Immune System Diseases Commons^™

Self-Assembly Of Anti-Inflammatory Peptide Amphiphiles For Mucosal Health, Maria José Gómara, Ignacio Pérez-Pomeda, Ramon Pons, Paul Ziprin, Carolina Herrera, Isabel Haro

CONRAD Publications

Broad spectrum anti-inflammatory peptide amphiphiles (AIF-PAs) have been developed as an innovative strategy for the treatment of chronic mucosal inflammation and the prevention of HIV transmission. Novel lipopeptides based on two linear sequences of anti-inflammatory peptides were obtained by solid-phase peptide chemistry. In a pilot study, ex vivo exposure of colorectal tissue explants from Crohn's disease patients to AIF-PAs induced a downregulation of the proinflammatory profile. Furthermore, the HIV inhibitory potency of AIF-PAs was evaluated ex vivo in colorectal tissue explants, obtaining sub-micromolar IC₅₀ values. Characterization of AIF-PAs self-aggregation in aqueous solution revealed that the net charge distribution within the …

Predicting Oral Hiv Pre-Exposure Prophylaxis Efficacy In Cisgender Women Across Pregnancy And Postpartum, Yifan Yu, Kristina M. Brooks, Gustavo F. Doncel, Brookie M. Best, Mark A. Marzinke, Mark Mirochnick, Peter L. Anderson, Landon Myer, Connie Celum, Renee Heffron, Jenell Coleman, Dvora L. Joseph Davey, Lanxin Zhang, Max Von Kleist, Craig W. Hendrix, Jeremiah D. Momper, Robert Bies, Rachel K. Scott

CONRAD Publications

Cisgender women face an increased risk of HIV acquisition during pregnancy and postpartum. Oral pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate (F/TDF) is recommended in pregnancy despite limited published pharmacokinetic (PK) and efficacy data during pregnancy. Altered PK during pregnancy may reduce prophylactic efficacy and necessitate higher adherence. Tenofovir alafenamide (TAF) is a newer tenofovir prodrug with higher tenofovir diphosphate (TFV-DP) exposure in peripheral blood mononuclear cells (PBMCs), but the prophylactic efficacy of F/TAF across different reproductive stages in women is understudied. We adapted a multiscale modeling framework to predict the prophylactic efficacy of F/TDF and F/TAF across …

Development Of A Semi-Mechanistic Population Pharmacokinetic Model For Predicting Tenofovir Disoproxil Fumarate And Tenofovir Alafenamide Exposure In Plasma And Cellular Matrices During Pregnancy And Postpartum, Yifan Yu, Kristina M. Brooks, Gustavo F. Doncel, Brookie M. Best, Mark A. Marzinke, Mark Mirochnick, Peter Anderson, Landon Myer, Connie Celum, Renee Heffron, Jenell Coleman, Dvora Joseph Davey, Craig W. Hendrix, Jeremiah D. Momper, Robert Bies, Rachel K. Scott

CONRAD Publications

Background and Objective

Tenofovir (TFV)-based regimens are backbones of both HIV treatment and pre-exposure prophylaxis during pregnancy. Multiple studies have shown up to one-third decreases in dried blood spot tenofovir-diphosphate concentrations during pregnancy among participants taking tenofovir disoproxil fumarate (TDF). Currently, there are no mechanism-based models describing the pharmacokinetics of tenofovir diphosphate (the active anabolite) in peripheral blood mononuclear cells (PBMCs) of pregnant individuals receiving TDF or tenofovir alafenamide (TAF), and the mechanisms behind observed differences between dried blood spots and PBMCs remain unclear.

Methods

To address this gap, we developed a semi-mechanistic model to simultaneously describe the pharmacokinetics of …

A Comparison Of F/Taf And F/Tdf As Hiv Pre-Exposure Prophylaxis In A Predominantly Cisgender Women Population In East And South Africa: A Randomised, Factorial, Non-Inferiority Trial, Sheena Mccormack, David Dunn, Sylvia Kusemererwa, Patricia Munseri, Nishanta Singh, Wiston William, Gertrude Mutonyi, Henry Bern, Lauriane Goldwirt, Cherry Kingsley, Arne Kkroidl, Christian Holm Hansen, Song Ding, Rachel Kawuma, Mary Amondi, Ubaldo Bahemuka, Deus Buma, Daniel Clutterbuck, Zakir Gaffoor, Angus Jennings, Agricola Joachim, Ayoub Kakande, Berna Kalanzi, Abisai Kisinda, Mabela Matsoso, Thomas Miller, Neetha Mmedsci Morar, Jacqueline Musau, Jane Nabbuto, Ayanda Nzuza, Doreen Pamba, Simona Salomone, Thandiwe Sithole, Edith Tarimo, Kubashni Woeber, Kundai Chinyenze, Glenda Gray, Eligius Lyamuya, Muhammad Bakari, Said Aboud, Lucas Maganga, Gustavo Doncel, Janet Seeley, Jonathan Weber, Pontiano Kaleebu, Julie Fox, Eugene Ruzagira, On Behalf Of The Prepvacc Study Group

CONRAD Publications

Background:

F/TAF was shown to be non-inferior to F/TDF as pre-exposure prophylaxis (PrEP) in men, but approval was not extended to cisgender women. We report the results of PrEPVacc, in which a predominantly female population was randomly allocated to receive daily oral F/TDF or F/TAF for ∼6 months within a HIV-1 prophylactic vaccine trial.

Setting:

Five study sites in three African countries (Uganda, Tanzania, South Africa).

Methods:

The two regimens were compared by the averted infections ratio (AIR) - the proportion of infections averted by F/TAF relative to F/TDF. The counterfactual HIV incidence, an essential component of this metric, was …

Longitudinal Changes In Plasma Biomarkers Of Immune Activation, Neuronal Inflammation And Injury In Persons With Hiv Initiating Art, Merle Henderson, Peter Dutey-Magni, Carolina Herrera, Wolfgang Stöhr, Alejandro Arenas-Pinto, Owen Swann, Amanda Heslegrave, Henrik Zetterberg, John Tregoning, Sarah Fidler, François Raffi, Andrea Calcagno, Ab Babiker, Alan Winston

CONRAD Publications

Background

Data on changes in biomarkers of brain health, and their associations with cognitive function in adults commencing either dual- or triple-antiretroviral therapy (ART) are sparse.

Methods

Plasma biomarkers (neurofilament light [NfL], glial fibrillary acidic protein [GFAP], sCD14, CXCL10, neopterin and IL-6) were measured at baseline and after 96 weeks on ART in individuals randomized to darunavir/ritonavir and either tenofovir-DF/emtricitabine (triple-ART, n = 119) or raltegravir (dual-ART, n = 119) in NEAT-001/ANRS143. Regression models examined associations of baseline and week-96 biomarker concentrations with HIV clinical parameters, composite cognitive test scores (Standardized neuropsychological test [NPZ], 7-domains) and treatment arm.

Results

In …

Formulation Development Of Topical Inserts Containing Doxycycline And Doxycycline Combined With Tenofovir Alafenamide And Elvitegravir For The Prevention Of Sexually Transmitted Infections, Vivek Agrahari, M. Melissa Peet, Jasmin Monpara, Rijo John, Sriramakamal Jonnalagadda, Pardeep K. Gupta, Meredith R. Clark, Gustavo F. Doncel

CONRAD Publications

Despite advances in oral and injectable HIV prevention options and oral prophylaxis for sexually transmitted infections (STIs) of bacterial origin, there remains a critical need for effective on-demand topical (vaginal and rectal) products for pre- and post-exposure prophylaxis (PrEP and PEP). To fill this gap, we have developed single and first-in-kind multi-active topical inserts for bacterial STIs and HIV/STIs prevention. We have formulated two different inserts, one containing doxycycline (DOX) at 10, 50, and 100 mg doses for bacterial STI prevention, and a multipurpose prevention product (TED insert) that combines DOX (10 mg) with the antiretrovirals tenofovir alafenamide (TAF; 20 …

Partial Post-Exposure Protection By Topical Inserts Containing Tenofovir Alafenamide Fumarate/Elvitegravir In A Macaque Model Of Rectal Simian Hiv (Shiv) Infection, Natalia Makarova, Tyana Singletary, M. Melissa Peet, Kristen Kelley, Ryan Johnson, Vivek Agrahari, Maria Mendoza, Yi Pan, Walid Heneine, Meredith R. Clark, J. Gerardo García Lerma, Gustavo F. Doncel, James W. Smith

CONRAD Publications

On-demand topical inserts for HIV prevention may be a good option for people who have a low frequency of sexual activity. We recently demonstrated in a preclinical macaque model that rectal application of inserts containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) conferred protection against SHIV infection (93% efficacy) when applied as pre-exposure prophylaxis 4 hours before SHIV exposure. Here, we show that the same inserts provide significant postexposure protection (82.9% efficacy) when applied 4 hours after SHIV exposure. Our findings further support the ongoing clinical development of TAF/EVG inserts for on-demand HIV prevention.