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.

Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation.

Despite effective antiretroviral therapy (ART), persons living with HIV harbor reservoirs of persistently infected CD4+ cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV-specific CD4+ T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute ART initiators would be integrated into antiviral genes, whereas integration sites (ISs) in chronic ART initiators would favor genes associated with cell proliferation and exhaustion. We found that the HIV DNA distribution across HIV-specific versus herpesvirus-specific CD4+ T cells was as hypothesized. HIV ISs in acute ART initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1α-mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. ISs in chronic ART initiators were enriched in a gene set controlling EZH2 histone methylation, and methylation has been associated with diminished long terminal repeat transcription. These differences that we found in antigen specificities and IS distributions within HIV-infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation.

Pioneering cord blood transplantation in relapsed/refractory HIV-related lymphoma: a case study with concurrent intramuscular antiretroviral therapy.

A 44-year-old HIV-positive man diagnosed with diffuse large B-cell lymphoma in 2021 achieved complete remission with six cycles of R-CHOP therapy but had a relapse in November 2022. ESHAP therapy failed to induce remission, leading to complete remission with four cycles of Pola-BR therapy. Post-failure of autologous stem cell harvest, cord blood transplantation (CBT) was performed in June 2023. Notably, this case used recently approved intramuscular antiretroviral therapy (ART) with cabotegravir and rilpivirine, addressing gastrointestinal complications during CBT. This innovative use of intramuscular ART in the treatment of malignancy represents a first in the field, offering a pioneering approach to HIV-related lymphoma.

Cardioprotective effects of early versus late initiated antiretroviral treatment in adolescents with perinatal HIV-1 infection.

Whether, and how, cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) vary with age at treatment initiation is unknown. We used magnetic resonance imaging to compare cardiac status between APHIV initiated on ART at < 5 years of age (early ART, n = 37) and ≥ 5 years of age (delayed ART, n = 34) versus HIV-uninfected peers (n = 21), reporting z-score mean differences adjusted for confounders. Relative to HIV-uninfected adolescents, APHIV with early ART had higher left ventricular (LV) global circumferential strain (GCS) [adjusted mean (95%CI) z-score: 0.53 (0.13, 0.92)] and maximum indexed left atrium volume (LAVi) [adjusted z-score: 0.55 (0.08, 1.02)]. In contrast, APHIV with delayed ART had greater indexed LV end-diastolic volume (LVEDVi) [adjusted z-score: 0.47 (0.09, 0.86)] and extracellular volume fraction [adjusted z-score: 0.79 (0.20, 1.37)], but lower GCS [adjusted z-score: -0.51 (-0.91, -0.10)] than HIV-uninfected peers. APHIV had distinct albeit subclinical cardiac phenotypes depending on ART initiation age. Changes in early ART suggested comparatively worse diastology with preserved systolic function while delayed ART was associated with comparatively increased diffuse fibrosis and LV dilatation with reduced systolic function. The long-term clinical significance of these changes remains to be determined.

Injectable antiretroviral therapy: best practice guide for nurses providing care to people living with HIV.

Oral antiretroviral therapy (ART) is extremely effective, allowing people living with HIV to have a normal life expectancy. Most treatments consist of oral tablets that must be taken at the same time every day for the rest of an individual's life. For a variety of reasons, some people cannot adhere to a daily regimen, resulting in a deterioration in their health. The introduction in 2021 of long-acting injectable ART has provided an alternative option for those who would prefer not to take oral therapy. This article provides an overview of the practicalities and challenges of setting up nurse clinics to administer these injections. It also highlights how this type of treatment has improved the quality of life for people receiving them. HIV nurse specialists are leading the way in delivering this innovative new treatment, and the article concludes by discussing which patients may benefit from injectables in the future. This guide is aimed at nurses who work within the HIV field or are supporting this treatment in other settings, for example in outpatient parenteral antimicrobial therapy (OPAT) services.

Post-intervention perceptions on the antiretroviral therapy community group model in Trans Nzoia County, Kenya.

Introduction: the increasing number of people receiving antiretroviral therapy (ART) in sub-Saharan Africa has stressed already overburdened health systems. A care model utilizing community-based peer-groups (ART Co-ops) facilitated by community health workers (CHW) was implemented (2016-2018) to address these challenges. In 2018, a post-intervention study assessed perceptions of the intervention. Methods: forty participants were engaged in focus group discussions consisting of ART Co-op clients, study staff, and health care providers from Kitale HIV clinic. Data were analyzed thematically for content on the intervention, challenges, and recommendations for improvement. Results: all participants liked the intervention. However, some reported traveling long distances to attend ART Co-op meetings and experiencing stigma with ART Co-ops participation. The ART Co-op inclusion criteria were considered appropriate; however, additional outreach to deliberately include spouses living with HIV, the disabled, the poor, and HIV pregnant women was recommended. Participants liked CHW-directed quarterly group meetings which included ART distribution, adherence review, and illness identification. The inability of the CHW to provide full clinical care, inconvenient meeting venues, poor timekeeping, and non-attendance behaviors were noted as issues. Participants indicated that program continuation, regular CHW training, rotating meetings at group members´ homes, training ART Co-ops leaders to assume CHW tasks, use of pill diaries to check adherence, nutritional support, and economically empowering members through income generation projects would be beneficial. Conclusion: the intervention was viewed positively by both clinic staff and clients. They identified specific challenges and generated actionable key considerations to improve access and acceptability of the community-based model of care.

Antiretroviral Stewardship: Top 10 Questions Encountered by Stewardship Teams and Solutions to Optimize Therapy.

PURPOSE: Infectious disease pharmacists and physicians overseeing antimicrobial stewardship programs possess expertise and often advanced certification in management of antiretrovirals to treat HIV. Stewardship programs are responsible for managing facility formularies and must stay up to date with the latest antiretrovirals, including once daily formulations and depot injectables. Furthermore, stewardship program members need to understand drug-interactions, short-, and long-term toxicities of these regimens, including dyslipidemia and cardiovascular effects. Patients receiving chronic antiretroviral therapy may present to the acute care, ambulatory care, and long-term care settings. Like other antimicrobials, audit-and-feedback, drug monitoring, and dose-optimization are often required to prevent antiretroviral associated medication errors and minimize resistance. METHODS: A narrative review was conducted on antiretroviral stewardship, addressing common clinical questions encountered by stewardship teams and best practices to optimize antiretroviral therapy and reduce the risk for treatment interruptions, resistance, drug interactions, long term toxicities, and other adverse effects. FINDINGS: People living with HIV are often hospitalized and treated by medical teams without formal HIV training. For this reason, these patients are at greater risk for medication errors during hospitalization and between transitions of care. Many opportunities are present for antiretroviral stewardship to mitigate these errors. Frequent updates to simplify HIV regimen, maintain select patients on fixed-dose combination tablets, and strategies to minimize drug interactions make it difficult for even the seasoned clinician to keep up regularly. IMPLICATIONS: Despite the availability of free online HIV resources and progress made in HIV management, significant opportunities for antiretroviral stewardship remain. Implementing electronic order entry updates, formulary upgrades, and formal pharmacy renal dose adjustments to optimize antiretroviral therapy will help clinicians harness these opportunities. Dedicated time and expertise for antiretroviral stewardship as part of local antimicrobial stewardship programs are needed.

Parenteral platforms for tunable, long-acting administration of a highly hydrophobic antiretroviral drug.

GSK2838232 (GSK8232) is a second-generation maturation inhibitor (MI) developed for the treatment of HIV with excellent broad-spectrum virological profiles. The compound has demonstrated promising clinical results as an orally administered agent. Additionally, the compound's physical and pharmacological properties present opportunities for exploitation as long-acting parenteral formulations. Despite unique design constraints including solubility and dose of GSK8232, we report on three effective tunable drug delivery strategies: active pharmaceutical ingredient (API) suspensions, ionic liquids, and subdermal implants. Promising sustained drug release profiles were achieved in rats with each approach. Additionally, we were able to tune drug release rates through a combination of passive and active strategies, broadening applicability of these formulation approaches beyond GSK8232. Taken together, this report is an important first step to advance long-acting formulation development for critical HIV medicines that do not fit the traditional profile of suitable long-acting candidates.

An update on drug-drug interactions in older adults living with human immunodeficiency virus (HIV).

INTRODUCTION: People with HIV are living longer due to advances in antiretroviral therapy. With improved life expectancy comes an increased lifetime risk of comorbid conditions - such as cardiovascular disease and cancer - and polypharmacy. Older adults, particularly those living with HIV, are more vulnerable to drug interactions and adverse effects, resulting in negative health outcomes. AREA COVERED: Antiretrovirals are involved in many potential drug interactions with medications used to treat common comorbidities and geriatric conditions in an aging population of people with HIV. We review the mechanisms and management of significant drug-drug interactions involving antiretroviral medications and non-antiretroviral medications commonly used among older people living with HIV. The management of these interactions may require dose adjustments, medication switches to alternatives, enhanced monitoring, and considerations of patient- and disease-specific factors. EXPERT OPINION: Clinicians managing comorbid conditions among older people with HIV must be particularly vigilant to side effect profiles, drug-drug interactions, pill burden, and cost when optimizing treatment. To support healthier aging among people living with HIV, there is a growing need for antiretroviral stewardship, multidisciplinary care models, and advances that promote insight into the correlations between an individual, their conditions, and their medications.

Avances en el tratamiento de los niños y adolescentes con infección por HIV / Advances in the treatment of children and adolescents with HIV infection

El uso de antirretrovirales (ARV) en el embarazo, el parto y el recién nacido y la aplicación de tratamientos combinados en los niños se han asociado con una disminución del sida en pediatría y el aumento de la sobrevida. La introducción de los inhibidores de integrasa en una dosis diaria ha eliminado barreras para la adherencia, pero los medicamentos orales diarios continúan planteando problemas de privacidad y estigma. Las nuevas tecnologías de administración de los medicamentos y las nuevas drogas junto con la combinación de ARV y los anticuerpos ampliamente neutralizantes (bNAb), ofrecen un potencial de opciones futuras para el tratamiento pediátrico del HIV. Los bNAb son anticuerpos que pueden reconocer diferentes tipos de HIV, bloquear su entrada en las células sanas y ayudar a destruir las células ya infectadas, pueden administrarse por vía parenteral y constituyen un enfoque novedoso y seguro con potencial para el tratamiento y la prevención del HIV, incluida la transmisión vertical. En los lactantes que contraen HIV, los bNAb podrían ofrecer ventajas terapéuticas al reducir el reservorio del virus, mejorar la inmunidad adquirida y, en el futuro, proporcionar un camino hacia la cura funcional. Dentro de los ARV inyectables de acción prolongada, cabotegravir/ rilpivirina se ha incorporado en las guías internacionales de adultos y adolescentes tanto para el tratamiento como para la prevención. A medida que el tratamiento del HIV en adultos va evolucionando, es fundamental asegurar que los neonatos, lactantes, niños y adolescentes tengan acceso a las mejores opciones de tratamiento y prevención a lo largo de su vida (AU)

The use of antiretrovirals (ARVs) during pregnancy, delivery, and in the newborn and the use of combination therapy in children have been associated with a decrease in pediatric AIDS and increased survival. The introduction of once-daily integrase inhibitors has removed barriers to adherence, but daily oral medications continue to pose privacy and stigma issues. New drug delivery technologies and new drugs along with the combination of ARVs and broadly neutralizing antibodies (bNAbs) offer potential future options for pediatric HIV treatment. bNAbs are antibodies that can recognize different types of HIV, block their entry into healthy cells and help destroy already infected cells, can be delivered parenterally, and represent a novel and safe approach with potential for the treatment and prevention of HIV, including mother-to-child transmission. In infants who contract HIV, bNBAs could offer therapeutic advantages by reducing the viral reservoir, enhancing acquired immunity and, in the future, providing a pathway to a functional cure. Within the long-acting injectable ARVs, cabotegravir/rilpivirine has been incorporated into international guidelines for adults and adolescents for both treatment and prevention. As adult HIV treatment evolves, it is critical to ensure that newborns, infants, children and adolescents have access to the best treatment and prevention options throughout their lives (AU)

Development of a physiologically-based pharmacokinetic model to simulate the pharmacokinetics of intramuscular antiretroviral drugs.

There is growing interest in the use of long-acting (LA) injectable drugs to improve treatment adherence. However, their long elimination half-life complicates the conduct of clinical trials. Physiologically-based pharmacokinetic (PBPK) modeling is a mathematical tool that allows to simulate unknown clinical scenarios for LA formulations. Thus, this work aimed to develop and verify a mechanistic intramuscular PBPK model. The framework describing the release of a LA drug from the depot was developed by including both the physiology of the injection site and the physicochemical properties of the drug. The framework was coded in Matlab® 2020a and implemented in our existing PBPK model for the verification step using clinical data for LA cabotegravir, rilpivirine, and paliperidone. The model was considered verified when the simulations were within twofold of observed data. Furthermore, a local sensitivity analysis was conducted to assess the impact of various factors relevant for the drug release from the depot on pharmacokinetics. The PBPK model was successfully verified since all predictions were within twofold of observed clinical data. Peak concentration, area under the concentration-time curve, and trough concentration were sensitive to media viscosity, drug solubility, drug density, and diffusion layer thickness. Additionally, inflammation was shown to impact the drug release from the depot. The developed framework correctly described the release and the drug disposition of LA formulations upon intramuscular administration. It can be implemented in PBPK models to address pharmacological questions related to the use of LA formulations.

Analysis of antiretroviral therapy interruption in people living with HIV during the 2010-2021 period.

INTRODUCTION: In the context of the advancement of antiretroviral therapy and as the characteristics of people living with HIV progress toward an ageing population, understanding the causes of treatment interruption becomes crucial. The aim of the study was to determine the change in reasons for antiretroviral treatment discontinuation for 12 years. Secondarily, compare annual antiretroviral regimen discontinuation rate and factors associated. METHODS: We conducted an analysis using data from people living with HIV who were receiving antiretroviral therapy and discontinued it for any reason. The study included people with HIV infection who visited an outpatient hospital pharmacy clinic from January 2010 to December 2021. Two periods were differentiated for the analysis: 2010-2015 and 2016-2021. The reasons for antiretroviral treatment discontinuation followed classification described by Swiss cohort. In the context of this study, it is pertinent to note that the term "discontinuation" is employed synonymously with "interruption". The term "discontinuation" will be consistently used in this article to refer to the act of switching or stopping antiretroviral treatment. To examine factors associated with antiretroviral therapy discontinuation, we utilised Kaplan-Meier methods and Cox proportional models. RESULTS: We included 789 people living with HIV, predominantly male (81.5%). The main reason for discontinuation was clinical decision (50.2%) followed by adverse effects (37.9%). Focusing on clinical decision, we observed a trend change that went from antiretroviral treatment simplification regimen (56.1%) in the first part of the period analysed to the therapeutic optimisation (53.6%) in the second half. Furthermore, factors that were statistically significantly associated with antiretroviral treatment discontinuation were people with HIV≥50 years (HR 1.60; 95%CI 1.25-2.04), post-discontinuation single-tablet regimen (HR 1.49; 95%CI 1.06-2.11) and antiretroviral drug classes. CONCLUSION: Over the 12 years, there has been a change in the main cause of antiretroviral treatment discontinuation, currently therapeutic optimisation being the main reason. Integrase inhibitors-based regimens and single-tablet regimen strategies were less likely to be discontinued than others antiretroviral drug classes, allowing for better clinical management due to the efficacy profile, especially in people living with HIV≥50 years with comorbidities.

Preexposure Prophylaxis to Prevent Acquisition of HIV: US Preventive Services Task Force Recommendation Statement.

Importance: An estimated 1.2 million persons in the US currently have HIV, and more than 760 000 persons have died of complications related to HIV since the first cases were reported in 1981. Although treatable, HIV is not curable and has significant health consequences. Therefore, effective strategies to prevent HIV are an important public health and clinical priority. Objective: The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of preexposure prophylaxis with antiretroviral therapy for the prevention of HIV acquisition, and the diagnostic accuracy of risk assessment tools to identify persons at increased risk of HIV acquisition. Population: Adolescents and adults who do not have HIV and are at increased risk of HIV. Evidence Assessment: The USPSTF concludes with high certainty that there is a substantial net benefit from the use of effective antiretroviral therapy to reduce the risk of acquisition of HIV in persons at increased risk of acquiring HIV. Recommendation: The USPSTF recommends that clinicians prescribe preexposure prophylaxis using effective antiretroviral therapy to persons at increased risk of HIV acquisition to decrease the risk of acquiring HIV. (A recommendation).

Registro argentino de COVID-19 en VIH (Estudio COVIDARE): características clínicas, epidemiológicas y factores asociados a hospitalización / Argentine Registry of COVID-19 in HIV (COVIDARE Study): clinical and epidemiological characteristics and factors associated with hospitalization

INTRODUCCIÓN: Existe controversia con respecto a los factores que determinan un mayor riesgo de gravedad y complicaciones por COVID-19 en personas que viven con VIH (PVVIH). Asimismo, hay datos limitados sobre el impacto de la vacunación contra SARS-CoV-2 en la hospitalización en esta población. OBJETIVOS: Describir las características clínicas y evolutivas de COVID-19 en PVVIH; Evaluar factores de riesgo para hospitalización; Evaluar el impacto de la vacunación en la hospitalización. Pacientes y MÉTODOS: Estudio observacional, prospectivo, multicéntrico (septiembre de 2020 a junio de 2022). Se registraron variables clínicas, inmunovirológicas, tratamiento antirretroviral (TARV), vacunación contra SARS-CoV-2 y hospitalización en PVVIH con COVID-19. Se realizaron análisis uni y multivariados examinando factores asociados a hospitalización utilizando dos modelos: primer modelo (sin vacunación) y segundo modelo (vacunación, mínimo una dosis). RESULTADOS: Se incluyeron 1.201 PVVIH. La mediana de edad fue 45 años. El 65,3% fueron hombres; el 38,7% presentó comorbilidades. Recibía TARV el 92,8% y presentó carga viral (CV) indetectable el 83,1%. La mediana de linfocitos T CD4+ fue de 600 céls/mm3. El 95,7% presentó síntomas. Las tasas de hospitalización, ingreso a UCI, requerimiento de oxígeno y muerte fueron 17,8%, 2,8%, 10,7% y 1,39%, respectivamente. De acuerdo con el análisis multivariado para el primer modelo, la edad > 60 años y las comorbilidades se asociaron a mayor riesgo de hospitalización, mientras que el sexo femenino y un recuento de linfocitos T CD4+ > 500 céls/mm3 tuvieron un efecto protector. En el segundo modelo sólo las comorbilidades se relacionaron con un mayor riesgo de hospitalización mientras que la vacunación y células CD4+ > 500 céls/mm3 la redujeron. CONCLUSIONES: En PVVIH las comorbilidades se asociaron con mayor tasa de hospitalización, mientras que tener linfocitos T CD4+ elevados y estar vacunado tuvieron un efecto protector. El TARV y la CV no tuvieron impacto en modelo alguno mientras que la edad y el sexo solo influyeron cuando no se consideró la vacunación.

BACKGROUND: There is controversy regarding the factors that determine a greater risk of severity and complications from COVID-19 in people living with HIV (PLHIV). Likewise, there are limited data on the impact of SARS-CoV-2 vaccination on hospitalization in this population. AIMS: To describe clinical characteristics and outcome of COVID-19 in PLHIV; To assess risk factors for hospitalization; To evaluate the impact of vaccination on hospitalization. METHODS: Multicenter, prospective, observational study (September 2020 to June 2022). Clinical and immunovirological variables, antiretroviral treatment (ART), SARS-CoV-2 vaccination, and hospitalization in PLHIV with COVID-19 were recorded. Univariate and multivariate analyzes were performed examining factors associated with hospitalization using two models: first model (without vaccination) and second model (vaccination, minimum one dose). RESULTS: 1,201 PLHIV were included. The median age was 45 years. 65.3% were men; 38.7% presented comorbidities. 92.8% received ART and 83.1% presented undetectable viral load (VL). The median CD4+ T-cell count was 600/mm3. 95.7% presented symptoms. The rates of hospitalization, ICU admission, oxygen requirement, and death were 17.8 %, 2.8%, 10.7% and 1.39%, respectively. According to the multivariate analysis for the first model, age > 60 years and comorbidities were associated with a higher risk of hospitalization, while female sex and CD4+ > 500/mm3 had a protective effect. In the second model, only the comorbidities were associated with a higher risk of hospitalization, while vaccination and CD4+ > 500/mm3 reduced it. CONCLUSIONS: in PLHIV, comorbidities were associated with a higher hospitalization rate, while having elevated CD4+ T-cell counts and being vaccinated had a protective effect. ART and VL had no impact in any model, while age and sex only had an influence when vaccination was not considered.