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Introduction: Pre-exposure prophylaxis (PrEP) is an effective medication to reduce the risk of acquiring HIV. PrEP is available free of charge in the UK from sexual health clinics. Expanding PrEP delivery to community pharmacies holds promise and aligns with UK government goals to eliminate new cases of HIV by 2030. The aim of this scoping review was to describe the existing evidence about the barriers to and facilitators of community pharmacy oral PrEP delivery, for pharmacists and pharmacy clients, as aligned with the Capacity Opportunity, Motivation Behaviour (COM-B) Model., Methods: Five bibliographic and five review databases were searched from inception to August 2023. Literature of any study design was included if it discussed barriers and facilitators of community pharmacy PrEP delivery. Trial registrations, protocols and news articles were excluded., Results: A total of 649 records were identified, 73 full texts were reviewed and 56 met the inclusion criteria, predominantly from high-income/westernized settings. Most of the included literature was original research (55%), from the United States (77%) conducted during or after the year 2020 (63%). Barriers to PrEP delivery for pharmacists included lack of knowledge, training and skills (capability), not having the necessary facilities (opportunity), concern about the costs of PrEP and believing that PrEP use could lead to risk behaviours and sexually transmitted infections (motivation). Facilitators included staff training (capability), time, the right facilities (opportunity), believing PrEP could be a source of profit and could reduce new HIV acquisitions (motivation). For clients, barriers included a lack of PrEP awareness (capability), pharmacy facilities (opportunity) and not considering pharmacists as healthcare providers (motivation). Facilitators included awareness of PrEP and pharmacist's training to deliver it (capability), the accessibility of pharmacies (opportunity) and having an interest in PrEP (motivation)., Discussion: To effectively enhance oral PrEP delivery in UK community pharmacies, the identified barriers and facilitators should be explored for UK relevance, addressed and leveraged at the pharmacy team, client and care pathway level., Conclusions: By comprehensively considering all aspects of the COM-B framework, community pharmacies could become crucial providers in expanding PrEP accessibility, contributing significantly to HIV prevention efforts., (© 2024 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

Background: Expanding statin use may help to alleviate the excess burden of atherosclerotic cardiovascular disease in people living with HIV (PLHIV). Pravastatin and pitavastatin are preferred agents due to their lack of substantial interaction with antiretroviral therapy. We aimed to evaluate the cost-effectiveness of pravastatin and pitavastatin for the primary prevention of atherosclerotic cardiovascular disease among PLHIV in the United States., Methods: We developed a microsimulation model that randomly selected (with replacement) individuals from the Data-collection on Adverse Effects of Anti-HIV Drugs study with follow-up between 2013 and 2016. Our study population was PLHIV aged 40 to 75 years, stable on antiretroviral therapy, and not currently using lipid-lowering therapy. Direct medical costs and quality-adjusted life-years (QALYs) were assigned in annual cycles and discounted at 3% per year. We assumed a willingness-to-pay threshold of $100,000/QALY gained. The interventions assessed were as follows: (1) treating no one with statins; (2) treating everyone with generic pravastatin 40 mg/day (drug cost $236/year) and (3) treating everyone with branded pitavastatin 4 mg/day (drug cost $2,828/year). The model simulated each individual's probability of experiencing atherosclerotic cardiovascular disease over 20 years., Results: Persons receiving pravastatin accrued 0.024 additional QALYs compared with those not receiving a statin, at an incremental cost of $1338, giving an incremental cost-effectiveness ratio of $56,000/QALY gained. Individuals receiving pitavastatin accumulated 0.013 additional QALYs compared with those using pravastatin, at an additional cost of $18,251, giving an incremental cost-effectiveness ratio of $1,444,000/QALY gained. These findings were most sensitive to the pill burden associated with daily statin administration, statin costs, statin efficacy and baseline atherosclerotic cardiovascular disease risk. In probabilistic sensitivity analysis, no statin was optimal in 5.2% of simulations, pravastatin was optimal in 94.8% of simulations and pitavastatin was never optimal., Conclusions: Pravastatin was projected to be cost-effective compared with no statin. With substantial price reduction, pitavastatin may be cost-effective compared with pravastatin. These findings bode well for the expanded use of statins among PLHIV in the United States. To gain greater confidence in our conclusions it is important to generate strong, HIV-specific estimates on the efficacy of statins and the quality-of-life burden associated with taking an additional daily pill., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction: With improved survival, adolescents with perinatal HIV (PHIV) are transitioning from paediatric to adult care, but there are few published data on clinical outcomes post-transfer. Using linked data from patients in the national UK/Ireland paediatric cohort (CHIPS) and an adult UK cohort of outpatient clinics (UK CHIC), we describe mortality and changes in immunological status post-transfer., Methods: Participants in CHIPS aged ≥13 years by the end of 2013 were linked to the UK CHIC database. Mixed effects models explored changes in CD4 count before and after transfer, including interactions between time and variables where interaction p  < 0.05., Results: Of 1,215 paediatric participants aged ≥13 years, 271 (22%) had linked data in UK CHIC. One hundred and forty-six (53%) were female, median age at last visit in paediatric care was 17 [interquartile range, IQR 16,18] years, median duration in paediatric care was 11.8 [6.6,15.5] years, and in adult care was 2.9 [1.5,5.9] years. At last visit in paediatric care, 74% ( n  = 200) were on ART, increasing to 84% ( n  = 228, p  = 0.001) at last visit in adult care. In the 12 months before leaving paediatric care, 92 (47%) had two consecutive viral loads >400 copies/mL or one viral load >10,000 copies/mL, and likewise 102 (52%) in the 12 months post-transfer ( p  = 0.79). Seven (3%) people died in adult care. In multivariable analysis, CD4 declined as patients approached transition with a greater decline in those with higher nadir CD4 count (mean rates of decline of 3, 13, 15, 30 cells/mm 3 per year for those with nadir CD4 < 100, 100-199, 200-299 and ≥300 cells/mm 3 , respectively). Post-transition, CD4 continued to decline in some groups (e.g. black males, -20 (-34, -5) cells/mm 3 per year post transition, p  = 0.007)) while it improved in others. Overall CD4 was higher with later year of birth (14 (7, 21) cells/mm 3 per later year). There was no effect of age at transfer or changing hospital at transfer on CD4., Conclusions: Our findings suggest that CD4 in adolescents with perinatal HIV in the UK was declining in the period before transition to adult care, and there was some reversal in this trend post-transfer in some groups. Across the transition period, CD4 was higher in those with later birth years, suggesting improvements in clinical care and/or transition planning over time., Competing Interests: The authors declare that they have no competing interests.

Introduction: A recent meta-analysis of 4 RCTs showed an increased rate of suicidality events (suicidal ideation or attempted/completed suicide) associated with efavirenz (EFV) compared to other regimens, but only a trend towards a higher rate of completed/attempted suicides, as only 17 events occurred. We investigated the association between EFV use and completed suicide., Materials and Methods: All D:A:D participants were followed from study entry to the first of death, last study visit or 1 February 2013. Deaths are centrally validated using cause of death methodology, which assigns underlying, immediate and up to four contributing causes of death. Two endpoints were considered: 1) suicide or psychiatric disease as the underlying cause, and 2) suicide or psychiatric disease mentioned as an underlying, immediate or contributing cause of death (anywhere). Adjusted rate ratios were calculated using Poisson regression., Results: A total of 4420 deaths occurred in 49,717 people over 371,333 person-years (PY) (rate 11.9 per 1000 PY; 95% CI 11.6-12.3). A total of 193 deaths (rate 0.52; 0.45-0.59) had an underlying cause of suicide or psychiatric disease, and 482 deaths (1.30; 1.18-1.41) had suicide or psychiatric disease mentioned anywhere. A strong association with current CD4 count was seen: for suicide or psychiatric disease mentioned anywhere, rates were: 3.18 (2.55-3.80) for <200 cells/uL, 1.60 (1.29-1.90) for 201-350 cells/uL, 1.07 (0.86-1.29) for 351-500 cells/uL, 0.95 (0.80-1.09) for >500 cells/uL and 1.30 (1.18-1.41) for unknown. Highest rate of suicide or psychiatric deaths were seen in ART-experienced people currently off ART, but no differences were seen according to current ART regimen, which remained after adjustment (Table 1). Consistent results were obtained when considering additional endpoints of suicide alone as the underlying cause and death from suicide or any possibly related cause (psychiatric disease, drug overdose, alcohol related, accidental or violent), as well as considering recent EFV use in the previous 3 and 6 months., Conclusions: The finding of no higher death rates from suicide amongst those receiving EFV is reassuring. However, there is likely confounding by indication in our observational study. In light of conflicting results from RCTs, this potentially could suggest that in clinical practice EFV may be less frequently prescribed in those with underlying psychiatric conditions.

Introduction: There is a lack of data on potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) in HIV-positive individuals. We investigated whether such differences exist in the D:A:D study., Materials and Methods: Follow-up was from 01/02/99 until the earliest of death, 6 months after last visit or 01/02/13. Rates of initiation of lipid-lowering drugs (LLDs), angiotensin-converting enzyme inhibitors (ACEIs), anti-hypertensives and receipt of invasive cardiovascular procedures (ICPs; bypass, angioplasty, endarterectomy) were calculated in those without a myocardial infarction (MI) or stroke at baseline, overall and in groups known to be at higher CVD risk: (i) age >50, (ii) total cholesterol >6.2 mmol/l, (iii) triglyceride >2.3 mmol/l, (iv) hypertension, (v) previous MI, (vi) diabetes, or (vii) predicted 10-year CVD risk >10%. Poisson regression was used to assess whether rates of initiation were higher in men than women, after adjustment for these factors., Results: At enrolment, women (n=13,039; median (interquartile range) 34 (29-40) years) were younger than men (n=36,664, 39 (33-46) years, p=0.001), and were less likely to be current smokers (29% vs. 39%, p=0.0001), to have diabetes (2% vs. 3%, p=0.0001) or to have hypertension (7% vs. 11%, p=0.0001). Of 49,071 individuals without a MI/stroke at enrolment, 0.6% women vs. 2.1% men experienced a MI while 0.8% vs. 1.3% experienced a stroke. Overall, women received ICPs at a rate of 0.07/100 person-years (PYRS) compared to 0.29/100 PYRS in men. Similarly, the rates of initiation of LLDs (1.28 vs. 2.46), anti-hypertensives (1.11 vs. 1.38) and ACEIs (0.82 vs. 1.37) were all significantly lower in women than men (Table 1). As expected, initiation rates of each intervention were higher in the groups determined to be at moderate/high CVD risk; however, within each high-risk group, initiation rates of most interventions (with the exception of anti-hypertensives) were generally lower in women than men. These gender differences persisted after adjustment for potential confounders (Table 1)., Conclusion: Use of most CVD interventions was lower among women than men in the D:A:D study. Our findings suggest that actions should be taken to ensure that both men and women are monitored for CVD and, if eligible, receive appropriate CVD interventions.

Introduction: Several resistance mutations have been shown to affect viral fitness, and the presence of certain mutations might result in clinical benefit for patients kept on a virologically failing regimen due to an exhaustion of drug options. We sought to quantify the effect of resistance mutations on CD4 slopes in patients undergoing episodes of viral failure., Materials and Methods: Patients from the EuroSIDA and UK CHIC cohorts undergoing at least one episode of virological failure (>3 consecutive RNA measurements >500 on ART) with at least three CD4 measurements and a resistance test during the episode were included. Mutations were identified using the IAS-US (2013) list, and were presumed to be present from detection until the end of an episode. Multivariable linear mixed models with a random intercept and slope adjusted for age, baseline CD4 count, hepatitis C, drug type, RNA (log-scale), risk group and subtype were used to estimate CD4 slopes. Individual mutations with a population prevalence of >10% were tested for their effect on the CD4 slope., Results: A total of 2731 patients experiencing a median of 1 (range 1-4) episodes were included in this analysis. The prevalence of any resistance per episode was 88.4%; NNRTI resistance was most common (78.5%). Overall, CD4 counts declined by 17.1 (-19.7; -14.5) cells per year; this decline was less marked with partial viral suppression (current HIV RNA more than 1.5 log below the setpoint; p=0.01). In multivariable models adjusting for viral load, CD4 decline was slower during episodes with detected resistance compared to episodes without detected resistance (21.0 cells/year less, 95% CI 11.75-30.31, p<0.001). Among those with more than one resistance mutation, there was only weak evidence that class-specific mutations had any effect on the CD4 slope (Table 1). The effects of individual mutations (incl. M184V) were explored, but none were significantly associated with the CD4 slope; for these comparisons, a Bonferroni-corrected p-value level was 0.003., Conclusions: In our study population, detected resistance was associated with slightly less steep CD4 declines. This may be due to a biological effect of resistance on CD4 slopes, or other unmeasured factors such as poor adherence among individuals without resistance. Among individuals with detected drug resistance, we found no evidence suggesting that the presence of individual mutations was associated with beneficial CD4 slope changes.

Introduction: High rates of hepatotoxicity have been observed among HIV-positive pregnant women using antiretroviral therapy (ART). However, the extent to which pregnancy affects the risk of ART-induced hepatotoxicity is unclear since studies in this area have generated conflicting results., Material and Methods: Combined data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC) were used. Alanine aminotransferase (ALT) data were assessed according to the Division of AIDS toxicity guidelines to identify factors associated with liver enzyme elevation (LEE) (grade 1-4). Women starting ART in 2000-11 aged 16-49 years were included irrespective of pregnancy status at ART start. Cox proportional hazards were used to assess the associations between fixed (ethnicity, exposure group, HBV/HCV co-infection, prior ART use, and age, year, pregnancy status, viral load and CD4 count at ART start) and time-dependent covariates (pregnancy status, age, year, CD4 count, viral load, duration on ART) and the risk of LEE., Results: Of the 3426 women included, one-quarter (25.0%, n=857) were pregnant during follow-up and 14.4% (n=492) started ART during pregnancy. The rate of LEE was 15/100 person-years (PY) during pregnancy and 6.1/100 PY outside pregnancy. The risk of LEE was increased during pregnancy (adjusted hazard ratio (aHR) 1.61 [1.26-2.06], p<0.001), including in secondary analysis excluding 493 women pregnant when starting ART. Other factors independently associated with LEE were lower CD4 count (<250 cells/mm(3) vs. 251-350 cells/mm(3) aHR 1.25 [1.02-1.54], p=0.03), HBV/HCV co-infection (aHR 1.94 [1.58-2.39], p<0.001), HIV acquired via injecting drug use (aHR 1.61 [1.15-2.24], p=0.01 vs. heterosexually) and calendar year (aHR 1.05 [1.02-1.08], p<0.001 per one year increase). Three ART drugs were associated with increased risk of LEE (efavirenz aHR 1.27 [1.06-1.50], p-value 0.008; maraviroc 4.19 [1.34-13.1], p=0.01; and nevirapine 1.59 [1.30-1.95], p-value <0.001). Use of zidovudine was associated with decreased risk of LEE (aHR 0.74 [0.63-0.87], p<0.001) as was increasing time on an NNRTI-based regimen (aHR 0.91 [0.86-0.96], p<0.001 per additional year)., Conclusions: Pregnant women were at increased risk of LEE, highlighting the importance of close monitoring of toxicity biomarkers during pregnancy.

Introduction: Most people achieve and maintain viral load (VL) suppression on first-line antiretroviral therapy (ART) but for a minority this does not happen. It is unclear whether those who have maintained VL suppression for several years will be able to continue to do so, or if rates of VL failure - due to poor adherence, ART interruption and/or resistance - remain at appreciable levels., Methods: Eligible participants were ART-naïve and started treatment after 1st January 2000, with ≥3 antiretrovirals and ≥9 months follow-up. VL failure was defined as failure to achieve VL suppression (≤50 copies/mL) by 9 months on ART or a single VL >200 copies/mL after 9 months after start of ART. Kaplan-Meier estimates were used to examine the cumulative probability of experiencing a VL >200 copies/mL over time, irrespective of treatment interruption (Figure 1). Follow-up was censored at last VL assessment but not at treatment interruption. In a sensitivity analysis, VL failure was instead defined as two consecutive VL >1000 copies/mL., Results: A total of 13,556 participants were included. Median (IQR) age at start of ART was 37 (32-43), median follow-up 4.1 (2.3-6.7) years, pre-ART VL 71,400 (17,400-221,900) copies/mL and pre-ART CD4 count 204 (110-290) cells/mm(3). Fifty-one percent were white, 71% male and 50% MSM. Of which, 5,351 (39%) participants experienced a VL >200 copies/mL. In sub-groups of participants the proportion experiencing a VL >200 copies/mL by one year after start of ART were: <50 years 22%, ≥50 years 17%, men 20%, women 26%, MSM 19%, black heterosexuals 23%, white heterosexuals 26% and other 23%. The median time to VL >200 copies/ml was 8 years. In sensitivity analyses based on 12,811 participants, 4274 (33%) experienced two consecutive VL >1000 copies/mL. Table 1 presents the rate of experiencing a VL >200 copies/mL (two consecutive VL >1000 copies/mL) by time since start of ART. The rate of VL >200 copies/mL declines over time, from 30 per 100 person-years after up to two years after ART, to two per 100 person-years after up to 11.5 years after ART. A sum of 2,047 (15%) participants stopped ART at some point (10, 14 and 17% had stopped ART by 1, 3, and 5 years, respectively)., Conclusions: Although resistance will often not be present and, even if present, several drug options will likely remain, first occurrence of VL > 200 copies/mL after having attained viral suppression continues to occur after 10 years on ART.

Introduction: Combination antiretroviral therapy (cART) may affect vitamin D [25(OH)D], parathyroid hormone (PTH), bone mineral density (BMD) and bone turnover (BT). Reduced BMD and secondary hyperparathyroidism have been reported with tenofovir (TDF). We investigated the associations between TDF and bone markers, especially in 25(OH)D-deficient patients., Materials and Methods: In a single-centre longitudinal study investigating BMD in HIV-positive men, serum 25(OH)D, calcium, phosphate, PTH and alkaline phosphatase (ALP) were measured. Lumbar spine, non-dominant total hip and non-dominant femoral neck BMD (g/cm(2)) were measured using dual-energy X-ray absorptiometry. BT was assessed by serum type 1 procollagen (P1NP) and carboxy-terminal collagen cross-links (CTX). Mann-Whitney U tests compared serum markers and BT, and t-tests compared BMD according to TDF in all and 25(OH)D-deficient patients., Results: A total of 422 men were recruited: mean age 47 (SD 9.8) years, 94% white ethnicity, 93% MSM, diagnosed HIV positive for median 9.6 (IQR 5.0,15.5) years, median CD4 547 (IQR 411,696) cells/µL, HIV RNA <40 copies/mL in 87% (96% of those on cART). 25(OH)D (nmol/L) was normal (>75), insufficient (50-75), deficient (25-50) and severely deficient (<25) in 14%, 29%, 50% and 7%, respectively. Of 381 men on cART, 77% were currently on TDF. TDF was not associated with median calcium (p=0.69) or phosphate (p=0.52), but patients had higher (but normal) median ALP [81 (IQR 69,103) vs. 73 (IQR 60,89) IU/L, p=0.005) compared to non-TDF cART. There was no difference in the association between vitamin D and PTH according to whether someone currently was (r=0.11, p=0.06, Figure 1) or was not using TDF (r=0.12, p=0.29, Figure 1). TDF was also not associated with PTH, BMD or BT in either all patients on cART (Table 1a) or in patients with 25(OH)D deficiency (Table 1b)., Conclusions: In this largely TDF-experienced cohort of HIV-positive men, there was no association between TDF and 25(OH)D deficiency, hyperparathyroidism, reduced BMD or increased BT, although patients on TDF had higher but normal ALP. We found no evidence to support additional monitoring of bone markers in patients on TDF regardless of 25(OH)D status.