Long-Acting HIV Drugs for Treatment and Prevention

2019 ◽  
Vol 70 (1) ◽  
pp. 137-150 ◽  
Author(s):  
Roy M. Gulick ◽  
Charles Flexner
Keyword(s):  
Drug Regimen ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Phase Iii ◽  
Treatment And Prevention ◽  
Drug Concentrations ◽  
Phase Iii Trials ◽  
Long Acting ◽  
Hiv Drugs ◽  
Exposure Prophylaxis

Antiretroviral drugs have revolutionized the treatment and prevention of HIV infection; however, adherence is critical for sustained efficacy. Current HIV treatment consists of three-drug regimens, and current HIV pre-exposure prophylaxis (PrEP) consists of a two-drug regimen; both generally require adherence to once-daily dosing. Long-acting formulations are useful in the treatment and prevention of other conditions (e.g., contraceptives, antipsychotics) and help promote adherence. Newer long-acting formulations of approved and investigational antiretroviral drugs in existing and newer mechanistic classes are under study for HIV treatment and prevention, including some phase III trials. Although long-acting antiretroviral drugs hold promise, some clinical challenges exist, including managing side effects, drug-drug interactions, pregnancy, and long-lasting drug concentrations that could lead to the development of drug resistance. This review aims to summarize currently available information on long-acting antiretroviral drugs for HIV treatment and prevention.

scholarly journals The Potential Impact of Long-Acting Cabotegravir for HIV Prevention in South Africa: A Mathematical Modeling Study

2020 ◽  
Author(s):  
Jennifer A Smith ◽  
Geoffrey P Garnett ◽  
Timothy B Hallett
Keyword(s):  
South Africa ◽  
Hiv Risk ◽  
Adult Population ◽  
Phase Iii ◽  
Substantial Impact ◽  
Hiv Epidemic ◽  
Phase Iii Trials ◽  
Long Acting ◽  
Exposure Prophylaxis ◽  
The Impact

Abstract Background Although effective, some oral pre-exposure prophylaxis (PrEP) users face barriers to adherence using daily pills, which could be reduced by long-acting formulations. Long-acting cabotegravir (CAB LA) is a potential new injectable formulation for human immunodeficiency virus (HIV) PrEP being tested in phase III trials. Methods We use a mathematical model of the HIV epidemic in South Africa to simulate CAB LA uptake by population groups with different levels of HIV risk. We compare the trajectory of the HIV epidemic until 2050 with and without CAB LA to estimate the impact of the intervention. Results Delivering CAB LA to 10% of the adult population could avert more than 15% of new infections from 2023 to 2050. The impact would be lower but more efficient if delivered to populations at higher HIV risk: 127 person-years of CAB LA use would be required to avert one HIV infection within 5 years if used by all adults and 47 person-years if used only by the highest risk women. Conclusions If efficacious, a CAB LA intervention could have a substantial impact on the course of the HIV epidemic in South Africa. Uptake by those at the highest risk of infection, particularly young women, could improve the efficiency of any intervention.

scholarly journals Treatment with commonly used antiretroviral drugs induces a type I/III interferon signature in the gut in the absence of HIV infection

2019 ◽  
Author(s):  
Sean M. Hughes ◽  
Claire N. Levy ◽  
Fernanda L. Calienes ◽  
Joanne D. Stekler ◽  
Urvashi Pandey ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Cellular Proliferation ◽  
Rectal Biopsy ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Type I ◽  
Treatment And Prevention ◽  
Tenofovir Gel ◽  
Droplet Pcr ◽  
Exposure Prophylaxis

AbstractTenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here we assessed the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induced type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r=0.91) and between the rectum and duodenum (r=0.81). Gene set testing also indicated stimulation of type I/III pathways in the ectocervix, as well as of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence staining confirmed IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN-I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.

scholarly journals The Promise of Improved Adherence With Long-Acting Antiretroviral Therapy: What Are the Data?

2021 ◽  
Vol 20 ◽  
pp. 232595822110090
Author(s):  
Kimberly K. Scarsi ◽  
Susan Swindells
Keyword(s):  
Medication Adherence ◽  
Antiretroviral Therapy ◽  
Hiv Treatment ◽  
Virologic Suppression ◽  
Social Barriers ◽  
Treatment And Prevention ◽  
Undetectable Viremia ◽  
Long Acting ◽  
Available Information ◽  
Living With Hiv

As with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers. Unfortunately, high levels of adherence to antiretroviral therapy are required to maintain virologic suppression. Alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products. Phase 3 data support the efficacy of nanoformulated injectable cabotegravir and rilpivirine for HIV treatment in patients with undetectable viremia, but we have yet to learn how this strategy may benefit those with medication adherence challenges. Despite this, the affected community and HIV providers are very interested in exploring the role of long-acting therapies to address some types of barriers to medication adherence. This review summarizes available information about the potential for long-acting therapy to improve adherence for some patients and outlines associated opportunities and challenges with the implementation of long-acting therapy for the treatment and prevention of HIV.

scholarly journals Tonse Pamodzi: Developing a combination strategy to support adherence to antiretroviral therapy and HIV pre-exposure prophylaxis during pregnancy and breastfeeding

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0253280
Author(s):  
Lauren M. Hill ◽  
Friday Saidi ◽  
Kellie Freeborn ◽  
K. Rivet Amico ◽  
Nora E. Rosenberg ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Intervention Development ◽  
Hiv Treatment ◽  
Child Health Services ◽  
Maternal Child Health ◽  
Combination Strategy ◽  
Antiretroviral Adherence ◽  
Treatment And Prevention ◽  
Adherence Support ◽  
Exposure Prophylaxis

To eliminate mother-to-child transmission of HIV (EMTCT), scalable strategies to enhance antiretroviral adherence for both antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) are needed as part of integrated HIV and maternal-child health services. We developed Tonse Pamodzi (“all of us together”), an adaptable intervention integrating biomedical and behavioral components to support HIV treatment and prevention. We describe our intervention development process, which comprised formative qualitative research, a review of the literature, and technical input from stakeholders representing the community, health systems, and policymakers. The resulting intervention, described herein, integrates patient-centered counseling and engagement of a patient-selected adherence supporter for pregnant and breastfeeding women initiating ART or PrEP. Patients receiving the intervention engage in Integrated Next Step Counseling (iNSC) sessions delivered by trained counselors to build and maintain adherence skills. Each patient also has the option of selecting an adherence supporter (partner, family member, or friend) who may participate in iNSC sessions and provide adherence support outside of these sessions. This flexible intervention is adaptable not only to ART or PrEP use, but also to the needs and preferences of each woman and the clinical context. If shown to be acceptable and feasible, the Tonse Pamodzi intervention may be an important tool in continuing efforts for EMTCT.

scholarly journals Ultra-long-acting removable drug delivery system for HIV treatment and prevention

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Martina Kovarova ◽  
S. Rahima Benhabbour ◽  
Ivana Massud ◽  
Rae Ann Spagnuolo ◽  
Brianna Skinner ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Delivery System ◽  
Hiv Treatment ◽  
Treatment And Prevention ◽  
Long Acting

scholarly journals Long-Acting Anti-HIV Drugs Targeting HIV-1 Reverse Transcriptase and Integrase

2019 ◽  
Vol 12 (2) ◽  
pp. 62 ◽  
Author(s):  
Kamal Singh ◽  
Stefan G. Sarafianos ◽  
Anders Sönnerborg
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Reverse Transcriptase ◽  
Treatment Regimens ◽  
Drug Concentrations ◽  
The Status ◽  
Long Acting ◽  
Major Factors ◽  
Hiv Drugs ◽  
Hiv 1

One of the major factors contributing to HIV-1 drug resistance is suboptimal adherence to combination antiretroviral therapy (cART). Currently, recommended cART for HIV-1 treatment is a three-drug combination, whereas the pre-exposure prophylaxis (PrEP) regimens consist of one or two antivirals. Treatment regimens require adherence to a once or twice (in a subset of patients) daily dose. Long-acting formulations such as injections administered monthly could improve adherence and convenience, and thereby have potential to enhance the chances of expected outcomes, although long-lasting drug concentrations can also contribute to clinical issues like adverse events and development of drug resistance. Globally, two long-acting antivirals have been approved, and fifteen are in clinical trials. More than half of investigational long-acting antivirals target HIV-1 reverse transcriptase (HIV-1 RT) and/or integrase (HIV-1 IN). Here, we discuss the status and potential of long-acting inhibitors, including rilpivirine (RPV), dapivirine (DPV), and 4-ethynyl-2-fluoro-2-deoxyadenosine (EFdA; also known as MK-8591), which target RT, and cabotegravir (CAB), which targets IN. The outcomes of various clinical trials appear quite satisfactory, and the future of long-acting HIV-1 regimens appears bright.

scholarly journals Expanded access use of rezafungin for salvage therapy of invasive Candida glabrata infection: A case report

2021 ◽  
Author(s):  
Alina Adeel ◽  
Ming D Qu ◽  
Efaza Siddiqui ◽  
Stuart M Levitz ◽  
Richard T Ellison
Keyword(s):  
Candida Glabrata ◽  
Graft Infection ◽  
Multidrug Resistant ◽  
Phase Iii ◽  
Vascular Graft Infection ◽  
Expanded Access ◽  
Mediastinal Infection ◽  
Phase Iii Trials ◽  
One Year ◽  
Long Acting

Abstract Rezafungin is a semi-synthetic, long acting echinocandin with broad spectrum activity against many Candida species (spp)., and Aspergillus spp., including subset of drug-resistant strains. It is currently in phase III trials and was found to be safe and effective for treatment of candidemia and/or invasive Candida infections in a phase II trial. However, there are no long-term safety or efficacy data. We report on the successful ongoing compassionate use of rezafungin obtained through expanded access for over one year in a patient with a multidrug-resistant Candida glabrata mediastinal infection from a vascular graft infection and retained foreign material.

scholarly journals Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
S. Rahima Benhabbour ◽  
Martina Kovarova ◽  
Clinton Jones ◽  
Daijha J. Copeland ◽  
Roopali Shrivastava ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Plasma Concentrations ◽  
Chemical Properties ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Sustained Drug Delivery ◽  
Wide Range ◽  
One Year ◽  
Long Acting ◽  
Multiple Drugs

Abstract Here we report an ultra-long-acting tunable, biodegradable, and removable polymer-based delivery system that offers sustained drug delivery for up to one year for HIV treatment or prophylaxis. This robust formulation offers the ability to integrate multiple drugs in a single injection, which is particularly important to address the potential for drug resistance with monotherapy. Six antiretroviral drugs were selected based on their solubility in N-methyl-2-pyrrolidone and relevance as a combination therapy for HIV treatment or prevention. All drugs released with concentrations above their protein-adjusted inhibitory concentration and retained their physical and chemical properties within the formulation and upon release. The versatility of this formulation to integrate multiple drugs and provide sustained plasma concentrations from several weeks to up to one year, combined with its ability to be removed to terminate the treatment if necessary, makes it attractive as a drug delivery platform technology for a wide range of applications.

scholarly journals Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Stephanie E. Barrett ◽  
Ryan S. Teller ◽  
Seth P. Forster ◽  
Li Li ◽  
Megan A. Mackey ◽  
...  
Keyword(s):  
Health Care Providers ◽  
Single Agent ◽  
Hiv Treatment ◽  
Oral Drug ◽  
Drug Candidate ◽  
Care Providers ◽  
Sustained Drug Release ◽  
Treatment And Prevention ◽  
Extended Duration ◽  
Long Acting

ABSTRACT Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence. MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine [EFdA]) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for preexposure prophylaxis (PrEP). The active triphosphate of MK-8591 (MK-8591-TP) exhibits protracted intracellular persistence and, together with the potency of MK-8591, supports its consideration for extended-duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release in vitro and in vivo. Implants, administered subcutaneously, were studied in rodents and nonhuman primates to establish MK-8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models, as well as data generated in phase 1a (Ph1a) and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels, resulting in a 1.6-log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.

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