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The long-acting antiretroviral cabotegravir and rilpivirine combination has just received FDA, EMA and Health Canada approval. This novel drug delivery approach is about to revolutionize the therapy of people living with HIV, decreasing the 365 daily pill burden to only six intramuscular injections per year. In addition, islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor, is intended to be formulated as an implant with a dosing interval of 1 year or more. At present, long-acting antiretroviral therapies (LA-ARTs) are given at fixed standard doses, irrespectively of the patient’s weight and BMI, and without consideration for host genetic and non-genetic factors likely influencing their systemic disposition. Despite a few remaining challenges related to administration (e.g. pain, dedicated medical procedure), the development and implementation of LA-ARTs can overcome long-term adherence issues by improving patients’ privacy and reducing social stigma associated with the daily oral intake of anti-HIV treatments. Yet, the current ‘one-size-fits-all’ approach does not account for the recognized significant inter-individual variability in LA-ART pharmacokinetics. Therapeutic drug monitoring (TDM), an important tool for precision medicine, may provide physicians with valuable information on actual drug exposure in patients, contributing to improve their management in real life. The present review aims to update the current state of knowledge on these novel promising LA-ARTs and discusses their implications, particularly from a clinical pharmacokinetics perspective, for the future management and prevention of HIV infection, issues of ongoing importance in the absence of curative treatment or an effective vaccine.

Background: Depression may contribute to neurocognitive impairment (NCI) in people with HIV (PWH). Attributing NCI to depression rather than to HIV is complicated as depression may be both a causal factor and an effect of NCI. This study aimed to determine the association between depressive symptoms and NCI among PWH with well-controlled infection. Methods: The Neurocognitive Assessment in the Metabolic and Ageing Cohort study is an ongoing, prospective, longitudinal study of PWH aged ≥45 years old nested within the Swiss HIV Cohort Study. Neurocognitive Assessment in the Metabolic and Ageing Cohort study participants underwent neurocognitive assessment and grading of depressive symptoms using the Centre for Epidemiological Studies Depression Scale. Neurocognitive impairment categories were defined using Frascati criteria. Participants with NCI related to neurological or psychiatric confounders other than depression were excluded. The cross-sectional association between the Centre for Epidemiological Studies Depression score and neurocognitive impairment was examined taking Centre for Epidemiological Studies Depression score as a continuous variable and then as a binary variable using two score thresholds, 16 and 27. Results: Excluding 79 participants with confounding factors, 902 participants were studied: 81% were men; 96% had plasma viral loads

Purpose Drug-drug interactions (DDIs) with antiretroviral drugs (ARVs) represent an important issue in elderly people living with HIV (PLWH). Amlodipine is a commonly prescribed antihypertensive drug metabolized by CYP3A4, thus predisposed to a risk of DDIs. Guidance on the management of DDIs is mostly based on theoretical considerations derived from coadministration with other CYP3A4 inhibitors. This study aimed at characterizing the magnitude of DDIs between amlodipine and ARV drugs in order to establish dosing recommendations. Methods A population pharmacokinetic analysis was developed using non-linear mixed effect modelling (NONMEM) and included 163 amlodipine concentrations from 55 PLWH. Various structural and error models were compared to characterize optimally the concentration-time profile of amlodipine. Demographic and clinical characteristics as well as comedications were tested as potential influential covariates. Model-based simulations were performed to compare amlodipine exposure (i.e. area under the curve, AUC) between coadministered ARV drugs. Results Amlodipine concentration-time profile was best described using a one-compartment model with first-order absorption and a lag-time. Amlodipine apparent clearance was influenced by both CYP3A4 inhibitors and efavirenz (CYP3A4 inducer). Model-based simulations revealed that amlodipine AUC increased by 96% when coadministered with CYP3A4 inhibitors, while efavirenz decreased drug exposure by 59%. Conclusion Coadministered ARV drugs significantly impact amlodipine disposition in PLWH. Clinicians should adjust amlodipine dosage accordingly, by halving the dosage in PLWH receiving ARV with inhibitory properties (mainly ritonavir-boosted darunavir), whereas they should double amlodipine doses when coadministering it with efavirenz, under appropriate monitoring of clinical response and tolerance.

BackgroundThe extent of inappropriate prescribing observed in geriatric medicine has not been thoroughly evaluated in people ageing with HIV. We determined the prevalence of and risk factors for inappropriate prescribing in individuals aged ≥75 years enrolled in the Swiss HIV Cohort Study.MethodsRetrospective review of medical records was performed to gain more insights into non-HIV comorbidities. Inappropriate prescribing was screened using the Beers criteria, the STOPP/START criteria and the Liverpool drug–drug interactions (DDIs) database.ResultsFor 175 included individuals, the median age was 78 years (IQR 76–81) and 71% were male. The median number of non-HIV comorbidities was 7 (IQR 5–10). The prevalence of polypharmacy and inappropriate prescribing was 66% and 67%, respectively. Overall, 40% of prescribing issues could have deleterious consequences. Prescribing issues occurred mainly with non-HIV drugs and included: incorrect dosage (26%); lack of indication (21%); prescription omission (drug not prescribed although indicated) (17%); drug not appropriate in elderly individuals (18%) and deleterious DDIs (17%). In the multivariable logistic regression, risk factors for prescribing issues were polypharmacy (OR: 2.5; 95% CI: 1.3–4.7), renal impairment (OR: 2.7; 95% CI: 1.4–5.1), treatment with CNS-active drugs (OR: 2.1; 95% CI: 1.1–3.8) and female sex (OR: 8.3; 95% CI: 2.4–28.1).ConclusionsPolypharmacy and inappropriate prescribing are highly prevalent in elderly people living with HIV. Women are at higher risk than men, partly explained by sex differences in the occurrence of non-HIV comorbidities and medical care. Medication reconciliation and periodic review of prescriptions by experienced physicians could help reduce polypharmacy and inappropriate prescribing in this vulnerable, growing population.

Background: The primary hurdle for the eradication of HIV-1 is the establishment of a latent viral reservoir early after primary infection. Here, we investigated the potential influence of human genetic variation on the HIV-1 reservoir size and its decay rate during suppressive antiretroviral treatment. Setting: Genome-wide association study and exome sequencing study to look for host genetic determinants of HIV-1 reservoir measurements in patients enrolled in the Swiss HIV Cohort Study, a nation-wide prospective observational study. Methods: We measured total HIV-1 DNA in peripheral blood mononuclear cells from study participants, as a proxy for the reservoir size at 3 time points over a median of 5.4 years, and searched for associations between human genetic variation and 2 phenotypic readouts: the reservoir size at the first time point and its decay rate over the study period. We assessed the contribution of common genetic variants using genome-wide genotyping data from 797 patients with European ancestry enrolled in the Swiss HIV Cohort Study and searched for a potential impact of rare variants and exonic copy number variants using exome sequencing data generated in a subset of 194 study participants. Results: Genome-wide and exome-wide analyses did not reveal any significant association with the size of the HIV-1 reservoir or its decay rate on suppressive antiretroviral treatment. Conclusions: Our results point to a limited influence of human genetics on the size of the HIV-1 reservoir and its long-term dynamics in successfully treated individuals.

Background Integrase strand transfer inhibitors (InSTIs) are recommended for first-line treatment of persons with human immunodeficiency virus (HIV). We identified risk factors, including baseline minor InSTI resistance mutations, for treatment failure of InSTI-based regimens. Methods We studied time-to-treatment failure and time to viral suppression among 1419 drug-naive patients in the Swiss HIV Cohort Study. We performed Cox regression models adjusted for demographic factors, baseline HIV RNA/CD4 cell counts, AIDS-defining events, and the type of InSTI. In 646 patients with a baseline genotypic resistance test of the integrase, we studied the impact of minor integrase resistance mutations. Results We observed 121 virological failures during 18 447 person-years of follow-up. A baseline viral load ≥100 000 copies/mL (multivariable hazard ratio [mHR], 2.2; 95% confidence interval [CI], 1.3–3.6) and an AIDS-defining event (mHR, 1.8; 95% CI. 1.1–3.0) were associated with treatment failure. CD4 counts between 200 and 500 cells/µL (mHR, 0.5; 95% CI, .3–.8) and >500 cells/µL (mHR, 0.4; 95% CI, .2–.7) were protective. Time to suppression was shorter in lower viral load strata (mHR, 0.7; 95% CI, .6–.8) and in dolutegravir-based therapy (mHR, 1.2; 95% CI, 1.0–1.4). Minor resistance mutations were found at baseline in 104 of 646 (16%) patients with no effect on treatment outcome. Conclusions Factors associated with treatment failure on InSTI-based first-line regimen remained similar to those of older treatments, in particular high viral load and low CD4 counts., Integrase strand transfer inhibitor–based therapies are effective as first-line treatment of persons living with human immunodeficiency virus. Among 1419 patients, we identified a high baseline viral load, low CD4 cell counts, and an AIDS-defining event before treatment initiation as predictors for treatment failure.

International audience; Human immunodeficiency virus (HIV) infection is associated with an increased risk of non-Hodgkin lymphoma (NHL). Even in the era of suppressive antiretroviral treatment, HIV-infected individuals remain at higher risk of developing NHL compared to the general population. To identify potential genetic risk loci, we performed case-control genome-wide association studies and a meta-analysis across three cohorts of HIV+ patients of European ancestry, including a total of 278 cases and 1924 matched controls. We observed a significant association with NHL susceptibility in the C-X-C motif chemokine ligand 12 (CXCL12) region on chromosome 10. A fine mapping analysis identified rs7919208 as the most likely causal variant (P = 4.77e-11), with the G>A polymorphism creating a new transcription factor binding site for BATF and JUND. These results suggest a modulatory role of CXCL12 regulation in the increased susceptibility to NHL observed in the HIV-infected population.

Background It is unclear whether data-driven machine learning models, which are trained on large epidemiological cohorts, may improve prediction of comorbidities in people living with human immunodeficiency virus (HIV). Methods In this proof-of-concept study, we included people living with HIV in the prospective Swiss HIV Cohort Study with a first estimated glomerular filtration rate (eGFR) >60 mL/minute/1.73 m2 after 1 January 2002. Our primary outcome was chronic kidney disease (CKD)—defined as confirmed decrease in eGFR ≤60 mL/minute/1.73 m2 over 3 months apart. We split the cohort data into a training set (80%), validation set (10%), and test set (10%), stratified for CKD status and follow-up length. Results Of 12 761 eligible individuals (median baseline eGFR, 103 mL/minute/1.73 m2), 1192 (9%) developed a CKD after a median of 8 years. We used 64 static and 502 time-changing variables: Across prediction horizons and algorithms and in contrast to expert-based standard models, most machine learning models achieved state-of-the-art predictive performances with areas under the receiver operating characteristic curve and precision recall curve ranging from 0.926 to 0.996 and from 0.631 to 0.956, respectively. Conclusions In people living with HIV, we observed state-of-the-art performances in forecasting individual CKD onsets with different machine learning algorithms., In people living with HIV who participate in the Swiss HIV Cohort Study, we observed state-of-the-art performances in forecasting individual onsets of chronic kidney disease with different machine learning algorithms.

Background People living with HIV (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) and prone to statin-related adverse events from drug-drug interactions with certain antiretroviral regimens. Objectives This study sought to evaluate the efficacy and safety of evolocumab in dyslipidemic PLHIV. Methods BEIJERINCK is a randomized, double-blind, multinational trial comparing monthly subcutaneous evolocumab 420 mg with placebo in PLHIV with hypercholesterolemia/mixed dyslipidemia taking maximally-tolerated statin therapy. The primary endpoint was the percent change (baseline to week 24) in low-density lipoprotein cholesterol (LDL-C); secondary endpoints included achievement of LDL-C Results A total of 464 patients were analyzed (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). ASCVD was documented in 35.6% of patients, and statin intolerance/contraindications to statin use were present in 20.7% of patients. Evolocumab reduced LDL-C by 56.9% (95% CI: 61.6%, 52.3%) from baseline to week 24 versus placebo. An LDL-C level of Conclusions Evolocumab was safe and significantly reduced lipid levels in dyslipidemic PLHIV on maximally-tolerated statin therapy. Evolocumab is an effective therapy for lowering atherogenic lipoproteins in PLHIV with high cardiovascular risk.

Background Identifying local outbreaks and their drivers is a key step toward curbing human immunodeficiency virus (HIV) transmission and potentially achieving HIV elimination. Such outbreaks can be identified as transmission clusters extracted from phylogenetic trees constructed of densely sampled viral sequences. In this study, we combined phylogenetic transmission clusters with extensive data on virological suppression and behavioral risk of cluster members to quantify the drivers of ongoing transmission over 10 years. Methods Using the comprehensive Swiss HIV Cohort Study and its drug-resistance database, we reconstructed phylogenetic trees for each year between 2007 and 2017. We identified HIV transmission clusters dominated by men who have sex with men (MSM) and determined their annual growth. We used Poisson regression to assess if cluster growth was associated with a per-cluster infectivity and behavioral risk score. Results Both infectivity and behavioral risk scores were significantly higher in growing MSM transmission clusters compared to nongrowing clusters (P ≤ .01). The fraction of transmission clusters without infectious members acquiring new infections increased significantly over the study period. The infectivity score was significantly associated with per-capita incidence of MSM transmission clusters in 8 years, while the behavioral risk score was significantly associated with per-capita incidence of MSM transmission clusters in 3 years. Conclusions We present a phylogenetic method to identify hotspots of ongoing transmission among MSM. Our results demonstrate the effectiveness of treatment as prevention at the population level. However, the significantly increasing number of new infections among transmission clusters without infectious members highlights a relative shift from diagnosed to undiagnosed individuals as drivers of HIV transmission in Swiss MSM.

Background People living with HIV (PLWH) are aging and experience age-related physiological changes and comorbidities. Atorvastatin is a widely prescribed lipid-lowering agent metabolized by cytochrome P450 (CYP) 3A4, whose hepatocyte uptake is facilitated by organic anion transporting polypeptide (OATP) 1B1/1B3. Inhibition or induction of this enzyme and hepatic transporter can increase or decrease atorvastatin exposure, respectively. Objective This study aimed to describe the pharmacokinetic profile of atorvastatin and its major metabolite, and to evaluate drug–drug interactions (DDIs) with antiretrovirals (ARVs). Methods The atorvastatin pharmacokinetic profile was best described by a two-compartment model with first-order absorption and elimination. Metabolite concentrations were described by considering both linear metabolism from atorvastatin and presystemic metabolism. The influence of demographic and clinical covariates on drug and metabolite pharmacokinetics was assessed using NONMEM®. Model-based simulations were performed to evaluate the magnitude of DDIs with ARVs. Results Full pharmacokinetic profiles (98 atorvastatin + 62 o-OH-atorvastatin concentrations) and sparse concentrations (78 and 53 for atorvastatin and o-OH-atorvastatin, respectively) were collected in 59 PLWH. Interindividual variability was high. The coadministration of boosted ARVs decreased atorvastatin clearance by 58% and slowed down o-OH-atorvastatin formation by 88%. Atorvastatin clearance increased by 78% when coadministered with CYP3A4 inducers. Simulations revealed a 180% increase and 44% decrease in atorvastatin exposure (area under the curve) in the presence of ARVs with inhibiting and inducing properties, respectively. Conclusion This study showed an important interindividual variability in atorvastatin pharmacokinetics that remains largely unexplained after the inclusion of covariates. Since boosted ARVs double atorvastatin exposure, the initial dosage might be reduced by half, and titrated based on individual clinical targets. Electronic supplementary material The online version of this article (10.1007/s40262-020-00876-0) contains supplementary material, which is available to authorized users.

Machine Learning (ML) can improve the analysis of complex and interrelated factors that place adherent people at risk of viral rebound. Our aim was to build ML model to predict RNA viral rebound from medication adherence and clinical data. Patients were followed up at the Swiss interprofessional medication adherence program (IMAP). Sociodemographic and clinical variables were retrieved from the Swiss HIV Cohort Study (SHCS). Daily electronic medication adherence between 2008-2016 were analyzed retrospectively. Predictor variables included: RNA viral load (VL), CD4 count, duration of ART, and adherence. Random Forest, was used with 10 fold cross validation to predict the RNA class for each data observation. Classification accuracy metrics were calculated for each of the 10-fold cross validation holdout datasets. The values for each range from 0 to 1 (better accuracy). 383 HIV+ patients, 56% male, 52% white, median (Q1, Q3): age 43 (36, 50), duration of electronic monitoring of adherence 564 (200, 1333) days, CD4 count 406 (209, 533) cells/mm3, time since HIV diagnosis was 8.4 (4, 13.5) years, were included. Average model classification accuracy metrics (AUC and F1) for RNA VL were 0.6465 and 0.7772, respectively. In conclusion, combining adherence with other clinical predictors improve predictions of RNA.

BackgroundSince the advent of universal test-and-treat , more people living with human immunodeficiency virus (PLHIV) initiating antiretroviral therapy (ART) are asymptomatic with a preserved immune system. We explored the impact of asymptomatic status on adherence and clinical outcomes.MethodsPLHIV registered in the Swiss HIV Cohort Study (SHCS) between 2003 and 2018 were included. We defined asymptomatic as Centers for Disease Control and Prevention stage A within 30 days of starting ART, non-adherence as any self-reported missed doses and viral failure as two consecutive viral load>50 copies/mL after >24 weeks on ART. Using logistic regression models, we measured variables associated with asymptomatic status and adherence and Cox proportional hazard models to assess association between symptom status and viral failure.ResultsOf 7131 PLHIV, 76% started ART when asymptomatic and 1478 (22%) experienced viral failure after a median of 1.9 years (interquartile range, 1.1–4.2). In multivariable models, asymptomatic PLHIV were more likely to be younger, men who have sex with men, better educated, have unprotected sex, have a HIV-positive partner, have a lower viral load, and have started ART more recently. Asymptomatic status was not associated with nonadherence (odds ratio, 1.03 [95% confidence interval {CI}, .93–1.15]). Asymptomatic PLHIV were at a decreased risk of viral failure (adjusted hazard ratio, 0.87 [95% CI, .76–1.00]) and less likely to develop resistance (14% vs 27%, P ConclusionsDespite concerns regarding lack of readiness, our study found no evidence of adherence issues or worse clinical outcomes in asymptomatic PLHIV starting ART.

Objective: The aim of this study was to examine neurocognitive course over time among people with well treated HIV. Design: The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is an ongoing, prospective, longitudinal, multicenter and multilingual study within the Swiss HIV Cohort Study (SHCS). Participants undergo neuropsychological assessment at baseline and two-yearly follow-up. Setting: Seven SHCS centres. Participants: Patients aged at least 45 years enrolled in the SHCS with fluency in the local language (French, German or Italian) and agreeing to participate in the NAMACO study: 981 participants at baseline, 720 at 2-year follow-up of whom 644 had complete data sets. Intervention: Standardized neuropsychological assessment at baseline and 2-year follow-up. Main outcome measure: Neurocognitive performance using Frascati criteria and mean z-scores. Results: Four participants (of 644, 0.6%) had plasma HIV-1 RNA more than 50 copies/ml; median CD4+ cell count was 660 cells/μl. According to Frascati criteria, 204 participants (31.7%) had neurocognitive impairment (NCI) at baseline. NCI severity in these participants changed little over 2 years and comprehensive models based on Frascati criteria were not feasible. Examining mean z-scores, however, we observed neurocognitive stability or improvement over two years in five of seven neurocognitive domains assessed. Age at least 65 years (P = 0.02) and cognitive complaints (P = 0.004) were associated with neurocognitive decline, while black race (P = 0.01) and dolutegravir treatment (P = 0.002) were associated with improvement. Conclusion: Frascati criteria were less sensitive in measuring NCI change and therefore unsuitable for following neurocognitive course in our cohort of people with well treated HIV. Examining neurocognitive course by mean z-score change, we observed stability or improvement.

Background Effective cardiovascular preventive strategies are crucial among people living with HIV (PLWH), who are facing a high burden of atherosclerotic cardiovascular disease (ASCVD). However, it remains unclear which cardiovascular risk score is the most appropriate in clinical practice. Purpose We aimed to prospectively assess and compare the accuracy of widely used cardiovascular risk scores in PLWH and individuals from the general population. Methods We used data from the Swiss HIV Cohort Study (SHCS), a longitudinal study involving 20,802 HIV-infected adults aged over 18 years, and from the CoLaus|PsyCoLaus study, a Swiss population-based cohort including 6,733 individuals aged 35–75 years. The European Systematic Coronary Risk Evaluation Score (SCORE), the North American Pooled Cohort Equation (PCE) and the HIV-specific Data Collection o-n Adverse events of Anti-HIV Drugs (D:A:D) score were calculated for all participants free from ASCVD between January 1, 2003 and December 31, 2009. Accuracy of the scores was assessed based on discrimination and calibration metrics for each cohort separately using incident ASCVD as outcome. The value of adding HIV-specific factors to the model presenting the best predictive capacities between SCORE and PCE was evaluated using the net reclassification index (NRI). Results 6,373 PLWH (28.4% women; aged 40.6 [SD, 9.9]; 57.2% on antiretroviral therapy) and 5,403 individuals from the general population (53.5% women, aged 52.8 [SD, 10.7]) were included in the analysis with a mean follow-up time of 13.5 (SD, 4.1) and 9.9 (SD, 2.3) years, respectively. 533 (8.4%) participants in the SHCS and 374 (6.9%) in the CoLaus|PsyCoLaus study experienced an incident ASCVD translating into age-adjusted incidence rates of 12.9 vs. 7.5 per 1,000 person-year, respectively. In SHCS, PCE and D:A:D presented discriminative capacities with AUROC of 0.757 (95% CI, 0.736–0.777) and 0.763 (95% CI, 0.743–0.783), respectively, compared to SCORE (0.704 [95% CI, 0.681–0.728]). Calibration of all scores was suboptimal in SHCS, with under-prediction of ASCVD in the higher deciles of risk compared to the CoLaus|PsyCoLaus study. Adding CD4 nadir ( Conclusions PLWH presented a two-fold higher rate of incident ASCVD compared to individuals of the same age from the general population. The accuracy of PCE score to predict ASCVD in PLWH is equivalent to the D:A:D score and may represent a better alternative due to its reduced set of variables and its widespread use. Adding HIV-specific factors to PCE did not improve its predictive performance. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation

The pharmacokinetics of antiretroviral drugs may differ in elderly people living with HIV (PLWH) because of age-related physiological changes. We aimed to assess the pharmacokinetics of several antiretroviral drugs in aging PLWH enrolled in the Swiss HIV Cohort (SHCS).Full pharmacokinetic profiling nested in a multicenter, observational, prospective cohort study. Additional collection of single point pharmacokinetic data during SHCS follow-up visits (unselected PLWH).PLWH were eligible for the full pharmacokinetics investigation if they were over the age of 55 years, on a stable boosted darunavir-containing or dolutegravir-containing regimen. Single point measurements were prospectively collected during SHCS follow-up visits to compare antiretroviral drug exposure in aging (≥65 years) and younger (65 years) PLWH.Nineteen PLWH with a median age of 64 years participated in the full pharmacokinetic investigations. Single point pharmacokinetic data were collected for 804 PLWH with a median age of 52 years. Boosted darunavir clearance was 40% lower in aging (≥65 years) compared with younger (65 years) PLWH, consistent with other drugs predominantly metabolized by CYP3A. Dolutegravir exposure was similar between age groups whereas lamivudine exposure increased by 11% in aging PLWH. Median boosted darunavir, dolutegravir and lamivudine t1/2 were 148%, 45% and 32% higher in aging compared with younger PLWH.Advanced age did not affect boosted darunavir exposure to a clinically significant extent despite the observed high variability in exposure. Age minimally affected dolutegravir and lamivudine exposure. Thus, dose adjustment based on age is a priori not warranted.

Supplemental Digital Content is available in the text, Introduction: HIV cohort data from high-income European countries were compared with the UNAIDS Spectrum modelling parameters for these same countries to validate mortality rates and excess mortality estimates for people living with HIV (PLHIV) on antiretroviral therapy (ART). Methods: Data from 2000 to 2015 were analysed from the Antiretroviral Therapy Cohort Collaboration (ART-CC) for Austria, Denmark, France, Italy, the Netherlands, Spain, and Switzerland. Flexible parametric models were used to compare all-cause mortality rates in the ART-CC and Spectrum. The percentage of AIDS-related deaths and excess mortality (both are the same within Spectrum) were compared, with excess mortality defined as that in excess of the general population mortality. Results: Analyses included 94 026 PLHIV with 585 784 person-years of follow-up, from which there were 5515 deaths. All-cause annual mortality rates in Spectrum for 2000–2003 were 0.0121, reducing to 0.0078 in 2012–2015, whilst the ART-CC's corresponding annual mortality rates were 0.0151 [95% confidence interval (95% CI): 0.0130–0.0171] reducing to 0.0049 (95% CI: 0.0039–0.0060). The percentage of AIDS-related deaths in Spectrum was 74.7% in 2000–2003, dropping to 43.6% in 2012–2015. In the ART-CC, AIDS-related mortality constitutes 45.3% (95% CI: 38.4–52.9%) of mortality in 2000–2003 and 26.7% (95% CI: 19–46%) between 2012 and 2015. Excess mortality in the ART-CC was broadly similar to the Spectrum estimates, dropping from 75.3% (95% CI: 60.3–95.2%) in 2000–2003 to 30.7% (95% CI: 25.5–63.7%) in 2012–2015. Conclusion: All-cause mortality assumptions for PLHIV on ART in high-income European settings should be adjusted in Spectrum to be higher in 2000–2003 and decline more quickly to levels currently captured for recent years.

BACKGROUND HIV's capacity to escape immune recognition by Human Leukocyte Antigen (HLA) is a core component of HIV pathogenesis. A better understanding of the distribution of HLA Class I in HIV-infected patients would improve our knowledge of pathogenesis in relation to host HLA type, and could better improve therapeutic strategies against HIV. MATERIALS AND METHODS 301-325 transmission pairs and 469-496 clusters were identified for analysis among Swiss HIV Cohort Study (SHCS) participants using HIV pol sequences from the drug resistance database. HLA Class I data was compiled at three specificity levels: four-digit, two-digit alleles, and HLA-B supertype. The analysis tabulated HLA-I homogeneity as two measures: the proportion of transmission pairs which are HLA-concordant as well as the average percentage of allele matches within all clusters. These measures were compared to the mean value across randomizations with randomly assorted individuals. RESULTS We repeated the analysis for different HLA classification levels and separately for HLA-A, -B, and -C. Subanalyses by risk group were performed for HLA-B. HLA-B showed significantly greater homogeneity in the transmission chains (2-digit clusters: 0.291 vs.0.251, p-value=0.009; supertype clusters: 0.659 vs. 0.611, p-value=0.002; supertype pairs: 0.655 vs. 0.608, p-value=0.014). Risk group restriction caused the effect to disappear for men-who-have-sex-with-men (MSM) but not other risk groups. We also examined if protective HLA alleles B27 and B57 were under- or overrepresented in the transmission chains, though this yielded no significant pattern. CONCLUSIONS The HLA-B alleles of patients within HIV-1 transmission chains segregate in homogenous clusters/pairs, potentially indicating preferential transmission among HLA-B concordant individuals.

AIMS: The aims of this study were to characterize escitalopram pharmacokinetic profile, to identify factors influencing drug exposure, notably drug–drug interactions with antiretrovirals, and to simulate expected exposure under standard dosage regimen. METHODS: A population pharmacokinetic analysis was performed using NONMEM. A total of 159 plasma concentration measurements were obtained from 39 human immunodeficiency virus (HIV)‐infected and 71 uninfected psychiatric patients. The influence of age, weight, sex, HIV and psychiatric cohorts, racemic citalopram treatment, and comedications on oral clearance was examined. Simulations served to calculate the percentage of patients expected to be under‐ or over‐exposed, considering established therapeutic targets (15–80 ng/mL). RESULTS: A 1‐compartment model with first‐order absorption and elimination described the data adequately. The average escitalopram clearance and volume of distribution were 23.1 L/h (interindividual variability 51%), and 920 L, respectively. Escitalopram disposition did not differ between HIV‐infected and uninfected patients, and was not affected by antiretroviral treatments. Coadministration of at least 1 proton‐pump inhibitor (CYP2C19 inhibitor) modestly influenced escitalopram elimination (clearance decreased by 19%), with limited clinical relevance. Model‐based simulations showed that, under a standard regimen of 10 mg once daily, a significant proportion of patients (56%) might be under‐exposed. CONCLUSION: The variability in escitalopram disposition is large and poorly explained by demographic, clinical and environmental covariates, thus suggesting a role for dosage individualization based on therapeutic drug monitoring in case of poor clinical response. Escitalopram disposition is modestly impacted by comedications and therefore no a priori dosage adjustments are needed in patients receiving antiretroviral treatments, including boosted regimens.

Objectives Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir’s pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. Methods A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug–drug interactions. Results A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h−1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. Conclusions Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

Background Scale-up of direct-acting antiviral therapy is expected to abate hepatitis C virus (HCV) incidence among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). International transmission could influence this process. We classified HCV infections in HIV-positive MSM as either domestically or internationally acquired, and estimated how this classification changed over time. Methods HCV subtype 1a (the most frequent subtype among MSM) genomes from 99 persons enrolled in the Swiss HIV Cohort Study and diagnosed with replicating HCV infections, were sequenced. Sixty-six of these sequences were from MSM. We inferred maximum-likelihood phylogenetic trees and time trees containing a fragment of the NS5B region of these and 374 circulating strains. We inferred transmission clusters from these trees and used the country composition of such clusters to attribute infections to domestic or international transmission. Results Of HCV transmissions, 50% to 80% were classified as domestic depending on the classification criterion. Between 2000 and 2007, the fraction attributable to domestic transmission was 54% (range 0–75%). It increased to 85% (range 67%–100%) between 2008 and 2016. Conclusions International and domestic transmission have played major roles in this epidemic. While international transmission persists, local transmission has established as the main source of infections., We used phylogenetics and phylodynamics to classify over time HCV infections in HIV-positive MSM as either domestically or internationally acquired. We found that while international transmission dominated initially and persists, local transmission has established as the main source of infections.

Background For many people with HIV (PWH), taking antiretroviral therapy (ARV) every day is difficult. Methods Average adherence (Av-Adh) and log-transformed treatment interruption (TI) to ARV were prospectively measured over 6 months using electronic drug monitoring (EDM) in several cohorts of PWH. Multivariate linear regression models including baseline confounders explored the influence of EDM-defined adherence (R2) on 6-month log10 HIV-RNA. Multivariate logistic regression models were used to compare the risk of HIV-RNA detection (VR) within subgroups stratified by lower (≤95%) and higher (>95%) Av-Adh. Results Three hundred ninety-nine PWH were analyzed with different ARVs: dolutegravir (n = 102), raltegravir (n = 90), boosted PI (bPI; n = 107), and NNRTI (n = 100). In the dolutegravir group, the influence of adherence pattern measures on R2 for HIV-RNA levels was marginal (+2%). Av-Adh, TI, and Av-Adh × TI increased the R2 for HIV-RNA levels by 54% and 40% in the raltegravir and bPI treatment groups, respectively. TI increased the R2 for HIV-RNA levels by 36% in the NNRTI treatment group. Compared with the dolutegravir-based regimen, the risk of VR was significantly increased for raltegravir (adjusted odds ratio [aOR], 45.6; 95% CI, 4.5–462.1; P = .001), NNRTIs (aOR, 24.8; 95% CI, 2.7–228.4; P = .005), and bPIs (aOR, 28.3; 95% CI, 3.4–239.4; P = .002) in PWH with Av-Adh ≤95%. Among PWH with >95% Av-Adh, there were no significant differences in the risk of VR among the different ARVs. Conclusions These findings support the concept that dolutegravir in combination with 2 other active ARVs achieves greater virological suppression than older ARVs, including raltegravir, NNRTI, and bPI, among PWH with lower adherence., Ninety-five percent adherence rule revisited: compared to older antiretroviral combinations, dolutegravir-based triple therapy had a unique forgiveness profile to low-to-moderate electronic drug monitoring adherence levels in terms of HIV RNA replication and emerging resistance mutations amongst PWH.

Intravascular large B-cell lymphoma is a rare and aggressive EBV-negative large B-cell lymphoma with a dismal outcome. Here, we describe the case of a 76-year-old HIV-positive patient with an acute presentation of systemic symptoms and rapidly fatal outcome. Autopsy revealed a disseminated large B-cell lymphoma with an intravascular distribution involving the liver, lymph nodes, spleen, and bone marrow and associated to fibrin thrombi in hepatic capillary haemangiomas. The neoplastic B cells (CD79a + / − , CD20 + / − , CD30 + , MUM1 + , PD-L1 +) showed a Hodgkin and Reed-Sternberg-like morphology and were EBV-positive with a latency type II (LMP1 + , EBNA2-). Haemophagocytosis was documented in the bone marrow and lymph nodes. This case illustrates the diagnostic challenges of large B-cell lymphoma with intravascular presentation. We found only five other cases of EBV-positive large B-cell lymphoma with an intravascular presentation in the literature, three of which had an underlying immunodeficiency adding to the broad spectrum of EBV-associated lymphoma in the setting of immunosuppression.

BackgroundWomen and girls are relatively under-represented across the HIV treatment cascade. Two conditions unique to women, pregnancy and cervical cancer/dysplasia, share a common acquisition mode with HIV. This scoping review aimed to explore HIV testing practices in voluntary termination of pregnancy (TOP) and colposcopy services.MethodsThe scoping review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. We searched articles published up to 20 December 2020 using three electronic databases (PubMed/Medline, Embase, Google Scholar) and including the keywords “HIV Testing”, “Abortion, Induced”, “Colposcopy”, “HIV screen*” and “termination of pregnancy”.ResultsA total of 1496 articles were identified, of which 55 met the inclusion criteria. We included studies providing background HIV prevalence in addition to prevalence in the study population and studies of women seeking TOP rather than presenting with TOP complications. This limited our review to high-income, low HIV prevalence settings. We observed two study phases: studies pre-antiretroviral therapy (ART) using unlinked anonymous testing data and examining HIV risk factors associated with positive HIV tests and studies post-ART using routine testing data and exploring HIV testing uptake. HIV prevalence was estimated at >0.2% in most TOP settings and >1% (range 1.7%–11.4%) in colposcopy services. Many TOP providers did not have local HIV testing policies and HIV testing was not mentioned in many specialist guidelines. Testing uptake was 49%–96% in TOP and 23%–75% in colposcopy services.ConclusionGiven the estimated HIV prevalence of >0.1% among women attending TOP and colposcopy services, HIV testing would be economically feasible to perform in high-income settings. Explicit testing policies are frequently lacking in these two settings, both at the local level and in specialist guidelines. Offering HIV testing regardless of risk factors could normalise testing, reduce late HIV presentation and create an opportunity for preventive counselling.

Background The effect of the Toll-like receptor 7 agonist imiquimod before intradermal (ID) or intramuscular (IM) influenza vaccine in immunocompromised hosts is unknown. Methods In this open-label randomized controlled trial, kidney transplant recipients (KT) and people living with HIV (PLWH) were randomized to receive IM trivalent inactivated influenza vaccine alone (IM), IM vaccine after topical imiquimod (imi+IM) or ID vaccine after topical imiquimod (imi+ID). Immunogenicity was assessed by hemagglutination inhibition assay. The primary outcome was vaccine response, defined as seroconversion to at least one viral strain at day 21. Results Seventy patients (35 KT and 35 PLWH) received IM (24), imi+IM (22), or imi+ID (24) vaccine. Vaccine response was 61% (14/23) with IM, 59% (13/22) with imi+IM, and 65% (15/23) with imi+ID vaccine (P = 0.909). Vaccine response was associated with HIV infection compared to kidney transplantation (adjusted-OR 3.74, 95% CI 1.25 – 11.23, P = 0.019), but not with imiquimod application nor ID injection. After vaccination, seroprotection to all viral strains was 79% (19/24) with IM, 68% (15/22) with imi+IM, and 70% (16/23) with imi+ID (P = 0.657). We did not observe any vaccine-related severe adverse event. Conclusions In our study, topical imiquimod did not improve the immunogenicity of influenza vaccine in KT and in PLWH.

BACKGROUND Tenofovir-based antiretroviral therapy (ART) has become first-line in all major HIV treatment guidelines. Compared with tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) has a favorable renal and bone safety profile, but concerns about metabolic complications remain. OBJECTIVE To assess weight changes, the development of overweight/obesity, and changes in lipid levels 18 months after replacing TDF with TAF. DESIGN Cohort study. SETTING 5 university hospitals, affiliated hospitals, and private physicians in Switzerland. PARTICIPANTS 4375 adults living with HIV who received TDF-containing ART for 6 months or longer. MEASUREMENTS Changes in weight and lipid levels were assessed using mixed-effect models. Differences in proportions of newly overweight/obese participants were calculated using 2-proportions Z tests. RESULTS 4375 individuals were included, with follow-up between 1 January 2016 and 31 July 2019. Median age was 50 years (interquartile range, 43 to 56 years), 25.9% were female, and 51.7% had a normal body mass index (BMI); 3484 (79.6%) switched to TAF and 891 (20.4%) continued TDF. After 18 months, switching to TAF was associated with an adjusted mean weight increase of 1.7 kg (95% CI, 1.5 to 2.0 kg), compared with 0.7 kg (CI, 0.4 to 1.0 kg) with the continued use of TDF (between-group difference, 1.1 kg [CI, 0.7 to 1.4 kg]). Among individuals with a normal BMI, 13.8% who switched to TAF became overweight/obese, compared with 8.4% of those continuing TDF (difference, 5.4 percentage points [CI, 2.1 to 8.8 percentage points]). Switching to TAF led to increases in adjusted mean total cholesterol (0.25 mmol/L [9.5 mg/dL]), high-density lipoprotein cholesterol (0.05 mmol/L [1.9 mg/dL]), low-density lipoprotein cholesterol (0.12 mmol/L [4.7 mg/dL]), and triglyceride (0.18 mmol/L [16.1 mg/dL]) levels after 18 months. LIMITATION Short follow-up, small subgroup analyses, and potential residual confounding. CONCLUSION Replacing TDF with TAF is associated with adverse metabolic changes, including weight increase, development of obesity, and worsening serum lipid levels. PRIMARY FUNDING SOURCE Swiss National Science Foundation.