IntroductionOral pre-exposure prophylaxis (PrEP) is an effective strategy to reduce the risk of HIV transmission in high risk individuals. However, the effectiveness of oral pre-exposure prophylaxis is highly dependent on user adherence, which some previous trials have struggled to optimise particularly in low and middle income settings. This systematic review aims to ascertain the reasons for non-adherence to pre-exposure prophylaxis to guide future implementation.MethodsWe performed structured literature searches of online databases and conference archives between August 8, 2016 and September 16, 2017. In total, 18 prospective randomized control trials and implementation studies investigating oral pre-exposure prophylaxis were reviewed. A structured form was used for data extraction and findings summarized regarding efficacy, effectiveness, adherence and possible reasons for non-adherence.ResultsAdherence varied between differing populations both geographically and socioeconomically. Common reasons for non-adherence reported over multiple studies were; social factors such as stigma, low risk perception, low decision making power, an unacceptable dosing regimen, side effects, and the logistics of daily life. Oral pre-exposure prophylaxis with included antiviral regimens was not associated with a high risk of antiviral resistance development in the reviewed studies.ConclusionOur findings indicate that oral pre-exposure prophylaxis should be delivered within a holistic intervention, acknowledging the other needs of the targeted demographic in order to maximise acceptability. Socioeconomic factors and poor governmental policy remain major barriers to widespread implementation of pre-exposure prophylaxis.

SUMMARYPolymorphism amongst the human leucocyte antigen (HLA) class II genes could influence antigen presentation and the ability to control human immunodeficiency virus (HIV)-1 by modulating the virus specific CD4 immune response. To examine the effect of such polymorphisms on disease progression, we studied a cohort of 46 HIV-1 infected long-term non-progressors (LTNPs), 87 intermediate progressors (IPs) and 26 rapid progressors. Kaplan-Meier survival analysis of all patients in the cohort on time to a CD4 count less than 350 cells/ll, showed a trend for a slower rate of CD4 decline in patients with, compared to those without, the DRB1*15-DQB1*06 haplotype (hazard ratio (HR) 0AE69, 95% CI 0AE46-1AE01, P = 0AE06). A similar effect was not observed with the DRB1*13-DQB1*06 haplotype (HR 1AE18, 95% CI 0AE75-1AE88, P = 0AE46), but was observed when DQB1*06 alleles were considered irrespective of their DR association (HR 0AE74, 95% CI 0AE52-1AE05, P = 0AE06). Major HLA-DQ6 alleles encode aspartate (Asp) at position 57 on the DQb chain, a phenotype associated with protection from other immune disorders. We therefore examined the frequency of all DQb57 Asp + alleles, but could not detect a significant effect on the rate of CD4 decline. To examine whether the genotype associated with slower CD4 decline was over-represented in patients with a slow rate of disease progression, we conducted a categorical analysis of a subset of patients with an extended follow-up of 14+years. We found a higher proportion of LTNPs at 14+ years possessed the DRB1*15-DQB1*06 haplotype compared to IPs at 14+ years (38AE46 versus 18AE18%), though this difference did not reach statistical significance. When DQB1*06 alleles irrespective of their DR association were considered, the protective effect was greater (76AE9% LTNPs versus 18AE18% IPs, P = 0AE04). Our results highlight the potential protective effect of HLA DQB1*06 alleles on the course of HIV disease.

On 20 August 2021, Ronapreve received conditional marketing authorisation for the prevention and treatment of covid-19 in the UK. 1 Ronapreve (REGEN-COV in the US) comprises two monoclonal antibodies, casirivimab and imdevimab, that target the SARS-CoV-2 spike protein to reduce the risk and severity of covid-19 in selected patients. 2 -5 Although Ronapreve's approval represents a welcome expansion in the armamentarium against covid-19, it also brings difficult questions about who should be eligible for treatment.

Objectives There is limited evidence that empirical antimicrobials affect patient-oriented outcomes in Gram-negative bacteraemia. We aimed to establish the impact of effective antibiotics at four consecutive timepoints on 30 day all-cause mortality and length of stay in hospital. Methods We performed a multivariable survival analysis on 789 patients with Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa bacteraemias. Antibiotic choices at the time of the blood culture (BC), the time of medical clerking and 24 and 48 h post-BC were reviewed. Results Patients that received ineffective empirical antibiotics at the time of the BC had higher risk of mortality before 30 days (HR = 1.68, 95% CI = 1.19–2.38, P = 0.004). Mortality was higher if an ineffective antimicrobial was continued by the clerking doctor (HR = 2.73, 95% CI = 1.58–4.73, P < 0.001) or at 24 h from the BC (HR = 1.83, 95% CI = 1.05–3.20, P = 0.033) when compared with patients who received effective therapy throughout. Hospital-onset infections, ‘high inoculum’ infections and elevated C-reactive protein, lactate and Charlson comorbidity index were independent predictors of mortality. Effective initial antibiotics did not statistically significantly reduce length of stay in hospital (−2.98 days, 95% CI = −6.08–0.11, P = 0.058). The primary reasons for incorrect treatment were in vitro antimicrobial resistance (48.6%), initial misdiagnosis of infection source (22.7%) and non-adherence to hospital guidelines (15.7%). Conclusions Consecutive prescribing decisions affect mortality from Gram-negative bacteraemia.

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