Cholesterol-conjugated siRNAs silence gene expression in mucosal dendritic cells in cervicovaginal tissue in mice.

BACKGROUND: RNA interference (RNAi) provides a powerful way to investigate the role of genes in disease pathogenesis and modulate gene expression to treat disease. In 2018, the FDA approved patisiran, the first RNAi-based drug, hence paving the way for a novel class of RNAi therapeutics. Harnessing RNAi to inhibit vaginal HIV transmission requires effective gene silencing in immune cells, which remains difficult. Knockdown in accessible mucosal tissues may be easier than systemic gene silencing. Vaginally applied cholesterol-conjugated small interfering RNAs (chol-siRNAs) blocked herpes simplex virus transmission in mice without tissue damage or immunostimulation. OBJECTIVES AND METHODS: To investigate using flow cytometry, confocal microscopy, and quantitative imaging if chol-siRNAs silence gene expression in vaginal immune cells in mice. RESULTS: Although chol-siRNAs and lipoplexed-siRNAs silence gene expression in dendritic cells (DCs) in vitro, most internalized siRNAs concentrate within multivesicular bodies, where they are inaccessible to the cellular RNAi machinery. When applied intravaginally in vivo, chol-siRNAs penetrate the vaginal mucosa, including the lamina propria, and are efficiently internalized by intraepithelial (IE) and lamina propria (LP) DCs, and CD11b+ CD45+ cells, but not by T cells. Chol-siRNAs induce partial gene silencing in IE and LP DCs throughout the genital mucosa in vivo but are inactive in F4/80+ CD11b+ macrophages and T cells. CONCLUSION: As mucosal DCs play an essential role for mucosal viral entry and dissemination, chol-siRNAs could be harnessed to target various host factors that are critical for viral uptake, DC migration and trans-infection of virions to T cells, hence allowing the development of a preventive vaginal HIV microbicide. Furthermore, chol-siRNAs could help elucidate the pathways of HIV transmission and understand the immunologic function of DCs in the genital tract.

Impact of SARS-CoV-2 vaccination on systemic immune responses in people living with HIV.

Despite the development of vaccines, which protect healthy people from severe and life-threatening Covid-19, the immunological responses of people with secondary immunodeficiencies to these vaccines remain incompletely understood. Here, we investigated the humoral and cellular immune responses elicited by mRNA-based SARS-CoV-2 vaccines in a cohort of people living with HIV (PLWH) receiving anti-retroviral therapy. While antibody responses in PLWH increased progressively after each vaccination, they were significantly reduced compared to the HIV-negative control group. This was particularly noteworthy for the Delta and Omicron variants. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase, which was comparable in both groups. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4+ T cell numbers do not necessarily interfere with cellular immune responses. Our data demonstrate that despite the lower CD4+ T cell counts SARS-CoV-2 vaccination results in potent cellular immune responses in PLWH. However, the reduced humoral response also provides strong evidence to consider PLWH as vulnerable group and suggests subsequent vaccinations being required to enhance their protection against COVID-19.

Changes in the user profiles of HIV pre-exposure prophylaxis (PrEP) before and after PrEP reimbursement.

BACKGROUND: In Germany, oral HIV pre-exposure prophylaxis (PrEP) was licensed in 2016. Health insurances have been covering the costs since 09/2019. This study compares the sociodemographic profiles of PrEP users before and after PrEP re-imbursement. METHODS: Participants were recruited in a cross-sectoral sexual health centre in Germany. baseline data were compared for 139 vs 138 individuals starting PrEP from 10/2017-12/2018 (pre-reimbursement cohort) and 09/2019-3/2020; respectively. The pre-reimbursement cohort was further analysed with respect to sexual behaviour and incident sexually transmitted infections (STIs). RESULTS: There were no significant differences in the sociodemographic characteristics between the two cohorts. Almost all PrEP users were men-who-have-sex-with-men (MSM). Before reimbursement, fewer individuals used PrEP on a daily base, and more had used PrEP prior to enrolment. During follow-up (pre-reimbursement cohort), the number of sexual and condomless intercourse partners increased, so did the proportion engaging in Chemsex. Incidences of infections with C.trachomatis, N.gonorrhoeae, M.genitalium, and T.pallidum were 45.2; 36.8; 30.1; and 9.2, respectively, per 100 person-years. CONCLUSION: The goal to make PrEP available to a broader range of people with the covering of costs was only partially reached. Medically supervised use is important to detect and treat STIs.

S1 Guidelines for the Kaposi Sarcoma.

Kaposi's sarcoma (KS) is a rare, malignant, multilocular vascular disease originating from lymphatic endothelial cells that can primarily affect the skin and mucous membranes, but also the lymphatic system and internal organs such as the gastrointestinal tract, lungs or liver. Five epidemiological subtypes of KS with variable clinical course and prognosis are distinguished, with increased incidence in specific populations: (1) Classical KS, (2) Iatrogenic KS in immunosuppression, (3) Endemic (African) lymphadenopathic KS, (4) Epidemic, HIV-associated KS and KS associated with immune reconstitution inflammatory syndrome (IRIS), and (5) KS in men who have sex with men (MSM) without HIV infection. This interdisciplinary guideline summarizes current practice-relevant recommendations on diangostics and therapy of the different forms of KS. The recommendations mentioned in this short guideline are elaborated in more detail in the extended version of the guideline (online format of the JDDG).

S1-Leitlinie: Kaposi-Sarkom.

Das Kaposi-Sarkom (KS) ist eine seltene, maligne, von lymphatischen Endothelzellen ausgehende, multilokuläre Gefäßerkrankung, die vor allem Haut und Schleimhäute, aber auch das lymphatische System und innere Organe wie den Gastrointestinaltrakt, die Lunge oder die Leber befallen kann. Fünf epidemiologische Subtypen des KS mit variablem klinischem Verlauf und unterschiedlicher Prognose werden unterschieden, die in spezifischen Populationen vermehrt auftreten: (1) klassisches KS, (2) iatrogenes KS bei Immunsuppression, (3) endemisches (afrikanisches) lymphadenopathisches KS, (4) epidemisches, HIV-assoziiertes KS und mit einem Immunrekonstitutions-Inflammations-Syndrom (IRIS) assoziiertes KS und (5) KS bei Männern, die Sex mit Männern haben (MSM) ohne HIV-Infektion. Diese interdisziplinäre Leitlinie fasst aktuelle praxisrelevante Empfehlungen zu Diagnostik und Therapie der verschiedenen Formen des KS zusammen. Die in dieser Kurzleitlinie genannten Empfehlungen werden in der Langfassung der Leitlinie (Online-Version des JDDG) detaillierter ausgeführt.

Online HIV/STI Risk Test (ORT): A prospective cross-sectional study among sexually active individuals in Germany.

BACKGROUND: Our goal was to develop and evaluate an anonymous self-administrable web-based test to determine risk for HIV/STI. METHODS: The Online HIV/STI Risk Test was developed and hosted since 12/2017. 11,529 participants completed the test and 10,668 were analyzed. The test included multiple choice questions about sociodemographic data, sexuality, sexual risk behavior, HIV/STI testing. Participant data was stratified by gender and sexuality and analyzed. RESULTS: 84.5 % were aged 18-39, 7.5 % < 18 and 8.1 % > 40. Males were 53.1 %, female 46.3 % and trans 0.6 %. 12.5 % were men who have sex with men (MSM). 59.1 % and 66.0 % of participants were vaccinated for hepatitis A and B respectively, but 75.1 % unvaccinated for HPV. Prior and repeated instances of HIV or other STI were higher among MSM. Yet, 61.4 % females, 70 % males and 55.4 % MSM had never tested for an STI. Although prevalence of > 3 sexual partners in the last twelve months was highest among MSM, condomless sex was greater among women. 34.5 % of males, 25.6 % of females, and 75 % of MSM engaged in anal sex respectively. CONCLUSIONS: The online HIV/STI Risk Test is a useful tool to acquire data on STI risk-behavior for strategizing STI prevention, testing, and vaccination, thus improving sexual health.

[Sexual behavior and prevention of sexually transmitted infections taking the SARS-CoV-2 pandemic into account. Data from a sexual healthcare and medicine center-WIR]. / Sexualverhalten und Prävention sexuell übertragbarer Infektionen unter Berücksichtigung der SARS-CoV-2-Pandemie. Daten aus einem Versorgungszentrum für sexuelle Gesundheit und Medizin ­ WIR.

BACKGROUND: Application-based data regarding sexual health and sexual behavior in various sexually active populations are scarce but at the same time relevant with regards to prevention and healthcare supply strategies. Given the structure of its attendees, the Walk In Ruhr (WIR) Center for Sexual Health and Medicine is able to obtain data from diverse living environments. OBJECTIVES: Based on the online HIV/STI risk test, questionnaires, and attendee data from the WIR, this study aims to deduce population-related findings with regards to age, gender, sexual orientation, and sexual and risk behavior as well as the respective needs for prevention. The influence of the SARS-CoV-19 pandemic on sexual behavior is examined by comparing various phases. METHODS: The analyzed data sources are the online HIV/STI risk test, the COWIR, and the PrEP study as well as the immunological outpatient clinic and the public health department at the WIR. RESULTS: Notwithstanding contact restrictions, sexually transmitted infections (STIs) have increased from 2019 to 2020. Apart from men having sex with men and females having sex with females, young people also have an increased risk of STIs based on sexual practices and the number of sexual contacts. A large number of bisexual and transsexual contacts was found. SARS-CoV­2 led to a decrease in sexual contacts; sexual practices continued. There was a growing proportion of STI tests and the treatment rate including partner treatment rose. DISCUSSION: Data from the WIR center show that young attendees with an active sexual life are being reached. The results from questionnaires and the online HIV/STI risk test are mirrored in increased positive STI test results. These results vary depending on sexual behavior and sexual preferences such that specific strategies for sexual education, prevention, testing, and therapy are required.

[Sexual health and medicine at the WIR-Walk In Ruhr: presentation of the center and results of the evaluation]. / Sexuelle Gesundheit und Medizin im WIR ­ Walk In Ruhr: Vorstellung des Zentrums und Ergebnisse der Evaluation.

BACKGROUND: Holistic sexual healthcare factors in diversity of social habitat and aims to improvise client outreach for prevention, testing, counseling, and treatment of STIs. Towards this goal, the immunology outpatient clinic, the public health department of Bochum, the AIDS Service Organization Bochum e. v., and other community-driven NGOs mutually cooperate under the umbrella of WIR - Walk In Ruhr, Centre for Sexual Health and Medicine. OBJECTIVES: WIR is an innovative concept for multi-professional in-house ambulatory healthcare with cross-sectoral and cross-legal reach. It has successfully improved accessibility, testing and treatment rates, and HIV/STI self-assessment. We present the results achieved at WIR. METHODS: A mixed-method design of qualitative and quantitative surveys. RESULTS: The WIR reaches more women (27.7%) and heterosexuals (56.4%) than other counseling/test centers. The rate of positive test results at the WIR increased from 9.3% in 2017 to 12.6% in 2018 and progress from prevention to medical care is a significant aspect of WIR. The Federal Ministry of Health has externally evaluated WIR for over three years. DISCUSSION: The integrative care model of WIR allows for early outreach and treatment of individuals with HIV/ST infections. Health advisors remain an important instrument facilitating outreach and psychosocial/psychotherapeutic counseling is administered frequently. Such a multi-layered approach in prevention, testing, and consultation, leads to improvement in both medical outcomes and the self-responsible attitude of patients towards their sexual health. Hence, expansion of integrative care models like WIR on a wider scale could arguably contribute to better health service and sexual health.

German evidence and consensus-based (S3) guideline: Vaccination recommendations for the prevention of HPV-associated lesions.

Anogenital and oropharyngeal infections with human papilloma viruses (HPV) are common. Clinically manifest disease may significantly impact quality of life; the treatment of HPV-associated lesions is associated with a high rate of recurrence and invasive neoplasms, such as cervical, anal, vulvar, penile, and oropharyngeal cancers, which are characterized by significant morbidity and mortality. Vaccination against HPV is an effective and safe measure for the primary prevention of HPV-associated lesions, but immunization rates are still low in Germany. The present publication is an abridged version of the German evidence and consensus-based guideline "Vaccination recommendations for the prevention of HPV-associated lesions", which is available on the website of the German Association of the Scientific Medical Societies (AWMF). On the basis of a systematic review with meta-analyses, a representative panel developed and agreed upon recommendations for the vaccination of different populations against HPV. In addition, consensus-based recommendations were developed for specific issues relevant to everyday practice. Based on current evidence and a representative expert consensus, these recommendations are intended to provide guidance in a field in which there is often uncertainty and in which both patients and health care providers are sometimes confronted with controversial and emotionally charged points of view.

[Rapid diagnosis of sexually transmitted infections : Joint statement of DSTIG, RKI, and PEI, as well as the reference centers for HIV, HBV, and HCV and consulting laboratories for Chlamydia, gonococci, and Treponema pallidum]. / Schnelltestdiagnostik sexuell übertragbarer Infektionen : Gemeinsame Stellungnahme von DSTIG, RKI, PEI sowie den Referenzzentren für HIV, HBV und HCV und Konsiliarlaboren für Chlamydien, Gonokokken und Treponema pallidum.

In February 2019, the fourth expert meeting on rapid diagnostic tests (RDTs) for sexually transmitted infections (STI) was held at the Robert Koch Institute (RKI) in Berlin. Novel technical developments and new aspects of RDT applications were discussed by representatives from the German STI Society (DSTIG); RKI; the Paul Ehrlich Institute; national reference centers for HIV, HBV, and HCV; and reference laboratories for Chlamydia, gonococci, and Treponema pallidum.As a result of this meeting, we present a revision of the joint statement on STI diagnostics with RDTs from 2017. The Regulation (EU) 2017/746 of the European Parliament and of the Council on in vitro diagnostic medical devices became effective in May 2017 and includes more stringent regulatory requirements for RDTs, mainly concerning conformity of manufacturing processes and performance characteristics of class D in vitro diagnostics (detection of HIV, HBV, HCV, and T. pallidum). Some RDTs for HIV, HCV, and T. pallidum have been evaluated in clinical studies and/or were WHO prequalified and may be used in low-threshold services. Among them are some HIV RDTs available and approved for self-testing. In addition, some HBV RDTs based on detection of HBs antigen (HBsAg) received WHO prequalification. However, false negative results may occur in samples with low HBsAg levels, as for instance in HIV-coinfected patients receiving antiretroviral therapy. For Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG), antigen-based RDTs still do not allow reliable detection of infection. Only PCR-based CT/NG RDTs possess sufficient diagnostic accuracy to be used as point-of-care tests. Rapid PCR tests for NG, however, do not provide any information about antimicrobial resistance.

[HIV pre-exposure prophylaxis care in intersectoral collaboration : Interim analysis of a monocentric, prospective study in Germany]. / HIV-Präexpositionsprophylaxe-Versorgung in intersektoraler Zusammenarbeit : Interimsanalyse einer monozentrischen, prospektiven Studie in Deutschland.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP), a further opportunity to prevent HIV, is available at the WIR-Walk In Ruhr, Centre for Sexual Health and Medicine, as part of an innovative model project for intersectoral PrEP care. RESEARCH OBJECTIVES: The present study describes the collective of persons provided with PrEP and how PrEP use influences sexual risk behaviour, the incidence of sexually transmitted diseases (STD) and adverse drug reactions. METHODS: A total of 139 men who started PrEP between 10/2017 and 12/2018 have been included in the study. During a period of 13 months of PrEP treatment, all PrEP users received questionnaires; side effects, HIV and other STI were also monitored via clinical laboratory examinations. RESULTS: The participants' average age was 38 years and 98.6% of them were men who had sex with men (MSM). Most of them had a high educational background; the unemployment rate was low. The average number of sexual partners within the last 6 months increased significantly, while the use of condoms decreased. In all, 44 STI were found in 34 participants within the first 4 months. No one was infected with HIV. Within the first 4 weeks of PrEP, 38.8% of the participants suffered from side effects, mainly gastrointestinal symptoms. CONCLUSION: Most of the participants were working in a job or a vocational training. The sexual risk behaviour increased in the course of using PrEP resulting in a high incidence of STD. Side effects appeared most frequently in the first few weeks after starting PrEP.

Final Analysis of DeCOG-SLT Trial: No Survival Benefit for Complete Lymph Node Dissection in Patients With Melanoma With Positive Sentinel Node.

PURPOSE: We have previously reported on the 3-year results of the phase III German Dermatologic Cooperative Oncology Group trial (DeCOG; ClinicalTrials.gov identifier: NCT02434107) comparing distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS) in patients with positive sentinel lymph-node biopsy who were randomly assigned to complete lymph node dissection (CLND) or observation. Here, we report the final analysis with 72 months of median follow up. PATIENTS AND METHODS: The multicenter randomized phase III trial included patients with cutaneous melanoma of the trunk and extremities who were randomly assigned (1:1) to undergo CLND or observation. DMFS was analyzed as the primary end point, and RFS, OS, and recurrences in the regional lymph node basin were secondary end points. The analysis was by intention to treat. Disease and survival information were collected quarterly. RESULTS: From January 2006 to December 2014, 5,547 patients were screened to identify 1,256 with metastases in the sentinel lymph node (SLN). Of these, 483 (39%) were included: 241 in the observation arm and 242 in the CLND arm. In the final analysis, median follow up was 72 months (interquartile range, 67-77 months). No significant treatment-related difference was seen in the 5-year DMFS between the observation and CLND arms (67.6% v 64.9%, respectively; hazard ratio [HR], 1.08; P = .87). The 5-year RFS and OS also showed no difference (HR, 1.01 and 0.99, respectively). Grade 3 and 4 adverse effects occurred in 32 patients (13%) in the CLND arm; lymphedema (n = 20) and delayed wound healing (n = 5) were most common and no serious adverse events were reported. CONCLUSION: The final results of the German Dermatologic Cooperative Oncology Group trial with a median follow up of 72 months showed higher event rates, but similar HRs compared with those at the 3-year analysis. These results confirm that immediate CLND in SLN-positive patients is not superior to observation in terms of DMFS, RFS, or OS and support not recommending CLND in patients with SLN metastasis.