HIV Viral load measurement in the Public Health Approach to HIV/AIDS

Background To end AIDS by 2030, the WHO 90-90-90 targets call for 90% virologic suppression in those on ART. In this context, it is crucial to understand which factors drive virologic suppression and how available resources can be targeted most effectively. This thesis evaluates a large HIV treatment program in Tanzania and explores performance and factors associated with treatment outcome on individual and on health system level. It then develops a clinical score to predict virologic failure and optimize patient management. Design This cross-sectional facility-based study assessed 702 patients stratified by time on ART at 7 study sites selected to represent regions of the study area and health care level. Methods Facility and patient-level information were collected during a single study visit. Logistic regression analysis and Generalized Boosted Model Technique derived Propensity Score Methods were used to explore health system and individual-level factors associated with virological failure. Predictive multilevel mixed logistic regression models were developed, externally validated and simplified into a normogram for the clinical score which was then tested against WHO recommended failure criteria using Decision Curve Analysis. Results Within the population on ART, 89% was virologically suppressed below 1000 copies/ml and 86% below 400 copies/ml. Differences could be found between health care levels but not regions. The study site had a direct impact on treatment outcome on the individual and health system level. Performance of the clinical scores was high with a ROC-AUC of 0.8 in the training, and ROC-AUC between 0.7 and 0.8 in the population and the geographic validation dataset. Decision Curve Analysis showed a net benefit against the WHO routine and targeted viral load monitoring strategies. Conclusion To fully reach the “the last 90” health system-level interventions should support sites. On individual level, the clinical score developed could be used to better identify and manage individuals at risk of treatment failure

Sustainable (‘grass-roots’) approach to Oral Health Promotion Utilising Established NGO and Rural Community Groups

The purpose of this research was to examine potential sustainable delivery methods for Oral Health Promotion (OHP) in developing populations in India, utilising non-dental rural community development groups, specifically those led by Non-Governmental Organizations (NGO) involved in community development. The focus of this research was based on a longitudinal cohort study experimental design for exploratory purposes conducted over a period of one year, using a randomised cluster sampling of community developmental projects within the rural-tribal villages of Ambernath, Maharashtra, India. The study was measured in 4 phases: oral health knowledge of village parents through a questionnaire, dental screenings of children, and integration of a ‘train-the-trainer’ type of Oral Health Awareness Programme (OHAP) for three test groups, followed by one-year comparison follow-up data. Findings show evidence of comprehension and dissemination of the information in the OHAP course. Screening data also showed a reduction in decay in primary and permanent teeth in the children, after one year, and a positive change in oral hygiene behaviours. The collaboration and utilisation of non-dental NGO teams and local participatory groups from a ‘grass-roots’ level was proven to be effective for disseminating information and activities for oral health awareness and promotional programmes within these populations. Evidence supports a collaboration of these groups can be recommended for introducing a structured and understandable oral health programme utilising non-dental NGO and local participatory groups

Lipometabolic side-effects of three ritonavir-boosted double protease inhibitor regimens without reverse transcriptase inhibitors

Poster presentation: Purpose of the study To compare the lipometabolic profiles of three double-boosted protease inhibitor (PI) regimens at standard dose, containing saquinavir and ritonavir in combination with lopinavir (LOPSAQ), atazanavir (ATSAQ) or fosamprenavir (FOSAQ) in HIV-positive patients, treated without reverse transcriptase inhibitors (RTI). ..

Gemeinsam gegen AIDS : Klinikpartnerschaft des HIVCENTER mit Lesotho und Südafrika

In einer vernetzten Welt machen Epidemien nicht an Ländergrenzen Halt. Mit der zunehmenden Verfügbarkeit von wirksamen Therapien in Entwicklungsländern wird nun auch das Wissen, das in den Industrieländern durch klinische Forschung gewonnen wurde, für Afrika und Südost-Asien interessant. Das Wissen um eine verbesserte Behandlung HIV-Infizierter mit benachteiligten Regionen in Afrika zu teilen, ist auch das Anliegen einer Klinikpartnerschaft zwischen dem Frankfurter HIVCENTER und der Karabong Klinik des Mafeteng Government Hospitals in Lesotho. Durch die Einbeziehung der Universitätsklinik in Stellenbosch, Südafrika, die eine Hochschulpartnerschaft mit der Universitätsklinik Frankfurt unterhält, soll zudem der Süd-Süd-Austausch zwischen den afrikanischen Partnern gestärkt werden

ADAP2 Is an Interferon Stimulated Gene That Restricts RNA Virus Entry

Interferon stimulated genes (ISGs) target viruses at various stages of their infectious life cycles, including at the earliest stage of viral entry. Here we identify ArfGAP with dual pleckstrin homology (PH) domains 2 (ADAP2) as a gene upregulated by type I IFN treatment in a STAT1-dependent manner. ADAP2 functions as a GTPase-activating protein (GAP) for Arf6 and binds to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) and PI(3,4)P2. We show that overexpression of ADAP2 suppresses dengue virus (DENV) and vesicular stomatitis virus (VSV) infection in an Arf6 GAP activity-dependent manner, while exerting no effect on coxsackievirus B (CVB) or Sendai virus (SeV) replication. We further show that ADAP2 expression induces macropinocytosis and that ADAP2 strongly associates with actin-enriched membrane ruffles and with Rab8a- and LAMP1-, but not EEA1- or Rab7-, positive vesicles. Utilizing two techniques—light-sensitive neutral red (NR)-containing DENV and fluorescence assays for virus internalization—we show that ADAP2 primarily restricts DENV infection at the stage of virion entry and/or intracellular trafficking and that incoming DENV and VSV particles associate with ADAP2 during their entry. Taken together, this study identifies ADAP2 as an ISG that exerts antiviral effects against RNA viruses by altering Arf6-mediated trafficking to disrupt viral entry

High turnaround times and low viral resuppression rates after reinforced adherence counselling following a confirmed virological failure diagnostic algorithm in HIV‐infected patients on first‐line antiretroviral therapy from Tanzania

Objective Early identification of confirmed virological failure is paramount to avoid accumulation of drug resistance in patients on antiretroviral therapy (ART). Scale‐up of HIV‐RNA monitoring in Africa and timely switch to second‐line regimens are challenged. Methods A WHO adapted confirmed virological treatment screening algorithm (HIV‐RNA screening, enhanced adherence counselling, confirmatory HIV‐RNA testing) was evaluated in HIV‐infected patients on first‐line ART from Tanzania. The main endpoints included viral resuppression and virological failure rates, retention and turnaround time of the screening algorithm until second‐line ART initiation. Secondary endpoints included risk factors for virological treatment failure and patterns of genotypic drug resistance. Results HIV‐RNA >1000 copies/ml at first screening was detected in 58/356 (16.3%) patients (median time‐on‐treatment 6.3 years, 25% immunological treatment failure). Adjusted risk factors for virological failure were age <30 years (RR 5.2 [95% CI: 2.5–10.8]), years on ART ≥3 years (RR 3.0 [1.0–8.9]), CD4‐counts <200 cells/µl (RR 9.3 [4.0–21.8]) and poor self‐reported treatment adherence (RR 2.0 [1.2–3.4]). Resuppression of HIV‐RNA <1000 copies/ml was observed in 5/50 (10%) cases after enhanced adherence counselling. Confirmatory testing within 3 months was performed in only 46.6% and switch to second‐line ART within 6 months in 60.4% of patients. Major NNRTI‐mutation were detected in all of 30 patients, NRTI mutations in 96.7% and ≥3 thymidine‐analogue mutations in 40%. No remaining NRTI options were predicted in 57% and limited susceptibility in 23% of patients. Conclusion We observed low levels of viral resuppression following adherence counselling, associated with high levels of accumulated drug resistance. High visit burden and turnaround times for confirmed virological failure diagnosis further delayed switching to second‐line treatment which could be improved using novel point‐of‐care viral load monitoring systems

Depletion and activation of mucosal CD4 T cells in HIV infected women with HPV-associated lesions of the cervix uteri

Background: The burden of HPV-associated premalignant and malignant cervical lesions remains high in HIV+ women even under ART treatment. In order to identify possible underlying pathophysiologic mechanisms, we studied activation and HIV co-receptor expression in cervical T-cell populations in relation to HIV, HPV and cervical lesion status. Methods Cervical cytobrush (n = 468: 253 HIV- and 215 HIV+;71% on ART) and blood (in a subset of 39 women) was collected from women in Mbeya, Tanzania. Clinical data on HIV and HPV infection, as well as ART status was collected. T cell populations were characterized using multiparametric flow cytometry-based on their expression of markers for cellular activation (HLA-DR), and memory (CD45RO), as well as HIV co-receptors (CCR5, alpha(4)beta(7)). Results Cervical and blood T cells differed significantly, with higher frequencies of T cells expressing CD45RO, as well as the HIV co-receptors CCR5 and alpha(4)beta(7)in the cervical mucosa. The skewed CD4/CD8 T cell ratio in blood of HIV+ women was mirrored in the cervical mucosa and HPV co-infection was linked to lower levels of mucosal CD4 T cells in HIV+ women (%median: 22 vs 32;p = 0.04). In addition, HIV and HPV infection, and especially HPV-associated cervical lesions were linked to significantly higher frequencies of HLA-DR+ CD4 and CD8 T cells (p-values < 0.05). Interestingly, HPV infection did not significantly alter frequencies of CCR5+ or alpha(4)beta(7)+ CD4 T cells. Conclusion The increased proportion of activated cervical T cells associated with HPV and HIV infection, as well as HPV-associated lesions, together with the HIV-induced depletion of cervical CD4 T cells, may increase the risk for HPV infection, associated premalignant lesions and cancer in HIV+ women. Further, high levels of activated CD4 T cells associated with HPV and HPV-associated lesions could contribute to a higher susceptibility to HIV in HPV infected women

Numerical and Experimental Investigation of Circulation in Short Cylinders

In preparation for an experimental study of magnetorotational instability (MRI) in liquid metal, we explore Couette flows having height comparable to the gap between cylinders, centrifugally stable rotation, and high Reynolds number. Experiments in water are compared with numerical simulations. Simulations show that endcaps corotating with the outer cylinder drive a strong poloidal circulation that redistributes angular momentum. Predicted azimuthal flow profiles agree well with experimental measurements. Spin-down times scale with Reynolds number as expected for laminar Ekman circulation; extrapolation from two-dimensional simulations at $Re\le 3200$ agrees remarkably well with experiment at $Re\sim 10^6$. This suggests that turbulence does not dominate the effective viscosity. Further detailed numerical studies reveal a strong radially inward flow near both endcaps. After turning vertically along the inner cylinder, these flows converge at the midplane and depart the boundary in a radial jet. To minimize this circulation in the MRI experiment, endcaps consisting of multiple, differentially rotating rings are proposed. Simulations predict that an adequate approximation to the ideal Couette profile can be obtained with a few rings