Antiretroviral Drug Exposure and Response in Obese and Morbidly Obese People With Human Immunodeficiency Virus (HIV): A Study Combining Modelling and Swiss HIV Cohort Data.

BACKGROUND: Obesity is increasingly prevalent among people with HIV (PWH) and can possibly result in suboptimal antiretroviral drug (ARV) exposure and response. However, this has not been thoroughly evaluated given that obese PWH are underrepresented in clinical trials. We performed virtual trials using physiologically based pharmacokinetic (PBPK) modelling combined with observed clinical data to provide ARV dosing guidance in obese individuals. METHODS: Each trial included a cohort of virtual adults with a body mass index (BMI) between 18.5 and 60 kg/m2. Therapeutic drug-monitoring data from the Swiss HIV Cohort Study (SHCS) were used to verify the predictive performance of the model. Subsequently, the model was applied to predict the pharmacokinetics of ARVs for different obesity classes. The association between ARV plasma concentrations and virological response was investigated in obese and nonobese individuals. RESULTS: The PBPK model predicted an average reduction in ARV exposure of ∼20% and trough concentrations of ∼6% in obese (BMI ≥30 kg/m2) compared with nonobese (BMI: 18.5-25 kg/m2) individuals, consistent with observed clinical data. Etravirine and rilpivirine were the most impacted, especially in individuals with BMI >40 kg/m2 whose trough concentrations were below the clinical target threshold. Obese PWH in the SHCS did not have a higher rate of unsuppressed viral load than nonobese PWH. CONCLUSIONS: The concentrations of ARVs are modestly reduced in obese individuals, with no negative impact on the virological response. Our data provide reassurance that standard doses of ARVs are suitable in obese PWH, including those who gained substantial weight with some of the first-line ARVs.

Major revision version 12.0 of the European AIDS Clinical Society guidelines 2023.

BACKGROUND: The European AIDS Clinical Society (EACS) guidelines were revised in 2023 for the 19th time, and all aspects of HIV care were updated. KEY POINTS OF THE GUIDELINES UPDATE: Version 12.0 of the guidelines recommend the same six first-line treatment options for antiretroviral treatment (ART)-naïve adults as versions 11.0 and 11.1: tenofovir-based backbone plus an unboosted integrase inhibitor or doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. The long-acting section has been expanded in the ART and drug-drug interaction (DDI) panels. Tables for preferred and alternative ART in children and adolescents have been updated, as has the section on prevention of vertical transmission, particularly with new guidance for breastfeeding. A new DDI table has been included for the ART and anti-infective drugs used for opportunistic infections, sexually transmitted infections, and other infectious conditions; lenacapavir has been included in all DDI tables. New sections on alcohol use and patient-reported outcome measures (PROMs) have been included in the comorbidity panel, in addition to updates on many relevant topics, such as new resource guidance for deprescribing in people with HIV. Other sections, including travel, cognitive impairment, cancer screening, sexual health, and diabetes have also been revised extensively. The algorithm for the management of acute hepatitis C virus infection has been removed, as current guidelines recommend immediate treatment of all people with recently acquired hepatitis C virus. Updates on vaccination for hepatitis B virus and recommendations for simplification to tenofovir-free two-drug regimens in people with isolated anti-hepatitis B core antibodies are provided. In the opportunistic infections and COVID-19 panel, guidance on the management of COVID-19 in people with HIV has been updated according to the most up-to-date evidence, and a new section on monkeypox has been added. CONCLUSIONS: In 2023, the EACS guidelines were updated extensively and now include several new sections. The recommendations are available as a free app, in interactive web format, and as a pdf online.

Association of a Polygenic Risk Score With Osteoporosis in People Living With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bone mineral density (BMD) loss may be accelerated in people with HIV (PLWH). It is unknown whether a polygenic risk score (PRS) is associated with low BMD in PLWH. METHODS: Swiss HIV Cohort Study participants of self-reported European descent underwent ≥2 per-protocol dual x-ray absorptiometry (DXA) measurements ≥2 years apart (2011-2020). Univariable and multivariable odds ratios (ORs) for DXA-defined osteoporosis were based on traditional and HIV-related risk factors and a genome-wide PRS built from 9413 single-nucleotide polymorphisms associated with low BMD in the general population. Controls were free from osteoporosis/osteopenia on all DXA measurements. RESULTS: We included 438 participants: 149 with osteoporosis and 289 controls (median age, 53 years; 82% male, 95% with suppressed HIV RNA). Participants with unfavorable osteoporosis PRS (top vs bottom quintile) had univariable and multivariable-adjusted osteoporosis ORs of 4.76 (95% CI, 2.34-9.67) and 4.13 (1.86-9.18), respectively. For comparison, hepatitis C seropositivity, 5-year tenofovir disoproxil fumarate exposure, and parent history of hip fracture yielded univariable osteoporosis ORs of 2.26 (1.37-3.74), 1.84 (1.40-2.43), and 1.54 (0.82-2.9). CONCLUSIONS: In PLWH in Switzerland, osteoporosis was independently associated with a BMD-associated PRS after adjustment for established risk factors, including exposure to tenofovir disoproxil fumarate.

Clinically relevant bidirectional drug-drug interaction between midostaurin and voriconazole.

Midostaurin is often prescribed with azole antifungals in patients with leukaemia, either for aspergillosis prophylaxis or treatment. Midostaurin is extensively metabolized by cytochrome (CYP) 3A4. In addition, it inhibits and induces various CYPs at therapeutic concentrations. Thus, midostaurin is associated with a high potential for drug-drug interactions (DDIs), both as a substrate (victim) and as a perpetrator. However, data on midostaurin as a perpetrator of DDIs are scarce, as most pharmacokinetic studies have focused on midostaurin as a victim drug. We report a clinically relevant bidirectional DDI between midostaurin and voriconazole during induction treatment. A 49-year-old woman with acute myeloid leukaemia developed invasive pulmonary aspergillosis after induction chemotherapy. She was treated with voriconazole at standard dosage. Six days after starting midostaurin, she developed visual hallucinations with a concurrent sharp increase in voriconazole blood concentration (Ctrough 10.3 mg L-1 , target Ctrough 1-5 mg L-1 ). Neurotoxicity was considered to be related to voriconazole overexposure. The concentration of midostaurin was concomitantly six-fold above the average expected level, but without safety issues. Midostaurin was stopped and the dosage of voriconazole was adjusted with therapeutic drug monitoring. The evolution was favourable, with quick resolution and no recurrence of visual hallucinations. To our knowledge, this is the first case suggesting that midostaurin and voriconazole reciprocally inhibit each other's metabolism, leading to increased exposure of both. This case highlights the knowledge gap regarding drug-drug interactions between midostaurin and azole antifungals. Close clinical and therapeutic drug monitoring is advised in such cases.

Effect of SLCO1B1 c.521T>C polymorphism on the lipid response to statins in people living with HIV on a boosted protease inhibitor-containing regimen.

AIMS: We previously observed that some individuals on HIV boosted protease inhibitor-containing regimen do not achieve their lipid targets despite elevated statin concentrations. This study evaluated whether the common single polymorphism c.521T>C in SLCO1B1, associated with reduced statin uptake in the liver, could explain this observation. METHODS: People living with HIV in the Swiss HIV Cohort Study were eligible if they were on a boosted protease inhibitor concomitantly with a statin for at least 6 months and if their SLCO1B1 genotype was available. Furthermore, their lipids had to be documented before and after the introduction of the statin. The statin efficacy was defined as % change in total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides levels after statin initiation compared to pretreatment levels. Lipid response was adjusted for differences in potency and dose between statins. RESULTS: In total, 88 people living with HIV were included, of whom 58, 28 and 2 carried the SLCO1B1 TT, TC and CC genotypes, respectively. The change in lipid levels after statin initiation tended to be lower in carriers of the polymorphism although the difference was not statistically significant (TT vs. TC/CC: total cholesterol: -11.7 vs. -4.8%; low-density lipoprotein- cholesterol: -20.6 vs. -7.4%; high-density lipoprotein-cholesterol: 1.6 vs. 0%; triglycerides: -11.5 vs. -7.9%). In the multiple linear regression, change in total cholesterol was inversely correlated with the total cholesterol level prestatin treatment (coefficient -6.60, 95% confidence interval: -9.63 to -3.56, P < .001). CONCLUSION: The lipid-lowering effect of statins tended to be attenuated by SLCO1B1 polymorphism and progressively declined as total cholesterol under the boosted protease inhibitor treatment decreased.

Leukocyte Count and Coronary Artery Disease Events in People With Human Immunodeficiency Virus: A Longitudinal Study.

BACKGROUND: People with human immunodeficiency virus (HIV; PWH) have increased cardiovascular risk. Higher leukocyte count has been associated with coronary artery disease (CAD) events in the general population. It is unknown whether the leukocyte-CAD association also applies to PWH. METHODS: In a case-control study nested within the Swiss HIV Cohort Study, we obtained uni- and multivariable odds ratios (OR) for CAD events, based on traditional and HIV-related CAD risk factors, leukocyte count, and confounders previously associated with leukocyte count. RESULTS: We included 536 cases with a first CAD event (2000-2021; median age, 56 years; 87% male; 84% with suppressed HIV RNA) and 1464 event-free controls. Cases had higher latest leukocyte count before CAD event than controls (median [interquartile range], 6495 [5300-7995] vs 5900 [4910-7200]; P < .01), but leukocytosis (>11 000/µL) was uncommon (4.3% vs 2.1%; P = .01). In the highest versus lowest leukocyte quintile at latest time point before CAD event, participants had univariable CAD-OR = 2.27 (95% confidence interval, 1.63-3.15) and multivariable adjusted CAD-OR = 1.59 (1.09-2.30). For comparison, univariable CAD-OR for dyslipidemia, diabetes, and recent abacavir exposure were 1.58 (1.29-1.93), 2.19 (1.59-3.03), and 1.73 (1.37-2.17), respectively. Smoking and, to a lesser degree, alcohol and ethnicity attenuated the leukocyte-CAD association. Leukocytes measured up to 8 years before the event were significantly associated with CAD events. CONCLUSIONS: PWH in Switzerland with higher leukocyte counts have an independently increased risk of CAD events, to a degree similar to traditional and HIV-related risk factors.

Anticholinergic and Sedative Medications Are Associated With Neurocognitive Performance of Well Treated People With Human Immunodeficiency Virus.

Background: We previously showed that anticholinergic (ACH) medications contribute to self-reported neurocognitive impairment (NCI) in elderly people with human immunodeficiency virus (PWH). The current cross-sectional study further evaluated the effect of ACH and sedative drugs on neurocognitive function in PWH who underwent comprehensive neuropsychological evaluation. Methods: A medication review was performed in PWH enrolled in the prospective Neurocognitive Assessment in Metabolic and Aging Cohort within the Swiss HIV Cohort Study. Neurocognitive functions were analyzed in 5 domains (motor skills, speed of information, attention/working memory, executive functions, and verbal learning memory). The effect of ACH and sedative medications on neurocognitive functioning was evaluated using linear regression models for the continuous (mean z-score) outcome and multivariable logistic regression models for the binary (presence/absence) outcome. Results: A total of 963 PWH (80% male, 92% Caucasian, 96% virologically suppressed, median age 52) were included. Fourteen percent of participants were prescribed ≥1 ACH medication and 9% were prescribed ≥1 sedative medication. Overall, 40% of participants had NCI. Sedative medication use was associated with impaired attention/verbal learning and ACH medication use with motor skills deficits both in the continuous (mean z-score difference -0.26 to -0.14, P < .001 and P = .06) and binary (odds ratio [OR], ≥1.67; P < .05) models. Their combined use was associated with deficits in overall neurocognitive functions in both models (mean z-score difference -0.12, P = .002 and OR = 1.54, P = .03). These associations were unchanged in a subgroup analysis of participants without depression (n = 824). Conclusions: Anticholinergic and sedative medications contribute to NCI. Clinicians need to consider these drugs when assessing NCI in PWH.

Practical recommendations to combine small-molecule inhibitors and direct oral anticoagulants in patients with nonsmall cell lung cancer.

BACKGROUND: The risk for thromboembolisms in nonsmall cell lung cancer (NSCLC) patients is increased and often requires treatment or prophylaxis with direct oral anticoagulants (DOACs). Small-molecule inhibitors (SMIs) to treat NSCLC may cause relevant drug-drug interactions (DDIs) with DOACs. Guidance on how to combine these drugs is lacking, leaving patients at risk of clotting or bleeding. Here, we give practical recommendations to manage these DDIs. METHODS: For all DOACs and SMIs approved in Europe and the USA up to December 2021, a literature review was executed and reviews by the US Food and Drug Administration and European Medicines Agency were analysed for information on DDIs. A DDI potency classification for DOACs was composed and brought together with DDI characteristics of each SMI, resulting in recommendations for each combination. RESULTS: Half of the combinations result in relevant DDIs, requiring an intervention to prevent ineffective or toxic treatment with DOACs. These actions include dose adjustments, separation of administration or switching between anticoagulant therapies. Combinations of SMIs with edoxaban never cause relevant DDIs, compared to more than half of combinations with other DOACs and even increasing to almost all combinations with rivaroxaban. CONCLUSIONS: Combinations of SMIs and DOACs often result in relevant DDIs that can be prevented by adjusting the DOAC dosage, separation of administration or switching between anticoagulants.

Magnitude of Drug-Drug Interactions in Special Populations.

Drug-drug interactions (DDIs) are one of the most frequent causes of adverse drug reactions or loss of treatment efficacy. The risk of DDIs increases with polypharmacy and is therefore of particular concern in individuals likely to present comorbidities (i.e., elderly or obese individuals). These special populations, and the population of pregnant women, are characterized by physiological changes that can impact drug pharmacokinetics and consequently the magnitude of DDIs. This review compiles existing DDI studies in elderly, obese, and pregnant populations that include a control group without the condition of interest. The impact of physiological changes on the magnitude of DDIs was then analyzed by comparing the exposure of a medication in presence and absence of an interacting drug for the special population relative to the control population. Aging does not alter the magnitude of DDIs as the related physiological changes impact the victim and perpetrator drugs to a similar extent, regardless of their elimination pathway. Conversely, the magnitude of DDIs can be changed in obese individuals or pregnant women, as these conditions impact drugs to different extents depending on their metabolic pathway.

Implications of Bariatric Surgery on the Pharmacokinetics of Antiretrovirals in People Living with HIV.

Bariatric surgery is increasingly applied among people living with HIV to reduce obesity and the associated morbidity and mortality. In people living with HIV, sufficient antiretroviral exposure and activity should always be maintained to prevent development of resistance and disease progression. However, bariatric surgery procedures bring various gastrointestinal modifications including changes in gastric volume, and acidity, gastrointestinal emptying time, enterohepatic circulation and delayed entry of bile acids. These alterations may affect many aspects of antiretroviral pharmacokinetics. Some drug characteristics may result in subtherapeutic exposure and the potential related risk of treatment failure and resistance. Antiretrovirals that require low pH, administration of fatty meals, longer intestinal exposure, and an enterohepatic recirculation for their absorption may be most impacted by bariatric surgery procedures. Additionally, some antiretrovirals can interact with the polyvalent cations in supplements or drugs inhibiting gastric acid, thereby preventing their use as these comedications are commonly prescribed post-bariatric surgery. Predicting pharmacokinetics on the basis of drug characteristics solely proved to be challenging, therefore pharmacokinetic studies remain crucial in this population. Here, we discuss general implications of bariatric surgery on antiretroviral outcomes in people living with HIV as well as drug properties that are relevant for the choice of antiretroviral treatment in this special patient population. Additionally, we summarise studies that evaluated the pharmacokinetics of antiretrovirals post-bariatric surgery. Finally, we performed a comprehensive analysis of theoretical considerations and published pharmacokinetic and pharmacodynamic data to provide recommendations on antiretrovirals for people living with HIV undergoing bariatric surgery.

Major revision version 11.0 of the European AIDS Clinical Society Guidelines 2021.

BACKGROUND: The European AIDS Clinical Society (EACS) Guidelines were revised in 2021 for the 17th time with updates on all aspects of HIV care. KEY POINTS OF THE GUIDELINES UPDATE: Version 11.0 of the Guidelines recommend six first-line treatment options for antiretroviral treatment (ART)-naïve adults: tenofovir-based backbone plus an unboosted integrase inhibitor or plus doravirine; abacavir/lamivudine plus dolutegravir; or dual therapy with lamivudine or emtricitabine plus dolutegravir. Recommendations on preferred and alternative first-line combinations from birth to adolescence were included in the new paediatric section made with Penta. Long-acting cabotegravir plus rilpivirine was included as a switch option and, along with fostemsavir, was added to all drug-drug interaction (DDI) tables. Four new DDI tables for anti-tuberculosis drugs, anxiolytics, hormone replacement therapy and COVID-19 therapies were introduced, as well as guidance on screening and management of anxiety disorders, transgender health, sexual health for women and menopause. The sections on frailty, obesity and cancer were expanded, and recommendations for the management of people with diabetes and cardiovascular disease risk were revised extensively. Treatment of recently acquired hepatitis C is recommended with ongoing risk behaviour to reduce transmission. Bulevirtide was included as a treatment option for the hepatitis Delta virus. Drug-resistant tuberculosis guidance was adjusted in accordance with the 2020 World Health Organization recommendations. Finally, there is new guidance on COVID-19 management with a focus on continuance of HIV care. CONCLUSIONS: In 2021, the EACS Guidelines were updated extensively and broadened to include new sections. The recommendations are available as a free app, in interactive web format and as an online pdf.

Anticholinergic medication use in elderly people living with HIV and self-reported neurocognitive impairment: a prospective cohort study.

BACKGROUND: Anticholinergic (ACH) medications have been associated with neurocognitive impairment, particularly in the elderly. This study determined prospectively the prevalence of prescribed ACH medications and their association with self-reported neurocognitive impairment (SRNI) in elderly people living with HIV (PLWH) of the Swiss HIV Cohort Study (SHCS). METHODS: A literature review was performed to identify ACH medications, which were scored 0 to 3 (higher score indicating more ACH burden). Prescriptions were reviewed in July 2019 for all SHCS participants ≥65 years old to assess the prevalence of ACH medications. Association between ACH burden and neurocognitive impairment was evaluated using the SHCS SRNI questions addressing memory loss, attention difficulties and slowing in reasoning. RESULTS: One thousand and nineteen PLWH (82% male) with a median age of 70 (IQR = 67-74) years were included. Most participants were on ART (99%). The average number of non-HIV drugs was 5.1 ± 3.6, representing a polypharmacy prevalence of 50%. Two hundred participants (20%) were on ≥1 ACH medication, with an average ACH score of 1.7 ± 1.3. SRNI, adjusted for age, sex, CD4, nadir CD4, viral load, efavirenz use and polypharmacy, was associated with depression (OR = 4.60; 95% CI = 2.62-8.09) and a trend was observed with being on ≥1 ACH medication (OR = 1.69; 95% CI = 0.97-2.95). In a subgroup analysis of participants without depression (n = 911), SRNI was associated with the use of ≥1 ACH medication (OR = 2.51; 95% CI = 1.31-4.80). CONCLUSIONS: ACH medication use is common in elderly PLWH and contributes to SRNI. The effect of ACH medications on neurocognitive impairment warrants further evaluation using neurocognitive tests.

Telomere Length Declines in Persons With Human Immunodeficiency Virus Before Antiretroviral Therapy Start but Not After Viral Suppression: A Longitudinal Study Over >17 Years.

BACKGROUND: In people with human immunodeficiency virus (PWH), long-term telomere length (TL) change without/with suppressive antiretroviral therapy (ART) and the contribution of genetic background to TL are incompletely understood. METHODS: We measured TL change in peripheral blood mononuclear cells by quantitative polymerase chain reaction in 107 Swiss HIV Cohort Study participants with longitudinal samples available both before and during suppressive ART. We applied mixed-effects multilevel regression to obtain uni-/multivariable estimates for longitudinal TL dynamics including age, sex, and CD4/CD8 ratio. We assessed the effect of (1) individual antiretrovirals and (2) an individual TL-polygenic risk score ([TL-PRS] based on 239 single-nucleotide polymorphisms) on TL in 798 additional participants from our previous longitudinal studies. RESULTS: During untreated human immunodeficiency virus (HIV) infection (median observation, 7.7; interquartile range [IQR], 4.7-11] years), TL declined significantly (median -2.12%/year; IQR, -3.48% to -0.76%/year; P = .002). During suppressive ART (median observation, 9.8; IQR, 7.1-11.1 years), there was no evidence of TL decline or increase (median + 0.54%/year; IQR, -0.55% to + 1.63%/year; P = .329). The TL-PRS contributed to TL change (global P = .019) but particular antiretrovirals did not (all P > .15). CONCLUSIONS: In PWH, TL is associated with an individual PRS. Telomere length declined significantly during untreated chronic HIV infection, but no TL change occurred during suppressive ART.

Coronary Artery Disease-Associated and Longevity-Associated Polygenic Risk Scores for Prediction of Coronary Artery Disease Events in Persons Living With Human Immunodeficiency Virus: The Swiss HIV Cohort Study.

BACKGROUND: Coronary artery disease (CAD) is in part genetically determined. Aging is accentuated in people with human immunodeficiency virus (HIV) (PLWH). It is unknown whether genetic CAD event prediction in PLWH is improved by applying individual polygenic risk scores (PRSs) and by considering genetic variants associated with successful aging and longevity. METHODS: In the Swiss HIV Cohort Study participants of self-reported European descent, we determined univariable and multivariable odds ratios (ORs) for CAD events, based on traditional CAD risk factors, adverse antiretroviral exposures, and different validated genome-wide PRSs. PRSs were built from CAD-associated single-nucleotide polymorphisms (SNPs), longevity-associated SNPs, or both. RESULTS: We included 269 patients with CAD events between 2000 and 2017 (median age, 54 years; 87% male; 82% with suppressed HIV RNA) and 567 event-free controls. Clinical (ie, traditional and HIV-related) risk factors and PRSs, built from CAD-associated SNPs, longevity-associated SNPs, or both, each contributed independently to CAD events (P < .001). Participants with the most unfavorable clinical risk factor profile (top quintile) had an adjusted CAD-OR of 17.82 (95% confidence interval [CI], 8.19-38.76), compared with participants in the bottom quintile. Participants with the most unfavorable CAD-PRSs (top quintile) had an adjusted CAD-OR of 3.17 (95% CI, 1.74-5.79), compared with the bottom quintile. After adding longevity-associated SNPs to the CAD-PRS, participants with the most unfavorable genetic background (top quintile) had an adjusted CAD-OR of 3.67 (95% CI, 2.00-6.73), compared with the bottom quintile. CONCLUSIONS: In Swiss PLWH, CAD prediction based on traditional and HIV-related risk factors was superior to genetic CAD prediction based on longevity- and CAD-associated PRS. Combining traditional, HIV-related, and genetic risk factors provided the most powerful CAD prediction.

Clinical Data Combined With Modeling and Simulation Indicate Unchanged Drug-Drug Interaction Magnitudes in the Elderly.

Age-related comorbidities and consequently polypharmacy are highly prevalent in the elderly, resulting in an increased risk for drug-drug interactions (DDIs). The effect of aging on DDI magnitudes is mostly uncertain, leading to missing guidance regarding the clinical DDI management in the elderly. Clinical data obtained in aging people living with HIV ≥ 55 years, who participated in the Swiss HIV Cohort Study, demonstrated unchanged DDI magnitudes with advanced aging for four studied DDI scenarios. These data plus published data for midazolam in the presence of clarithromycin and rifampicin in elderly individuals assessed the predictive potential of the used physiologically-based pharmacokinetic (PBPK) model to simulate DDIs in the elderly. All clinically observed data were generally predicted within the 95% confidence interval of the PBPK simulations. The verified model predicted subsequently the magnitude of 50 DDIs across adulthood (20-99 years) with 42 scenarios being only verified in adults aged 20-50 years in the absence of clinically observed data in the elderly. DDI magnitudes were not impacted by aging regardless of the involved drugs, DDI mechanism, mediators of DDIs, or the sex of the investigated individuals. The prediction of unchanged DDI magnitudes with advanced aging were proofed by 17 published, independent DDIs that were investigated in young and elderly subjects. In conclusion, this study demonstrated by combining clinically observed data with modeling and simulation that aging does not impact DDI magnitudes and thus, clinical management of DDIs can a priori be similar in aging men and women in the absence of severe comorbidities.

Prevalence of Potential Drug-Drug Interactions in Patients of the Swiss HIV Cohort Study in the Era of HIV Integrase Inhibitors.

BACKGROUND: Prevalence of potential drug-drug interactions (PDDIs) between antiretroviral drugs (ARVs) and co-medications was high in 2008 in a Swiss HIV Cohort Study (SHCS) survey. We reassessed the prevalence of PDDIs in the era of human immunodeficiency virus (HIV) integrase inhibitors (INIs), characterized by more favorable interaction profiles. METHODS: The prevalence of PDDIs in treated HIV-positive individuals was assessed for the period 01-12/2018 by linkage of the Liverpool HIV drug interactions and SHCS databases. PDDIs were categorized as harmful (red flagged), of potential clinical relevance (amber flagged), or of weak clinical significance (yellow flagged). RESULTS: In 9298 included individuals, median age was 51 years (IQR, 43-58), and 72% were males. Individuals received unboosted INIs (40%), boosted ARVs (30%), and nonnucleoside reverse transcriptase inhibitor (NNRTIs) (32%)-based regimens. In the entire cohort, 68% received ≥1 co-medication, 14% had polypharmacy (≥5 co-medications) and 29% had ≥1 PDDI. Among individuals with co-medication, the prevalence of combined amber and yellow PDDIs was 43% (33% amber-mostly with cardiovascular drugs-and 20% yellow-flagged PDDIs) compared to 59% in 2008. Two percent had red-flagged PDDIs (mostly with corticosteroids), the same as in the 2008 survey. Compared with 2008, fewer individuals received boosted ARVs (-24%) and NNRTIs (-13%) but the use of co-medications was higher. CONCLUSIONS: Prevalence of PDDIs was lower with more widespread use of INIs in 2018 than in 2008. Continued use of boosted regimens and increasing needs for co-medications in this aging population impeded lower rates of PDDIs.

Recommendations for Dosing of Repurposed COVID-19 Medications in Patients with Renal and Hepatic Impairment.

INTRODUCTION: In December 2019, an outbreak of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began, resulting in a number of antivirals and immune modulators being repurposed to treat the associated coronavirus disease 2019 (COVID-19). Many patients requiring treatment for COVID-19 may have either pre-existing renal or hepatic disease or experience acute renal/hepatic injury as a result of the acute infection. Altered renal or hepatic function can significantly affect drug concentrations of medications due to impaired drug metabolism and excretion, resulting in toxicity or reduced efficacy. The aim of this paper is to review the pharmacokinetics and available study data for the experimental COVID-19 therapies in patients with any degree of renal or hepatic impairment to make recommendations for dosing. METHODS: COVID-19 agents included in these recommendations were listed as primaries on the University of Liverpool COVID-19 drug interaction website ( www.covid19-druginteractions.org ), initially identified from Clinicialtrials.gov and ChicCTR.org.cn. A literature search was performed using PubMed and EMBASE as well as product licences and pharmacokinetic databases. FINDINGS: Remdesivir, dexamethasone, azithromycin, favipiravir, lopinavir/ritonavir, atazanavir, hydroxychloroquine, interferon beta, ribavirin, tocilizumab, anakinra and sarilumab were identified as experimental drugs being used in COVID-19 trials as of November 2020. Limited study data was found for these drugs in patients with renal or hepatic impairment for COVID-19 or other indications. Recommendations were made based on available data, consideration of pharmacokinetic properties (including variability), the dosing and anticipated treatment duration of each regimen in COVID-19 and known toxicities. CONCLUSION: Dosing of drugs used to treat COVID-19 in patients with renal or hepatic impairment is complex. These recommendations were produced to provide guidance to clinicians worldwide who are treating patients with COVID-19, many of whom will have some degree of acute or chronic renal or hepatic impairment.

Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity.

BACKGROUND: The 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. METHODS: Retrospective 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. RESULTS: For 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). CONCLUSIONS: Polypharmacy 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.

Influence of Drug-Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV.

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.