting from conflicts of interest should be a priority for guideline development groups

The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial : a randomised controlled trial of a protease inhibitor monotherapy strategy for long-term management of human immunodeficiency virus infection

Background Standard-of-care antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection uses a combination of drugs, until now considered essential to minimise treatment failure and development of drug resistance. Protease inhibitors (PIs) are potent with a high genetic barrier to resistance and have the potential for use as monotherapy after viral load (VL) suppression achieved on combination therapy. However, longer-term resistance and toxicity risks are uncertain. Objective To compare the effectiveness, toxicity profile and cost-effectiveness of PI monotherapy with those of standard-of-care triple therapy in a pragmatic long-term clinical trial. Design Open-label, parallel-group, randomised controlled trial. Setting Forty-three HIV clinical centres in the UK NHS. Participants HIV-positive adults taking standard combination ART with a suppressed VL for ≥ 6 months. Interventions Patients were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected ritonavir-boosted PI monotherapy (PI-mono), with prompt return to combination therapy in the event of VL rebound. Main outcome measures The primary outcome was reduction of future drug options, defined as new intermediate-/high-level resistance to one or more drugs to which the patient’s virus was considered to be sensitive at trial entry (non-inferiority comparison, 10% margin). Secondary outcomes included confirmed virological rebound, serious drug- or disease-related complications, total grade 3 or 4 adverse events (AEs), neurocognitive function change, cluster of differentiation 4 (CD4) cell count change, change in health-related quality of life, cardiovascular risk change, health-care costs and health economic analysis. Results In total, 587 participants were randomised (77% male, 68% white) to OT (n = 291) or PI-mono (n = 296) and followed for a median of 44 months, of whom 2.7% withdrew/were lost to follow-up. One or more episodes of confirmed VL rebound were observed in eight patients (Kaplan–Meier estimate 3.2%) in the OT group and 95 patients (35.0%) in the PI-mono group [absolute risk difference 31.8%, 95% confidence interval (CI) 24.6% to 39.0%; p < 0.001]. PI-mono patients who changed to ART after VL rebound all resuppressed (median 3.5 weeks). The proportions with loss of a future drug option at 3 years were 0.7% in the OT group and 2.1% in the PI-mono group (difference 1.4%, (95% CI –0.4% to 3.4%); non-inferiority demonstrated). There were no significant differences in serious disease complications between groups or in the frequency of grade 3 or 4 clinical AEs (16.8% OT group vs. 22% PI-mono group; absolute risk difference 5.1%, 95% CI –1.3% to 11.5%; p = 0.12). Overall, the PI-mono strategy was shown to be cost-effective compared with OT under most scenarios explored. PI-mono was cost saving because of the large savings in ART drug costs while being no less effective in terms of quality-adjusted life-years in the within-trial analysis and only marginally less effective when extrapolated to lifetime outcomes. Conclusions PI monotherapy, with prompt reintroduction of combination therapy for VL rebound, was non-inferior to combination therapy in preserving future treatment options and is an acceptable and cost-effective alternative for long-term management of HIV infection. Trial registration Current Controlled Trials ISRCTN04857074. Funding This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 21. See the NIHR Journals Library website for further project information

Differences in CD4 cell counts at seroconversion and decline among 5739 HIV-1-infected individuals with well-estimated dates of seroconversion.

We studied repeated measurements of CD4 cell counts on 5739 HIV-1-infected individuals with reliably estimated dates of seroconversion (SC) aged &gt; or =15 years at SC prior to initiation of highly active antiretroviral therapy (HAART) or AIDS using random effects models. Estimated CD4 cell count at SC differed significantly by sex, exposure group, and age, being higher in women, hemophilic men, and injection drug users (IDUs) as well as in those aged &gt;40 years at SC. The rate of CD4 cell count decline did not differ significantly by sex; thus, differences between men and women were stable throughout the HIV-1 incubation period. There was a monotonic relationship between CD4 slopes and age at SC, with steeper slopes in older subjects. At 5 years after SC, the median difference in CD4 cell counts between the oldest (&gt;40 years at SC) and youngest (16-20 years at SC) subjects was around 90 cells/microL. Mean rate of CD4 decline was significantly steeper in subjects diagnosed during acute infection. There was no evidence of a faster loss of CD4 cells in subjects who seroconverted after 1994. Apart from hemophilic men, who tended to have a steeper rate of CD4 decline on average, mean CD4 slopes did not differ by exposure category. These results suggest that before the initiation of HAART or other interventions based on immune status, consideration of demographic factors may be worthwhile