Long-term efficacy and safety of a treatment strategy for HIV infection using protease inhibitor monotherapy: 8-year routine clinical care follow-up from a randomised, controlled, open-label pragmatic trial (PIVOT).

Background: Treatment-simplification strategies are important tools for patient-centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy. Methods: Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician-selected PI monotherapy (PI-mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074. Findings: We randomised 587 participants to OT (291) or PI-mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI-mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference -0.6%, 95% CI -3.2% to 2.0%). Only one PI-mono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non-AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI-mono group (P = 0.08) over the entire follow-up period. Interpretation: A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient-centred, treatment-simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded. Funding: The National Institute for Health Research Health Technology Assessment programme.

Depression is associated with poor self-reported adherence to antiretroviral therapy among people living with HIV attending an HIV clinic in the UK: results from a cross-sectional study.

Contemporary evidence is needed to assess whether the prevalence of depression remains high among people living with HIV in the United Kingdom despite recent efforts to improve patients' mental health, and if depression is negatively associated with individuals' adherence to antiretroviral therapy. In a secondary analysis of a cross-sectional clinic-based survey of alcohol consumption and associated health behaviour among people living with HIV in London, of the 221 respondents, 106 (48%) had poor self-reported adherence to antiretroviral therapy (CASE Index) and 69 (31%) screened positive for depression (PHQ-9). Poor self-reported adherence to ART was 72% higher among participants who screened positive for depression in comparison with participants who screened negative. Respondents who were younger, unemployed, and reported problematic drug use were more likely to screen positive for depression. Screening and management of depression as a part of routine HIV care may support adherence to antiretroviral therapy.

Hepatic steatosis in people older and younger than fifty who are living with HIV and HIV-negative controls: A cross-sectional study nested within the POPPY cohort.

BACKGROUND: Hepatic steatosis is a major cause of chronic liver disease associated with several negative health outcomes. We compared the prevalence of and factors associated with steatosis in people living with and without HIV. METHODS: Older (>50 years) and younger (<50 years) people with HIV and older HIV-negative controls (>50 years) underwent liver transient elastography examination with controlled attenuation parameter (steatosis ≥238 dB/m, moderate/severe steatosis ≥280 dB/m, liver fibrosis ≥7.1 kPa). We compared groups using logistic regression/Chi-squared/Fisher's exact/Kruskal-Wallis tests. RESULTS: In total, 317 participants (109 older people with HIV; 101 younger people with HIV; 107 HIV-negative controls) were predominantly white (86%) and male (76%), and 21% were living with obesity (body mass index ≥30 kg/m2 ). Most (97%) people with HIV had undetectable HIV RNA. The prevalence of fibrosis was 8.4%, 3.0%, and 6.5% in the three groups, respectively (p = 0.26). Fibrosis was predominately (>65%) mild. The prevalence of steatosis was the same in older people with HIV (66.4%) and controls (66.4%) but lower in younger people with HIV (37.4%; p < 0.001). After adjustment, younger people with HIV were less likely to have steatosis (odds ratio [OR] 0.26; 95% confidence interval [CI] 0.14-0.52) than controls, but male sex (OR 2.45; 95% CI 1.20-4.50) and high waist-to-hip ratio (OR 3.04; 95% CI 1.74-5.33) were associated with an increased odds of steatosis. We found no association between steatosis and HIV-related variables. CONCLUSIONS: The prevalence of hepatic steatosis and fibrosis was similar between older participants regardless of HIV status. Age, sex, and abdominal obesity, but not HIV-related variables, were associated with steatosis. Interventions for controlling obesity should be integrated into routine HIV care.

Bone turnover change after randomized switch from tenofovir disoproxil to tenofovir alafenamide fumarate in men with HIV.

OBJECTIVE: Bone loss in people with HIV (PWH) is poorly understood. Switching tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) has yielded bone mineral density (BMD) increases. PETRAM (NCT#:03405012) investigated whether BMD and bone turnover changes correlate. DESIGN: Open-label, randomized controlled trial. SETTING: Single-site, outpatient, secondary care. PARTICIPANTS: Nonosteoporotic, virologically suppressed, cis-male PWH taking TDF/emtricitabine (FTC)/rilpivirine (RPV) for more than 24 weeks. INTERVENTION: Continuing TDF/FTC/RPV versus switching to TAF/FTC/RPV (1 : 1 randomization). MAIN OUTCOME MEASURES: :[ 18 F]NaF-PET/CT for bone turnover (standardized uptake values, SUV mean ) and dual-energy x-ray absorptiometry for lumbar spine and total hip BMD. RESULTS: Thirty-two men, median age 51 years, 76% white, median duration TDF/FTC/RPV 49 months, were randomized between 31 August 2018 and 09 March 2020. Sixteen TAF:11 TDF were analyzed. Baseline-final scan range was 23-103 (median 55) weeks. LS-SUV mean decreased for both groups (TAF -7.9% [95% confidence interval -14.4, -1.5], TDF -5.3% [-12.1,1.5], P  = 0.57). TH-SUV mean showed minimal changes (TAF +0.3% [-12.2,12.8], TDF +2.9% [-11.1,16.9], P  = 0.77). LS-BMD changes were slightly more favorable with TAF but failed to reach significance (TAF +1.7% [0.3,3.1], TDF -0.3 [-1.8,1.2], P  = 0.06). Bone turnover markers decreased more with TAF ([CTX -35.3% [-45.7, -24.9], P1NP -17.6% [-26.2, -8.5]) than TDF (-11.6% [-28.8, +5.6] and -6.9% [-19.2, +5.4] respectively); statistical significance was only observed for CTX ( P  = 0.02, P1NP, P  = 0.17). CONCLUSION: Contrary to our hypothesis, lumbar spine and total hip regional bone formation (SUV mean ) and BMD did not differ postswitch to TAF. However, improved LS-BMD and CTX echo other TAF-switch studies. The lack of difference in SUV mean may be due to inadequate power.

Trypanosoma cruzi screening in people living with HIV in the UK.

People living with HIV (PLWH) are at higher risk of reactivation of Chagas disease, a neglected tropical disease, caused by Trypanosoma cruzi. There are no data from UK HIV clinics on the prevalence of T. cruzi. We implemented T. cruzi screening at our clinic as part of routine care for PLWH with epidemiological risk factors. Among 86 patients screened, none had positive serology: one seropositive patient was identified due to increased clinician awareness. Implementing T. cruzi screening as part of routine clinical care was feasible, though labour intensive and identified at-risk individuals.

How surgical Trainee Research Collaboratives achieve success: a mixed methods study to develop trainee engagement strategies.

OBJECTIVES: This study aimed to understand the role of surgical Trainee Research Collaboratives (TRCs) in conducting randomised controlled trials and identify strategies to enhance trainee engagement in trials. DESIGN: This is a mixed methods study. We used observation of TRC meetings, semi-structured interviews and an online survey to explore trainees' motivations for engagement in trials and TRCs, including barriers and facilitators. Interviews were analysed thematically, alongside observation field notes. Survey responses were analysed using descriptive statistics. Strategies to enhance TRCs were developed at a workshop by 13 trial methodologists, surgical trainees, consultants and research nurses. SETTING: This study was conducted within a secondary care setting in the UK. PARTICIPANTS: The survey was sent to registered UK surgical trainees. TRC members and linked stakeholders across surgical specialties and UK regions were purposefully sampled for interviews. RESULTS: We observed 5 TRC meetings, conducted 32 semi-structured interviews and analysed 73 survey responses. TRCs can mobilise trainees thus gaining wider access to patients. Trainees engaged with TRCs to improve patient care, surgical evidence and to help progress their careers. Trainees valued the TRC infrastructure, research expertise and mentoring. Challenges for trainees included clinical and other priorities, limited time and confidence, and recognition, especially by authorship. Key TRC strategies were consultant support, initial simple rapid studies, transparency of involvement and recognition for trainees (including authorship policies) and working with Clinical Trials Units and research nurses. A 6 min digital story on YouTube disseminated these strategies. CONCLUSION: Trainee surgeons are mostly motivated to engage with trials and TRCs. Trainee engagement in TRCs can be enhanced through building relationships with key stakeholders, maximising multi-disciplinary working and offering training and career development opportunities.

Derivation of a Protein Risk Score for Cardiovascular Disease Among a Multiracial and Multiethnic HIV+ Cohort.

Background Cardiovascular disease risk prediction models underestimate CVD risk in people living with HIV (PLWH). Our goal is to derive a risk score based on protein biomarkers that could be used to predict CVD in PLWH. Methods and Results In a matched case-control study, we analyzed normalized protein expression data for participants enrolled in 1 of 4 trials conducted by INSIGHT (International Network for Strategic Initiatives in Global HIV Trials). We used dimension reduction, variable selection and resampling methods, and multivariable conditional logistic regression models to determine candidate protein biomarkers and to generate a protein score for predicting CVD in PLWH. We internally validated our findings using bootstrap. A protein score that was derived from 8 proteins (including HGF [hepatocyte growth factor] and interleukin-6) was found to be associated with an increased risk of CVD after adjustment for CVD and HIV factors (odds ratio: 2.17 [95% CI: 1.58-2.99]). The protein score improved CVD prediction when compared with predicting CVD risk using the individual proteins that comprised the protein score. Individuals with a protein score above the median score were 3.10 (95% CI, 1.83-5.41) times more likely to develop CVD than those with a protein score below the median score. Conclusions A panel of blood biomarkers may help identify PLWH at a high risk for developing CVD. If validated, such a score could be used in conjunction with established factors to identify CVD at-risk individuals who might benefit from aggressive risk reduction, ultimately shedding light on CVD pathogenesis in PLWH.

Long-Term Benefits from Early Antiretroviral Therapy Initiation in HIV Infection.

BACKGROUND: For people with HIV and CD4+ counts >500 cells/mm3, early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4+ counts are <350 cells/mm3. Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain. METHODS: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4+ counts .500 cells/mm3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021. RESULTS: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4+ count was 648 and 460 cells/mm3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4+ difference was 199 cells/mm3. After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4+ count difference was 155 cells/mm3. After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference). CONCLUSIONS: Among adults with CD4+ counts >500 cells/mm3, excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Peripheral Neuropathy in Virologically Suppressed People Living with HIV: Evidence from the PIVOT Trial.

The aim of this study is to identify the factors associated with peripheral neuropathy and to explore neurofilament light chain (NfL) as a biomarker for peripheral neuropathy (PN) in effectively virologically suppressed adults living with HIV. All protease inhibitor monotherapy versus ongoing triple therapy in the long-term management of HIV infection (PIVOT) trial participants with data on PN at baseline were included in the study. NfL plasma levels (pNfL) were measured in a sub-set of participants. Multivariable logistic regression was used to examine the associations of PN with potential risk factors (including age, sex, nadir CD4 cell count, history of dideoxynucleoside (d-drugs) exposure, and blood glucose levels) and NfL levels. Of the 585 participants included, 131 (22.4%) reported PN during the study period (median of 44 months). The participants were predominantly male (76.6%), White (68.2%), and virologically suppressed for a median period of 37 months (range of 20-63) before recruitment. The age at baseline was 44.3 years (standard deviation (SD) of 9.2). PN was independently associated with age (adjusted odds ratio (aOR) = 1.35, 95% CI of 1.20-1.52; additional 5 years), history of d-drugs (aOR 1.88, 95% CI of 1.12-3.16), height (aOR 1.19, 95% CI of 1.05-1.35; additional 5 cm), nadir CD4 cell count (aOR 1.10 CI of 1.00-1.20; 50 cells fewer), and metabolic syndrome (aOR 2.31, 95% CI of 1.27 4.20), but not pNfL. The excess risk for PN associated with d-drug use remains after the exposure has stopped for years, suggesting non-reversible toxicity. In people with HIV, metabolic syndrome is independently associated with PN. There was no additional value for pNfL as a screening test for peripheral neuropathy in effectively virologically suppressed adults living with HIV.

Learning and memory function in young people with and without perinatal HIV in England.

Learning and memory are important for successful education and career progression. We assess these functions in young people (YP) with perinatal HIV (PHIV) (with or without a previous AIDS-defining illness) and a comparable group of HIV-negative YP. 234 PHIV and 68 HIV-negative YP completed 9 tests; 5 National Institutes of Health (NIH) Toolbox tests (2 executive function, 1 speed of information processing, 2 memory); 2 Hopkins Verbal Learning Test Revised (HVLT-R) (learning (L), delayed recall (R)), and 2 verbal application measures. Z-scores for each test were calculated using normative data and averaged by domain where appropriate. The effect of predictors on test scores in the three domains with the lowest z-scores were analysed using linear regression. 139(59%) and 48(71%) PHIV and HIV-negative YP were female, 202(86%) and 52(76%) Black, and median age was 19 [17, 21] and 18 [16, 21] years respectively. 55(24%) PHIV had a previous Center for Disease Control and Prevention (CDC) class C AIDS-defining diagnosis (PHIV/C). For HVLT-R, there was a trend towards PHIV/C YP having the lowest mean z-scores (L -1.5 (95% CI -1.8,-1.2), R -1.7 (-2.0,-1.4)) followed by PHIV without a CDC C diagnosis (L -1.3 (-1.4,-1.1), R -1.4 (-1.5,-1.2)) and then the HIV-negative group (L -1.0 (-1.3,-0.7), R -1.1 (-1.3,-0.8)); all were greater than 1 SD below the reference mean. The same trend was seen for verbal application measures; however, z-scores were within 1 SD below the reference mean. NIH Toolbox tests were similar for all groups. In multivariable analyses PHIV/C and Black ethnicity predicted lower HVLT-R scores. Black ethnicity also predicted lower executive function scores, however each year increase in age predicted higher scores. In conclusion, cognitive performance in verbal learning and recall fell below population normative scores, and was more pronounced in PHIV/C, supporting wider findings that earlier antiretroviral therapy initiation, before the occurrence of AIDS-defining conditions, may protect aspects of cognitive development.

Alcohol, smoking, recreational drug use and association with virological outcomes among people living with HIV: cross-sectional and longitudinal analyses.

OBJECTIVES: There is increasing evidence to suggest that people living with HIV (PLWH) have significant morbidity from alcohol, recreational drug use and cigarette smoking. Our aim was to report associations of these factors with antiretroviral therapy (ART) non-adherence, viral non-suppression and subsequent viral rebound in PLWH. METHODS: The Antiretroviral Sexual Transmission Risk and Attitudes (ASTRA) study recruited PLWH attending eight outpatient clinics in England between February 2011 and December 2012. Data included self-reported excessive drinking (estimated consumption of > 20 units of alcohol/week), alcohol dependency (CAGE score ≥ 2 with current alcohol consumption), recreational drug use (including injection drug use in the past 3 months), and smoking status. Among participants established on ART, cross-sectional associations with ART non-adherence [missing ≥2 consecutive days of ART on ≥2 occasions in the past three months] and viral-non suppression [viral load (VL) > 50 copies/mL] were assessed using logistic regression. In participants from one centre, longitudinal associations with subsequent viral rebound (first VL > 200 copies/mL) in those on ART with VL ≤ 50 copies/mL at baseline were assessed using Cox regression during a 7-year follow-up. RESULTS: Among 3258 PLWH, 2248 (69.0%) were men who have sex with men, 373 (11.4%) were heterosexual men, and 637 (19.6%) were women. A CAGE score ≥ 2 was found in 568 (17.6%) participants, 325 (10.1%) drank > 20 units/week, 1011 (31.5%) currently smoked, 1242 (38.1%) used recreational drugs and 74 (2.3%) reported injection drug use. In each case, prevalence was much more common among men than among women. Among 2459 people on ART who started at least 6 months previously, a CAGE score ≥ 2, drinking > 20 units per week, current smoking, injection and non-injection drug use were all associated with ART non-adherence. After adjusting for demographic and socioeconomic factors, CAGE score ≥ 2 [adjusted odds ratio (aOR) = 1.52, 95% confidence interval (CI): 1.09-2.13], current smoking (aOR = 1.58, 95% CI: 1.10-2.17) and injection drug use (aOR = 2.11, 95% CI: 1.00-4.47) were associated with viral non-suppression. During follow-up of a subset of 592 people virally suppressed at recruitment, a CAGE score ≥ 2 [adjusted hazard ratio (aHR) = 1.66, 95% CI: 1.03-2.74], use of 3 or more non-injection drugs (aHR = 1.82, 95% CI: 1.12-3.57) and injection drug use (aHR = 2.73, 95% CI: 1.08-6.89) were associated with viral rebound. CONCLUSIONS: Screening and treatment for alcohol, cigarette and drug use should be integrated into HIV outpatient clinics, while clinicians should be alert to the potential for poorer virological outcomes.

SARS-CoV-2 inhibition using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray.

There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-COV-2 in A549ACE2+ and Vero E6 cells with a log removal value of - 3 to - 4 at a concentration of 10-100 µg/ mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 µg/ mL (p < 0.05 compared to untreated controls). In vivo studies using transgenic mice expressing the ACE-2 receptor, dosed nasally with SARS-COV-2 (426,000 TCID50/mL) showed a trend for nasal GCPQ (20 mg/kg) to inhibit viral load in the respiratory tract and brain, although the study was not powered to detect statistical significance. GCPQ's electrostatic binding to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/kg, GCPQ has a long residence time in mouse nares, with 13.1% of the injected dose identified from SPECT/CT in the nares, 24 h after nasal dosing. With a no observed adverse effect level of 18 mg/kg in rats, following a 28-day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted.

Human Immunotypes Impose Selection on Viral Genotypes Through Viral Epitope Specificity.

BACKGROUND: Understanding the genetic interplay between human hosts and infectious pathogens is crucial for how we interpret virulence factors. Here, we tested for associations between HIV and host genetics, and interactive genetic effects on viral load (VL) in HIV-positive antiretroviral treatment-naive clinical trial participants. METHODS: HIV genomes were sequenced and the encoded amino acid (AA) variants were associated with VL, human single nucleotide polymorphisms (SNPs), and imputed HLA alleles using generalized linear models with Bonferroni correction. RESULTS: Human (388 501 SNPs) and HIV (3010 variants) genetic data were available for 2122 persons. Four HIV variants were associated with VL (P < 1.66 × 10-5). Twelve HIV variants were associated with a range of 1-512 human SNPs (P < 4.28 × 10-11). We found 46 associations between HLA alleles and HIV variants (P < 1.29 × 10-7). HIV variants and immunotypes when analyzed separately were associated with lower VL, whereas the opposite was true when analyzed in concert. Epitope binding predictions supported our observations. CONCLUSIONS: Our results show the importance of immunotype specificity on viral antigenic determinants, and the identified genetic interplay emphasizes that viral and human genetics should be studied in the context of each other.Clinical Trials Registration: NCT00867048.

Factors Associated With Nonadherence to Antiretroviral Therapy Among Young People Living With Perinatally Acquired HIV in England.

Young people living with perinatally acquired HIV may be at risk of poor adherence to antiretroviral therapy; identification of predictors, using a conceptual framework approach proposed previously by others, is important to identify those at higher risk. In 261 young people with perinatally acquired HIV in England, 70 (27%) reported 3-day nonadherence, 82 (31%) last month nonadherence, and 106 (41%) nonadherence on either measure. Of those reporting nonadherence on both measures, 52% (23/44) had viral load of <50 copies/ml, compared with 88% (127/145) of those reported being fully adherent. In multivariable analysis, young person and medication theme factors were associated with nonadherence. The main predictors of 3-day nonadherence were antiretroviral therapy containing a boosted protease inhibitor and poorer quality of life. Predictors of last month nonadherence were having told more people about one's HIV status, worse self-perception about having HIV, and boosted protease inhibitor-based regimens. The consistency of individual young person and medication factors in predicting nonadherence gives insight into where interventions may best be targeted to improve adherence.

Genital secretion HIV RNA shedding in HIV-positive patients on ritonavir-boosted protease inhibitor monotherapy or standard combination ART: a cross-sectional sub-study from the PIVOT Trial.

BACKGROUND: Protease inhibitors (PI) have relatively low penetration into the genital tract, raising concerns about the potential for genital HIV RNA shedding in patients taking PI-based regimens, particularly PI monotherapy (PI-mono). METHODS: We measured HIV RNA and PI drug concentrations in samples of semen, cervico-vaginal and rectal mucosa secretions, and plasma in patients after 48-96 weeks on PI-mono or standard triple therapy. RESULTS: A total of 85 participants were recruited. Of the 43 participants on PI-mono (70% on darunavir [DRV]/ritonavir [r]), 3 had detectable virus in semen or vaginal secretions (all below quantification limit), and none in rectal mucosa or plasma. Among those taking triple therapy, five had detectable virus in semen or vaginal secretions (HIV RNA >50 copies/ml in one), none in rectal mucosa and one in plasma. The median (IQR) concentration of DRV and atazanavir in semen (659.7 [339-1,089] and 128.8 [63-368] ng/ml, respectively) and cervico-vaginal samples (2,768 [312-7,879] and 1,836 [359-3,314] ng/ml, respectively) exceeded their protein adjusted median inhibition concentration (MIC50). DRV concentration in rectal secretions showed higher variability compared with concentration in the other sites, with particularly high rectal secretion/blood ratios (median 8.4, IQR 2.6-68.7:1). CONCLUSIONS: We found no substantive evidence of HIV shedding in patients taking PI-mono, suggesting that PIs provide adequate control of virus in the genital compartment and are unlikely to lead to ongoing sexual transmission.

Risky Alcohol Consumption and Associated Health Behaviour Among HIV-Positive and HIV-Negative Patients in a UK Sexual Health and HIV Clinic: A Cross-Sectional Questionnaire Study.

Alcohol misuse has been associated with negative consequences among HIV-positive patients. Data on real prevalence of risky alcohol consumption among the HIV-positive population in the UK are lacking. A cross-sectional questionnaire study using standardised validated instruments among HIV-positive (n = 227) and HIV-negative (n = 69) patients was performed. The prevalence of risky alcohol consumption (AUDIT) and associations with depressive symptoms (PHQ-9), problematic drug use (DUDIT), adherence to ART (CASE Adherence Index), sexual behaviour and demographic characteristics were assessed among both patient groups independently. A quarter (25.1%) of HIV-positive patients and 36.1% of HIV-negative patients reported risky alcohol consumption (AUDIT-score ≥ 8). In the multivariable analysis among HIV-positive patients depressive symptoms (p = 0.03) and problematic drug use (p = 0.007) were associated with risky alcohol consumption. Among HIV-negative patients these associations were not present. Risky alcohol consumption among HIV-positive patients is prevalent, and together with depressive symptoms and problematic drug use, may influence HIV-disease progression and patients' wellbeing.

Reversible effect on lipids by switching from tenofovir disoproxil fumarate to tenofovir alafenamide and back.

OBJECTIVE: The aim of the current study is to assess the effect of tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) on lipids in patients switching from TDF to TAF and back. METHODS: Retrospective data collection on patients who were initially switched from TDF to TAF and switched back to TDF after generics of TDF became available. RESULTS: In total, 385 patients were included. Median duration of TDF exposure before switch was 317 weeks (interquartile range 172-494). After switching from TDF to TAF, mean total cholesterol (TC) increased from 186 ±â€Š37 mg/dl at baseline to 206 ±â€Š43 and 204 ±â€Š43 mg/dl at weeks 12 and 24 (P < 0.001). The increase in TC was mainly due to an increase in LDL cholesterol. However, ratio of TC/HDL remained unchanged, indicating a simultaneous rise of LDL and HDL cholesterol. Baseline triglycerides increased from mean 153 ±â€Š96 to 176 ±â€Š120 and 176 ±â€Š124 mg/dl at weeks, 12 and 24 (P < 0.001). From 385 patients 168 were switched back from TAF to TDF after median duration on TAF of 96 weeks (interquartile range 89-104). At switching back from TAF to TDF, mean TC was 202 ±â€Š40 mg/dl and decreased at weeks 12 and 24 to 183 ±â€Š41 and 185 ±â€Š35 mg/dl (P < 0.001). Mean triglycerides were 163 ±â€Š119 mg/dl and decreased to 145 ±â€Š108 and 157 ±â€Š112 mg/dl, respectively (P < 0.05). Patients with higher increases in TC after switching from TDF to TAF also showed more pronounced decreases after switching back. CONCLUSION: The results demonstrate a reversible effect on lipids by switching from TDF to TAF and back.

Brain Perfusion, Regional Volumes, and Cognitive Function in Human Immunodeficiency Virus-positive Patients Treated With Protease Inhibitor Monotherapy.

BACKGROUND: Protease inhibitor monotherapy (PIM) for human immunodeficiency virus (HIV) may exert suboptimal viral control in the central nervous system. We determined whether cerebral blood flow (CBF) and regional brain volumes were associated with PIM, and whether specific cognitive domains were associated with imaging biomarkers. METHODS: Cognitive assessments and brain magnetic resonance imaging were performed after the final visit of a randomized HIV-treatment strategy trial. Participants were virologically suppressed on triple therapy at trial entry and followed for 3-5 years. We studied 37 patients randomized to ongoing triple therapy and 39 randomized to PIM. Resting CBF and normalized volumes were calculated for brain regions of interest, and correlated with treatment strategy and neuropsychological performance. RESULTS: Mean age was 48.1 years (standard deviation 8.6 years), 63 male (83%), and 64 white (84%). Participants had median 8.1 years (interquartile range 6.4, 10.8) of antiretroviral therapy experience and CD4+ counts of median 640 cells/mm3 (interquartile range 490, 780). We found no difference between treatment arms in CBF or regional volumes. Regardless of treatment arm, poorer fine motor performance correlated with lower CBF in the caudate nucleus (P = .01), thalamus (P = .04), frontal cortex (P = .01), occipital cortex (P = .004), and cingulate cortex (P = .02), and was associated with smaller supratentorial white matter volume (decrease of 0.16 in Z-score per -1% of intracranial volume, 95% confidence interval 0.02-0.29; P = .023). CONCLUSIONS: PIM does not confer an additional risk of neurological injury compared with triple therapy. There were correlations between fine motor impairment, grey matter hypoperfusion, and white matter volume loss. CLINICAL TRIALS REGISTRATION: ISRCTN-04857074.

Benefit of Early versus Deferred Antiretroviral Therapy on Progression of Liver Fibrosis among People with HIV in the START Randomized Trial.

The role of antiretroviral therapy (ART) in reducing or contributing to liver fibrosis in persons with human immunodeficiency virus (HIV) is unclear. We evaluated participants in the Strategic Timing of AntiRetroviral Treatment (START) trial for liver fibrosis using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 Index (FIB-4), and assessed for a benefit of early versus delayed ART on liver fibrosis progression. ART-naïve persons with high CD4 counts (>500 cells/µL) from 222 clinical sites in 35 countries were randomized to receive ART either at study enrollment (immediate treatment arm) or when their CD4 count fell below 350 cells/µL (deferred treatment arm). The following outcomes were evaluated: fibrosis (APRI > 0.5 or FIB-4 > 1.45), significant fibrosis (APRI > 1.5 or FIB-4 > 3.25), hepatic flare, and resolution of elevated APRI and FIB-4 scores. Of the 4,684 enrolled into the START study, 104 did not have APRI or FIB-4 results and were excluded. Among 4,580 participants (2,273 immediate treatment; 2,307 deferred treatment), the median age was 36 years, 26.9% were female, and 30.4% were black. Three percent had an alcoholism or substance abuse history, 6.4% had hepatitis B and/or C, and 1.1% had significant fibrosis at baseline. The median CD4 count was 651, and 5.3% had HIV RNA ≤ 200. Immediate arm participants were at lower risk of developing increased fibrosis scores than deferred arm participants (hazard ratio [HR] = 0.66; 95% confidence interval [CI] = 0.57-0.78; P < 0.001) and more likely to have resolution of elevated baseline scores (HR 1.6; 95% CI 1.3-1.9; P < 0.001). Conclusions: Significant liver fibrosis was rare among ART-naïve HIV-positive persons with high CD4 counts. Our findings suggest a benefit of early ART in preventing the development of liver fibrosis.

Risk of Suicidal Behavior With Use of Efavirenz: Results from the Strategic Timing of Antiretroviral Treatment Trial.

Background: Randomized trials have shown increased risk of suicidality associated with efavirenz (EFV). The START (Strategic Timing of Antiretroviral Treatment) trial randomized treatment-naive human immunodeficiency virus (HIV)-positive adults with high CD4 cell counts to immediate vs deferred antiretroviral therapy (ART). Methods: The initial ART regimen was selected prior to randomization (prespecified). We compared the incidence of suicidal and self-injurious behaviours (suicidal behavior) between the immediate vs deferred ART groups using proportional hazards models, separately for those with EFV and other prespecified regimens, by intention to treat, and after censoring participants in the deferred arm at ART initiation. Results: Of 4684 participants, 271 (5.8%) had a prior psychiatric diagnosis. EFV was prespecified for 3515 participants (75%), less often in those with psychiatric diagnoses (40%) than without (77%). While the overall intention-to-treat comparison showed no difference in suicidal behavior between arms (hazard ratio [HR], 1.07, P = .81), subgroup analyses suggest that initiation of EFV, but not other ART, is associated with increased risk of suicidal behavior. When censoring follow-up at ART initiation in the deferred group, the immediate vs deferred HR among those who were prespecified EFV was 3.31 (P = .03) and 1.04 (P = .93) among those with other prespecified ART; (P = .07 for interaction). In the immediate group, the risk was higher among those with prior psychiatric diagnoses, regardless of prespecified treatment group. Conclusions: Participants who used EFV in the immediate ART group had increased risk of suicidal behavior compared with ART-naive controls. Those with prior psychiatric diagnoses were at higher risk.