Population-level impact of expanding PrEP coverage by offering long-acting injectable PrEP to MSM in three high-resource settings: a model comparison analysis

INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) in the HPTN 083/084 trials. We compared the potential impact of expanding PrEP coverage by offering CAB-LA to men who have sex with men (MSM) in Atlanta (US), Montreal (Canada) and the Netherlands, settings with different HIV epidemics. METHODS: Three risk-stratified HIV transmission models were independently parameterized and calibrated to local data. In Atlanta, Montreal and the Netherlands, the models, respectively, estimated mean TDF/FTC coverage starting at 29%, 7% and 4% in 2022, and projected HIV incidence per 100 person-years (PY), respectively, decreasing from 2.06 to 1.62, 0.08 to 0.03 and 0.07 to 0.001 by 2042. Expansion of PrEP coverage was simulated by recruiting new CAB-LA users and by switching different proportions of TDF/FTC users to CAB-LA. Population effectiveness and efficiency of PrEP expansions were evaluated over 20 years in comparison to baseline scenarios with TDF/FTC only. RESULTS: Increasing PrEP coverage by 11 percentage points (pp) from 29% to 40% by 2032 was expected to avert a median 36% of new HIV acquisitions in Atlanta. Substantially larger increases (by 33 or 26 pp) in PrEP coverage (to 40% or 30%) were needed to achieve comparable reductions in Montreal and the Netherlands, respectively. A median 17 additional PYs on PrEP were needed to prevent one acquisition in Atlanta with 40% PrEP coverage, compared to 1000+ in Montreal and 4000+ in the Netherlands. Reaching 50% PrEP coverage by 2032 by recruiting CAB-LA users among PrEP-eligible MSM could avert >45% of new HIV acquisitions in all settings. Achieving targeted coverage 5 years earlier increased the impact by 5-10 pp. In the Atlanta model, PrEP expansions achieving 40% and 50% coverage reduced differences in PrEP access between PrEP-indicated White and Black MSM from 23 to 9 pp and 4 pp, respectively. CONCLUSIONS: Achieving high PrEP coverage by offering CAB-LA can impact the HIV epidemic substantially if rolled out without delays. These PrEP expansions may be efficient in settings with high HIV incidence (like Atlanta) but not in settings with low HIV incidence (like Montreal and the Netherlands)

Missed Opportunities for HIV Testing and Late-Stage Diagnosis among HIV-Infected Patients in Uganda

BACKGROUND: Late diagnosis of HIV infection is a major challenge to the scale-up of HIV prevention and treatment. In 2005 Uganda adopted provider-initiated HIV testing in the health care setting to ensure earlier HIV diagnosis and linkage to care. We provided HIV testing to patients at Mulago hospital in Uganda, and performed CD4 tests to assess disease stage at diagnosis. METHODS: Patients who had never tested for HIV or tested negative over one year prior to recruitment were enrolled between May 2008 and March 2010. Participants who tested HIV positive had a blood draw for CD4. Late HIV diagnosis was defined as CD4≤250 cells/mm. Predictors of late HIV diagnosis were analyzed using multi-variable logistic regression. RESULTS: Of 1966 participants, 616 (31.3%) were HIV infected; 47.6% of these (291) had CD4 counts ≤250. Overall, 66.7% (408) of the HIV infected participants had never received care in a medical clinic. Receiving care in a non-medical setting (home, traditional healer and drug stores) had a threefold increase in the odds of late diagnosis (OR = 3.2; 95%CI: 2.1-4.9) compared to receiving no health care. CONCLUSIONS: Late HIV diagnosis remains prevalent five years after introducing provider-initiated HIV testing in Uganda. Many individuals diagnosed with advanced HIV did not have prior exposure to medical clinics and could not have benefitted from the expansion of provider initiated HIV testing within health facilities. In addition to provider-initiated testing, approaches that reach individuals using non-hospital based encounters should be expanded to ensure early HIV diagnosis

Impact of glucocorticoid receptor density on ligand-independent dimerization, cooperative ligand-binding and basal priming of transactivation: a cell culture model

Glucocorticoid receptor (GR) levels vary between tissues and individuals and are altered by physiological and pharmacological effectors. However, the effects and implications of differences in GR concentration have not been fully elucidated. Using three statistically different GR concentrations in transiently transfected COS-1 cells, we demonstrate, using co-immunoprecipitation (CoIP) and fluorescent resonance energy transfer (FRET), that high levels of wild type GR (wtGR), but not of dimerization deficient GR (GRdim), display ligand-independent dimerization. Whole-cell saturation ligand-binding experiments furthermore establish that positive cooperative ligand-binding, with a concomitant increased ligand-binding affinity, is facilitated by ligand-independent dimerization at high concentrations of wtGR, but not GRdim. The down-stream consequences of ligand-independent dimerization at high concentrations of wtGR, but not GRdim, are shown to include basal priming of the system as witnessed by ligand-independent transactivation of both a GRE-containing promoter-reporter and the endogenous glucocorticoid (GC)-responsive gene, GILZ, as well as ligand-independent loading of GR onto the GILZ promoter. Pursuant to the basal priming of the system, addition of ligand results in a significantly greater modulation of transactivation potency than would be expected solely from the increase in ligand-binding affinity. Thus ligand-independent dimerization of the GR at high concentrations primes the system, through ligand-independent DNA loading and transactivation, which together with positive cooperative ligand-binding increases the potency of GR agonists and shifts the bio-character of partial GR agonists. Clearly GR-levels are a major factor in determining the sensitivity to GCs and a critical factor regulating transcriptional programs

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Four-Stage Audit Demonstrating Increased Uptake of HIV Testing in Acute Neurology Admissions Using Staged Practical Interventions.

BACKGROUND: UK National Guidelines (UKNG) advise HIV testing in clinically indicated neurological presentations. We audited the impact of our practical strategies to increase uptake of HIV testing at a regional acute neurology admissions unit. METHODS: We audited HIV testing in 4 periods over 2 years: before we designed a UKNG-based "HIV testing in Neurology" protocol ("pre-protocol"); after dissemination of the protocol alone ("post-protocol"); post-protocol dissemination combined with both a tailored departmental admissions clerking proforma to prompt for HIV testing & consenting, and regular focussed tutorials to doctors on HIV testing in neurological patients ("post-proforma"); and finally one year after the post-proforma period ("+1 year"). We also looked at the total number of HIV tests sent from the unit during the two-year period. We assessed significance using Fisher's exact test. RESULTS: 47.8% of all acute neurology non-stroke admissions were eligible for HIV testing during all the audit periods. Testing rates were as follows: pre-protocol 21.9%; post-protocol 36.6%; post-proforma 83.3%; and at +1 year 65.4% (p<0.05 for both post-protocol and +1 year when compared to pre-protocol). Documentation of consent for HIV testing improved from 25% to 67.6% with the HIV-tailored clerking proforma. The total number of HIV tests requested from the unit doubled in the post-proforma period compared to pre-protocol (p<0.05). CONCLUSION: In conclusion: the combination of an HIV testing protocol, a tailored departmental clerking proforma and regular focussed teaching to doctors on indications for HIV testing led to a sustained increase in HIV testing uptake in our regional acute neurology admissions unit

The working alliance in supported employment for people with severe mental health problems

Aims: This study examined the utility of the Working Alliance Inventory Short form (WAI-S) for measuring the working alliance between supported employment service providers and service users with severe mental health problems

HIV treatment as prevention: optimising the impact of expanded HIV treatment programmes.

Until now, decisions about how to allocate ART have largely been based on maximising the therapeutic benefit of ART for patients. Since the results of the HPTN 052 study showed efficacy of antiretroviral therapy (ART) in preventing HIV transmission, there has been increased interest in the benefits of ART not only as treatment, but also in prevention. Resources for expanding ART in the short term may be limited, so the question is how to generate the most prevention benefit from realistic potential increases in the availability of ART. Although not a formal systematic review, here we review different ways in which access to ART could be expanded by prioritising access to particular groups based on clinical or behavioural factors. For each group we consider (i) the clinical and epidemiological benefits, (ii) the potential feasibility, acceptability, and equity, and (iii) the affordability and cost-effectiveness of prioritising ART access for that group. In re-evaluating the allocation of ART in light of the new data about ART preventing transmission, the goal should be to create policies that maximise epidemiological and clinical benefit while still being feasible, affordable, acceptable, and equitable