Protocol of a drug-drug interaction study between bictegravir/emtricitabine/tenofovir alafenamide and feminizing hormones in trans women living with HIV.

AIMS: Trans/transfeminine women are disproportionally affected by HIV. Concerns regarding negative drug-drug interactions (DDIs) between ART drugs and gender-affirming hormone therapy (GAHT), specifically feminizing hormone therapy (FHT), may contribute to the lower ART uptake by trans women with HIV compared with their cis counterparts. The aim of this study is to investigate the bidirectional pharmacokinetic effects of components of FHT regimens (oral oestradiol and androgen-suppressing medications) with the ART regimen (bictegravir/emtricitabine/tenofovir alafenamide [B/F/TAF)]. METHODS: We present a protocol for a three-armed, parallel-group, longitudinal (6-month), DDI study. Group 1 includes 15 3trans women with HIV taking FHT and ART; group 2 includes 15 premenopausal cis women with HIV taking ART; group 3 includes 15 trans women without HIV taking FHT. Women with HIV must be on or switch to B/F/TAF at baseline and be virally suppressed for ≥3 months. Trans women must be taking a stable regimen of ≥2 mg daily oral oestradiol and an anti-androgen (pharmaceutical, and/or surgical, and/or medical) for ≥3 months. Plasma ART drug concentrations will be sampled at Month 2 and compared between groups 1 and 2. Serum oestradiol concentrations will be sampled at baseline and Month 2 visits and compared between groups 1 and 3. The primary outcomes are B/F/TAF pharmacokinetic parameters (Cmin, Cmax and AUC) and oestradiol concentrations (Cmin, C4h, Cmax and AUC) at month 2. DISCUSSION: This study is of global importance as it provides critical information regarding safe coadministration of B/F/TAF and FHT, both of which are life-saving therapies for trans women with HIV.

Consensus recommendations for use of long-acting antiretroviral medications in the treatment and prevention of HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy, Canadian HIV and Viral Hepatitis Pharmacists Network, European AIDS Clinical Society, and Society of Infectious Diseases Pharmacists: An executive summary.

Five long-acting (LA) antiretrovirals (ARVs) are currently available in a limited number of countries worldwide for HIV-1 prevention or treatment - cabotegravir, rilpivirine, lenacapavir, ibalizumab, and dapivirine. Implementing use of LA ARVs in routine clinical practice requires significant changes to the current framework of HIV-1 prevention, treatment, and service provision. Given the novelty, complexity, and interdisciplinary requirements of safe and optimal use of LA ARVs, consensus recommendations on the use of LA ARVs will assist clinicians in optimizing use of these agents. The purpose of these recommendations is to provide guidance for the clinical use of LA ARVs for HIV-1 treatment and prevention. In addition, future areas of research are identified and discussed.

Consensus recommendations for use of long-acting antiretroviral medications in the treatment and prevention of HIV-1: Endorsed by the American Academy of HIV Medicine, American College of Clinical Pharmacy, Canadian HIV and Viral Hepatitis Pharmacists Network, European AIDS Clinical Society, and Society of Infectious Diseases Pharmacists.

Five long-acting (LA) antiretrovirals (ARVs) are currently available in a limited number of countries worldwide for HIV-1 prevention or treatment-cabotegravir, rilpivirine, lenacapavir, ibalizumab, and dapivirine. Implementing use of LA ARVs into routine clinical practice requires significant changes to the current framework of HIV-1 prevention, treatment, and service provision. Given the novelty, complexity, and interdisciplinary requirements needed to safely and optimally utilize LA ARVs, consensus recommendations on the use of LA ARVs will assist clinicians in optimizing use of these agents. The purpose of these recommendations is to provide guidance for the clinical use of LA ARVs for HIV-1 treatment and prevention. In addition, future areas of research are also identified and discussed.

A pharmacist-led interprofessional learning experience for family practice medical residents specializing in HIV care.

We developed a pharmacist-led one-month teaching rotation for medical residents to learn HIV pharmacotherapy. The postgraduate-year-3 residents found this interprofessional learning experience extremely valuable to their future practice in HIV care. The overarching concept of this rotation was for the medical trainee to "become-the-pharmacist," learning to recognize, prevent, and manage drug-related issues in HIV patients. To support medical training in other highly specialized pharmacotherapeutic areas we suggest considering a pharmacist-led interprofessional learning experience.

Nous avons développé un stage d'enseignement sur la pharmacothérapie du VIH guidé par un pharmacien pour les résidents en médecine de troisième année. Ces derniers ont trouvé cette expérience d'apprentissage interprofessionnel extrêmement enrichissante pour leur pratique future en lien avec le traitement du VIH. Le concept au cœur de ce stage d'une durée d'un mois était de mettre les apprenants dans la peau du pharmacien pour qu'ils apprennent à reconnaître, à prévenir et à prendre en charge les problèmes liés à la prise de médicaments chez les patients séropositifs. Nous recommandons des opportunités d'apprentissage interprofessionnel mené par un pharmacien pour appuyer la formation médicale dans d'autres domaines hautement spécialisés de la pharmacothérapie.

Oestradiol concentrations in trans women with HIV suppressed on unboosted integrase inhibitor regimens versus trans women without HIV taking oral oestradiol: a pilot study.

BACKGROUND: Feminizing hormone therapy (FHT) is essential to many trans women. Concern about negative drug interactions between FHT and ART can be an ART adherence barrier among trans women with HIV. OBJECTIVES: In this single-centre, parallel group, cross-sectional pilot study, we measured serum oestradiol concentrations in trans women with HIV taking FHT and unboosted integrase strand transfer inhibitor (INSTI)-based ART versus trans women without HIV taking FHT. METHODS: We included trans women with and without HIV, aged ≥18 years, taking ≥2 mg/day of oral oestradiol for at least 3 months plus an anti-androgen. Trans women with HIV were on suppressive ART ≥3 months. Serum oestradiol concentrations were measured prior to medication dosing and 2, 4, 6 and 8 h post-dose. Median oestradiol concentrations were compared between groups using Wilcoxon rank-sum tests. RESULTS: Participants (n = 8 with HIV, n = 7 without) had a median age of 32 (IQR: 28, 39) years. Among participants, the median oral oestradiol dose was 4 mg (range 2-6 mg). Participants had been taking FHT for a median of 4 years (IQR: 2, 8). Six trans women with HIV were taking bictegravir/emtricitabine/tenofovir alafenamide and two were taking dolutegravir/abacavir/lamivudine. All oestradiol concentrations were not significantly different between groups. Eleven (73%) participants had target oestradiol concentrations in the range 200-735 pmol/L at C4h (75% among women with HIV, 71% among those without HIV). CONCLUSIONS: Oestradiol concentrations were not statistically different in trans women with HIV compared with those without HIV, suggesting a low probability of clinically relevant drug-drug interactions between FHT and unboosted INSTI-based ART.

Feminizing hormone therapy in a Canadian cohort of transgender women with and without HIV.

BACKGROUND: Potential bidirectional drug-drug interactions between feminizing hormone therapy (FHT) and antiretroviral therapy (ART) are of concern for trans women with HIV and their healthcare providers. This study aimed to characterize patterns of FHT and ART among trans women with HIV and to compare serum hormone levels to trans women without HIV. METHODS: Charts of trans women were reviewed at seven HIV primary care or endocrinology clinics in Toronto and Montreal from 2018 to 2019. ART regimens, FHT use, serum estradiol, and serum testosterone levels were compared on the basis of HIV status (positive, negative, missing/unknown). RESULTS: Of 1495 trans women, there were 86 trans women with HIV, of whom 79 (91.8%) were on ART. ART regimens were most commonly integrase inhibitor-based (67.4%), many boosted with ritonavir or cobicistat (45.3%). Fewer (71.8%) trans women with HIV were prescribed FHT, compared to those without HIV (88.4%) and those with missing/unknown status (90.2%, p < 0.001). Among trans women on FHT with recorded serum estradiol (n = 1153), there was no statistical difference in serum estradiol between those with HIV (median: 203 pmol/L, IQR: 95.5, 417.5) and those with negative (200 mol/L [113, 407]) or missing/unknown HIV status (227 pmol/L [127.5, 384.5) (p = 0.633). Serum testosterone concentrations were also similar between groups. CONCLUSIONS: In this cohort, trans women with HIV were prescribed FHT less often than trans women with negative or unknown HIV status. There was no difference in serum estradiol or testosterone levels of trans women on FHT regardless of HIV status, providing reassurance regarding potential drug-drug interactions between FHT and ART.

COVID-19: A Review of Potential Treatments (Corticosteroids, Remdesivir, Tocilizumab, Bamlanivimab/Etesevimab, and Casirivimab/Imdevimab) and Pharmacological Considerations.

Objectives: In light of the ongoing global pandemic, this paper reviews data on a number of potential and approved agents for COVID-19 disease management, including corticosteroids, remdesivir, tocilizumab, and monoclonal antibody combinations. Dose considerations, potential drug-drug interactions, and access issues are discussed. Key findings: Remdesivir is the first antiviral agent approved for the treatment of COVID-19, based on results from large clinical trials showing reduction in recovery time, faster clinical improvement, and decrease in time to discharge with remdesivir. Dexamethasone and tocilizumab have demonstrated mortality benefits in large, randomized controlled trials. Consequently, the use of corticosteroids has become the standard of care for hospitalized patients with severe or critical COVID-19, while tocilizumab is recommended for use in combination with a corticosteroid in certain hospitalized patients. Recently, monoclonal antibody combinations bamlanivimab/etesevimab and casirivimab/imdevimab received emergency use authorizations for use in non-hospitalized patients with mild-to-moderate COVID-19 at high risk of disease progression. Summary: As data from large clinical trials emerge, the paradigm of COVID-19 treatments has shifted significantly. The use of corticosteroids, remdesivir, and tocilizumab depend on disease severity. Emerging data on monoclonal antibody combinations are promising, but further data are required. Pharmacists can play a role in ensuring appropriate access, correct administration, and safe use of COVID-19 treatments and are encouraged to stay abreast of new developments.

Use and safety of appearance and performance enhancing supplements in gay, bisexual, and other men who have sex with men receiving daily tenofovir disoproxil fumarate/emtricitabine as HIV pre-exposure prophylaxis.

Appearance- and performance-enhancing supplements (APES) may be associated with liver and renal toxicity, but use is often under-reported. This study describes the use and safety of APES among gay, bisexual, and other men-who-have-sex with men (gbMSM) attending an urban HIV pre-exposure prophylaxis (PrEP) clinic. A cross-sectional study was conducted between February 2018 to September 2018 to assess APES usage in gbMSM taking daily tenofovir disoproxil fumarate/emtricitabine for PrEP. Renal and liver function were assessed from electronic medical records. Among 50 participants (98% male, median 32 years, 52% White, on PrEP for a median 4.4 years), 72% reported lifetime APES use, with 52% currently using APES (median 1.5 products/person) and 28% never used APES. The most common products included whey protein, creatine supplements and anabolic steroids. The primary reason for APES use was to increase muscle mass. Three (12%) current APES users had elevated serum creatinine (stage 1) versus zero (0%) in the non-APES group. Two (8%) current APES users experienced grade 3-4 ALT/AST elevations versus zero (0%) in the non-APES group. APES usage among gbMSM taking PrEP was high and may be associated with liver/renal lab abnormalities. Increased awareness of APES use and potential toxicity is encouraged to enhance safety.

Polypharmacy-associated risk of hospitalisation among people ageing with and without HIV: an observational study.

BACKGROUND: Polypharmacy, defined as use of five or more medications concurrently, is associated with adverse health outcomes and people ageing with HIV might be at greater risk than similar uninfected individuals. We aimed to determine whether known pairwise drug interactions (KPDIs) were associated with risk of admission to hospital (hereafter referred to as hospitalisation) and medication count among people ageing with and without HIV after accounting for physiological frailty. METHODS: In this observational study, we collected individual-level data for participants of the Veterans Aging Cohort Study (VACS) with HIV on antiretroviral therapy (ART) and with supressed HIV-1 RNA and people without HIV who were receiving at least one prescription medication, based on active medications in the 2009 fiscal year (ie, Oct 1, 2008, to Sept 30, 2009). We identified KPDIs among these patients by linking prescription fill and refill data with data from DrugBank (version 5.0.11). We collected data on all-cause mortality and hospitalisations between Oct 1, 2009, and March 31, 2019. We compared KPDI counts using random selection and actual patterns of use across medication counts from two to 12. We created a weighted KPDI Index on the basis of the average association of each KPDI with mortality among people ageing without HIV and used nested Cox models stratified by HIV status to estimate the association between medication count and hospitalisation, with incremental adjustments for demographics, physiological frailty, and KPDI Index. FINDINGS: We collected data for 9186 people ageing with HIV and 37 930 individuals without HIV. 45 913 (97·4%) of 47 116 patients were men and the sample was predominantly aged 50-64 years (30 413 [64·6%]). Compared with a random sample of medications, real-world pattern of medication counts and combinations were associated with five-to-six times more KPDIs (eg, for a combination of six medications, KPDI count was 1·09 in the random sample, 5·49 in the HIV-negative population, and 7·13 in the HIV-positive population). For each additional observed medication, people ageing with HIV had approximately 2·94 additional KPDIs and comparators had approximately 2·67 additional KPDIs. Adjustment for demographics, physiological frailty, and KPDI Index reduced the association between medication count and risk of hospitalisation for people ageing with HIV (hazard ratio 1·08 [95% CI 1·07-1·09] reduced to 1·06 [1·05-1·07]) and those without HIV (1·08 [1·07-1·08] reduced to 1·04 [1·03-1·05]). INTERPRETATION: For each additional medication, people ageing with HIV have more drug-drug interactions than those without HIV. Adjusting for known non-ART drug-drug interactions, each additional non-ART medication confers excess risk of hospitalisation for people ageing with HIV. Randomised trials will be needed to determine whether reducing these interactions improves outcomes. FUNDING: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Department of Veterans Affairs Health Services Research & Development, and Office of Research and Development.

An update on neuropsychiatric adverse effects with second-generation integrase inhibitors and nonnucleoside reverse transcriptase inhibitors.

PURPOSE OF REVIEW: Neuropsychiatric adverse effects (NPAE) associated with integrase strand transfer inhibitors (INSTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a growing concern, with higher rates in the real-world compared to phase III trials. This paper reviews the incidence, risk factors, and management of NPAE with second-generation INSTIs, INSTI/rilpivirine dual therapy, and doravirine. RECENT FINDINGS: Recent cohort data confirm up to 8% NPAE-associated discontinuations for dolutegravir; NPAE with dolutegravir/rilpivirine therapy are higher than with dolutegravir alone, whereas bictegravir appears similar to dolutegravir. In contrast, NPAE with cabotegravir alone or with rilpivirine appears to be low. Doravirine has NPAE rates similar to rilpivirine and lower than efavirenz. Risk factors for NPAE include female gender, concurrent abacavir use, Sub-Saharan African descent, and age, whereas underlying psychiatric conditions do not appear to increase risk. Strategies to manage NPAE include changing administration time, therapeutic drug monitoring, or regimen modification including within-class INSTI changes. People experiencing NPAE with dolutegravir may tolerate bictegravir. SUMMARY: Overall, mild to moderate NPAE are associated with INSTIs and newer NNRTIs. Rarely, more severe symptoms may occur and lead to treatment discontinuation. Clinicians should be aware of NPAE to identify and manage drug-related adverse effects.

The intersection of drug interactions and adverse reactions in contemporary antiretroviral therapy.

PURPOSE OF REVIEW: Advances in antiretroviral therapy (ART) have transformed HIV infection into a chronic and manageable condition. The introduction of potent and more tolerable antiretrovirals (ARVs) with favorable pharmacokinetic profiles has changed the prevalence and nature of drug-drug interactions (DDIs). Here, we review the relevance of DDIs in the era of contemporary ART. RECENT FINDINGS: Management of DDIs remains an important challenge with modern ART, primarily due to increased polypharmacy in older persons living with HIV. Significant DDIs exist between boosted ARVs or older nonnucleoside reverse transcriptase inhibitors and comedications for chronic comorbidities (e.g., anticoagulants, antiplatelets, statins) or complex conditions (e.g., anticancer agents, immunosuppressants). Newer ARVs such as unboosted integrase inhibitors, doravirine, and fostemsavir have reduced DDI potential, but there are clinically relevant DDIs that warrant consideration. Potential consequences of DDIs include increased toxicity and/or reduced efficacy of ARVs and/or comedications. Management approaches include switching to an ARV with less DDI potential, changing comedications, or altering medication dosage or dosing frequency. Deprescribing strategies can reduce DDIs and polypharmacy, improve adherence, minimize unnecessary adverse effects, and prevent medication-related errors. SUMMARY: Management of DDIs requires close interdisciplinary collaboration from multiple healthcare disciplines (medicine, nursing, pharmacy) across a spectrum of care (community, outpatient, inpatient).

A practical clinical guide to counselling on and managing contraception, pre-conception planning, and menopause for women living with HIV.

Background: Women represent one quarter of the population living with HIV in Canada and are an increasingly important sector of the HIV community. While some women's health issues such as cervical cancer screening and management are well addressed in HIV management guidelines, others are not. These include sexual and reproductive health factors such as contraception, pre-conception planning, and menopause. Existing literature has shown that while women living with HIV in Canada receive good HIV care based on HIV care cascade indicators, their women's health and sexual and reproductive health care needs are not being met. Methods: In this article, we present a clinical guide for clinicians providing care for women living with HIV on three key women's health topics that are under-discussed during HIV care visits: (1) contraception, (2) pre-conception planning, and (3) menopause. Results: We have summarized the most pertinent clinical factors on each topic to support straightforward counselling and present important considerations in the context of HIV-related diseases and treatment. Finally, when relevant, we have provided practical stepwise approaches for addressing each of these women's health care topics when seeing a patient during a visit. Conclusions: It is important that HIV specialists stay well-versed in the complex clinical interactions between HIV treatment and management of women's health issues.

Historique: Les femmes forment le quart de la population qui vit avec le VIH au Canada et un segment croissant de la communauté du VIH. Certains problèmes de santé des femmes, comme le dépistage et la prise en charge du cancer du col de l'utérus, sont bien couverts dans les directives sur la prise en charge du VIH, mais d'autres non. Des facteurs liés à la santé sexuelle et reproductive, tels que la contraception, la planification avant la conception et la ménopause, en font partie. Les publications scientifiques ont démontré que les femmes qui vivent avec le VIH au Canada reçoivent de bons soins du VIH en fonction des indicateurs de soins du VIH ventilés en cascade, mais que leurs besoins en matière de santé des femmes, de santé sexuelle et de santé reproductive ne sont pas respectés. Méthodologie: Dans le présent article, les auteurs proposent un guide clinique à l'intention des cliniciens qui soignent des femmes atteintes du VIH, à l'égard de trois sujets en santé des femmes qui ne sont pas assez abordés pendant les rendez-vous sur les soins du VIH : 1) la contraception, 2) la planification avant la conception et 3) la ménopause. Résultats: Les auteurs ont résumé les facteurs cliniques les plus appropriés relatifs à chaque sujet pour favoriser un counseling franc et présentent des points de vue importants dans le contexte des maladies et des traitements liés au VIH. Enfin, lorsque c'est approprié, ils ont fourni une démarche pratique graduelle pour aborder chacun de ces sujets en santé des femmes lors d'un rendez-vous. Conclusions: Il est important que les spécialistes du VIH demeurent bien informés des interactions cliniques complexes entre le traitement du VIH et la prise en charge des problèmes de santé des femmes.

Drug Interactions with Gender-Affirming Hormone Therapy: Focus on Antiretrovirals and Direct Acting Antivirals.

INTRODUCTION: Gender-affirming care may include hormonal therapy to attain desired health outcomes in transgender (trans) individuals. To provide safe, affirming medical care for trans patients, health care providers must identify and manage drug-drug interactions (DDIs) between gender affirming hormonal therapy (GAHT) and other medication therapies. AREAS COVERED: This review summarizes available data on DDIs between GAHT and antiretrovirals (ARVs) or hepatitis C direct acting antivirals (DAAs). Potential pharmacokinetic and pharmacodynamic DDIs are predicted based on GAHT, ARV, and DAA pharmacology and adverse event profiles. Clinical management strategies are discussed. EXPERT OPINION: GAHT may be involved in pharmacokinetic and/or pharmacodynamic DDIs. Certain ARV classes (non-nucleoside reverse transcriptase inhibitors, protease inhibitors) may alter GAHT disposition, whereas selected ARVs (unboosted integrase inhibitors, doravirine, or rilpivirine) may have less impact on GAHT. DAAs may interact with GAHT, but the clinical relevance is unclear. ARV- and/or DAA-associated side effects (including depression, cardiovascular disease, hyperlipidemia) are important to consider in the clinical management of trans patients. Clinicians must evaluate potential DDIs and overlapping side effects between ARVs, DAAs and GAHT when providing care for trans patients.