Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

Concepts and System Design for the Rate-Controlled Drug Delivery Fundamentals of Rate-Controlled Drug Delivery Oral Drug Delivery and Delivery Systems Mucosal Drug Delivery: Potential Routes for Noninvasive Systemic Administration Nasal Drug Delivery and Delivery Systems Ocular Drug Delivery and Delivery Systems Transdermal Drug Delivery and Delivery Systems Parenteral Drug Delivery and Delivery Systems Vaginal Drug Delivery and Delivery Systems Intrauterine Drug Delivery and Delivery Systems Systemic Delivery of Peptide-Based Pharmaceuticals Regulatory Considerations in Controlled Drug Delivery

Antiretroviral therapies have proved life-saving in HIV infection, dramatically reducing morbidity and mortality.With longer survival, morbidities and mortalities in HIV infection are increasingly similar to the morbidities and mortalities associated with ageing.In treated HIV infection, the risk of these morbidities and mortalities is linked to immune activation, inflammation and coagulation indices.And in persons with treated HIV infection, failure to restore circulating CD4 T cell numbers is associated with a greater risk of morbidities and mortalities as well as to heightened levels of inflammation and coagulation.The drivers of immune activation, inflammation and coagulation in treated HIV infection are incompletely defined and could be related to sustained low levels of viral replication in tissues, to translocation of microbial products across a damaged gut mucosa, to replication of co-pathogens such as cytomegalovirus, to increased levels of inflammatory lipids, or to homeostatic responses to lymphocytopenia that may drive expansion of CD8 T cell numbers.We present here models that link inflammation and coagulation to morbid outcomes as well as to the pathogenesis of CD4 T cell restoration failure and CD8 T cell expansion.

Pre-exposure Prophylaxis Uptake, Adherence, and Persistence: A Narrative Review of Interventions in the U.S.

Drug delivery systems are now well developed and in use for various therapies. These systems surpass conventional mode of drug administration by efficiently delivering the desired concentrations of bioactive drug. Typically, drug delivery in the body is an interfacial phenomenon. Interaction of the administered carrier molecules with the body fluid depends on the physiochemical properties of the carrier molecules and hence controls its pharmacokinetics. However, nonspecific interactions and physiological stability of these molecules within biological systems may result in complications during the therapy and stimulate the immune responses. Also, the insolubility of hydrophobic drugs is a major problem in their therapeutic applications. Target-specific drug delivery with controlled interfacial interactions is a possible alternative to overcome these challenges. The regulation of interactions at biointerface allows modulating the in vivo administration of a carrier system. Various engineered nanomaterials, emulsion and polymer-based drug delivery systems, have been explored in the literature. Further, surface modifications and functionalization of these delivery systems are found to regulate interfacial interactions. The modification not only controls the reaction potency of drug with the biological systems but also enhances the stability and compatibility. This chapter describes the designing of engineered drug delivery systems using polymers, self-assembled monolayers, and emulsions. Application of these strategies to alter the surface chemistry of drug molecules and delivery systems is elaborated through recent studies. Bio-interfacial aspects of the above-designed systems are highlighted to confirm their fidelity to be used as effective drug delivery systems.

Clinical trial data have shown that oral pre-exposure prophylaxis (PrEP) is efficacious when taken as prescribed; however, PrEP adherence is complex and must be understood within the context of variable risk for HIV infection and use of other HIV prevention methods. Different levels of adherence may be needed in different populations to achieve HIV prevention, and the optimal methods for achieving the necessary adherence for both individual and public health benefits are unknown. Guidance for PrEP use must consider these questions to determine the success of PrEP-based HIV prevention programs. In this article, we propose a new paradigm for understanding and measuring PrEP adherence, termed prevention-effective adherence, which incorporates dynamic HIV acquisition risk behaviors and the use of HIV alternative prevention strategies. We discuss the need for daily PrEP use only during periods of risk for HIV exposure, describe key issues for measuring and understanding relevant behaviors, review lessons from another health prevention field (i.e., family planning), and provide guidance for prevention-effective PrEP use. Moreover, we challenge emerging calls for sustained, near perfect PrEP adherence regardless of risk exposure and offer a more practical and public health-focused vision for this prevention intervention.

A comparison between the effect of systemic and coated drug delivery in osteoporotic bone after dental implantation.

Drug delivery systems (DDS) have been the focus of intense research for several decades. Many approaches and strategies have been employed over the years, further expanding this field. For example, the advancements towards targeted drug delivery (TDD) enabled the use of DDS for diagnostic purposes. In addition, DDS research has provided the foundation for tissue engineering and theranostic systems (therapeutic systems with diagnostic properties). Drug delivery research has yielded many successes over the years with a significant amount of therapeutic and diagnostic products out in the market. Nevertheless, many challenges still remain. Herein, in this special edition, we asked various experts to review recent advancements in their field of expertise and report their latest findings. The special edition is well balanced and is comprised of 60% reviews and 40% research articles. One may find up-to-date reviews on advancements made in biomaterials, noninvasive drug delivery, drug conjugations, biosensors, diagnostics, implantable and ingestible devices, nanomaterials, cancer treatment, and endosome-derived vesicles. Additionally, research articles are provided, describing advanced new designs of microneedles (MNs), approaches to enhance tissue engineering capabilities, biomaterials, and DDS. The global market of protein- and nucleotide- based pharmaceutics accounted for $643 million in 2016, and is anticipated to reach over $8000 million by 2028. However, the use of these therapeutics is hindered by issues of immunogenicity, high molecular weight, fast renal clearance, and enzymatic degradation. For these reasons, to date, monoclonal antibodies (mAbs) are administered only via injection. Considering that, Angsantikul et al. propose the use of ionic liquid and eutectic solvent for the oral delivery of mAbs (article number 2002912). Their system reduced the mucosal viscosity and enhanced the paracellular transport of TNFα antibody in vitro. Additionally, Rondon and colleagues review the latest advancements in polymer chemistry and protein engineering in order to overcome part of these limitations (article number 2101633). Another approach to overcome these limitations is by using antibody-drug conjugates (ADCs). Accordingly, Firer and Luboshits review the recent developments employed in ADCs for the treatment of hematological malignancies (article number 2100032). They focus on the important link between the biology of the ADC and clinical efficacy, highlighting newer developments that strengthen this link to provide long-term clinical benefits. One of the most important purposes of drug delivery is achieving TDD. Dacoba and colleagues provide an overview on the concepts of passive and active targeting while exploring current venues for nanotechnology to solve the problems associated with drug delivery (article number 2009860). TDD is especially important for cancer therapy since killing cancerous cells is quite facile, but killing only cancerous cells is extremely challenging. Fu et al. review the latest strategies employed to overcome the barriers of chimeric antigen receptor T cells therapy in solid tumors (article number 2009489). Brain therapy is another challenging route for drug delivery requiring specific TDD system. To this end, Buaron et al. have developed a novel pectic galactan-based gene therapy approach that targets reactive gliosis via specific carbohydrate interaction between galactan and Gal-3 (article number 2100643). Their biocompatible pectin galatcan-plasmid DNA complexes were selectively transfected to glial cells in cortical lesions. Moreover, Avital et al. report their interesting application for nanosized DDS—foliar delivery of siRNA for treating grapevine leafroll associated virus-3 (GLRaV-3) infection that causes major economic losses (article number 2101003). By exploiting a lipid-modified polyethylenimine carrier, they show that a single dose can knock down GLRaV-3 titer, and multiple doses keeps the viral titer at baseline, which triggers the recovery of the vine and berries. Another important aspect of drug delivery research is the development of noninvasive drug administration routes. Rahamim and Azagury review the origins of biomimetic, bioinspired, and bioengineered noninvasive DDS and achievements made in the last decade (article number 2102033). Additionally, Zhang et al. review advances in DDS that access the ear through the tympanic membrane (article number 2008701). Transdermal drug delivery is one of the most used noninvasive drug delivery routes. An exciting approach for transdermal drug delivery is microneedles (MNs). Puigmal and colleagues propose applying MNs array to treat severe burns that simultaneously sample immune cells in the interstitial fluid to diagnose the response (article number 2100128). Their MNs design enables the local delivery of pharmaceutics—the chemokine CCL22 and the cytokine IL-2—thus increasing local immuno-suppression. They found that the immune cell population in the allograft and MN were similar so they can be harvested from the MN for downstream analysis. Moreover, Li et al. have also proposed an improved MNs design where they use a biphasic dissolvable MN patch with water-insoluble backing in order to tackle insufficient drug delivery with MN (article number 2103359). Their new design enables a drug delivery efficiency of >90% into the skin within 5 min. Biomaterials are the building blocks of drug delivery, diagnostics, and tissue engineering research. Therefore, there is an ever-growing need for novel biomaterials with new functionalities and improved properties. To this end, Arun et al. present an exclusive coverage of biocompatible injectable pasty or liquid polymers without the use of any solvent for drug delivery and regenerative medicine applications (article number 2010284). Moreover, Khait et al. review novel biomaterial-based strategies used to modulate the immune response post ischemic stroke while providing their perspective on the potential clinical translation of these therapies (article number 2010674). Additionally, Redenski et al. developed a new composite tissue made of soft-tissue matrices and decellularized bone for bone defect repair (article number 2008687). The use of their novel tissue composite supported a long-term bone defect repair, as well as muscle defect bridging. These aforementioned applications and additional applications use cell-based therapeutics. The major obstacles of cell-based therapeutics are their low yields (i.e., difficult to scale-up), insufficient drug loading, and inconsistencies. For this reason, Guo et al. have developed a scaled-up and facile magnetic-based extrusion method for preparing endosome-derived vesicles (article number 2008326). An additional application of diagnostics and therapeutics is implantable and ingestible devices. In this special edition, Yang and colleagues provide an up-to-date review on the state-of-the-art of powering technologies for implantable and ingestible electronics—one of the greatest challenges for ingestible devices (article number 2009289). Welch et al. have focused their review on the complex hierarchical nano-structures and nano-materials used in biosensors and diagnostic technologies (article number 2104126). Additionally, they discuss their unique advantages and clinical applications while proposing future directions. In this special edition Nakonechny and Nisnevitch provide an up-to-date review focused on ultrasound applications used to combat infections caused by microorganisms, and to promote the local release of antimicrobial drugs from liposomes and medical implants (article number 2011042). Precise and well-controlled scaffolds are highly desired for tissue engineering and regenerative medicine purposes. For example, Dubay et al. review the recent achievements of single-cell microgels and their potential alternatives, which are used when single cell resolution is needed, for example—modular bio-inks and 3D cellular microenvironments (article number 2009946). Another challenge for implantable devices is a foreign body response (FBR). Kutner et al. review the recent advantageous technologies used to overcome the FBR effect via surface modifications and localized DDS (article number 2010929). One such surface modification is reported by Israeli et al. who developed a general and versatile technology to engineer light-responsive protein-based biomaterials (article number 2011276). These novel biomaterials—consist of azobenzene containing elastin-like polypeptides—are capable of forming self-assembled nanostructures and exhibit a reversible, light-mediated phase transition, with up to a 12 °C difference in the transition temperature. We are certain that this assemblage of reviews and research papers on the use of DDS for therapeutic and diagnostic purposes is of high interest for anyone working in this field. It provides up-to-date reviews on state-of-the-art topics and research papers with promising results to further propel drug delivery research. Understanding what has been done in the past, while learning of new approaches and techniques, is crucial for any scholar who wishes to advance their personal research. Joseph Kost D.Sc. is a University Distinguished Professor, he holds The Abraham and Bessie Zacks Chair in Biomedical Engineering and was the Dean of the Faculty of Engineering Sciences at Ben-Gurion University of the Negev (BGU). He is a member of AIMBE, NAE, CRS, and the Israel Academy of Sciences and Humanities. His research interests are in the fields of biomedical engineering, biomaterials science, controlled drug delivery, gene therapy, and ultrasound. Edith Mathiowitz is a full Professor of Medical Science and Engineering at Brown University, Department of Department of Pathology and Laboratory Medicine. She Is an AIMBE, CRS, and NAI fellow member. She founded and directed the ABC/Biotechnology Graduate Program at Brown. Her interdisciplinary research is focused on developing smart oral bioadhesive delivery systems and novel insights in polymer morphology. Her laboratory serves as an incubator for several start-up companies such as Spherics, Perosphere, and Therapyx. Aharon (Roni) Azagury is an Assistant Professor in the Department of Chemical and Biotechnology Engineering in Ariel University. He received his PhD in chemical engineering from BGU. He is a member of the CRS, ICRS, and NAI societies. His current research focuses on developing novel noninvasive biomimetic and bioinspired drug delivery systems.

Simulation-based approaches for drug delivery systems: Navigating advancements, opportunities, and challenges

BackgroundPolymeric drug delivery systems have been achieved great development in the last two decades. Polymeric drug delivery has defined as a formulation or a device that enables the introduction of a therapeutic substance into the body. Biodegradable and bio-reducible polymers make the magic possible choice for lot of new drug delivery systems. The future prospects of the research for practical applications has required for the development in the field.Main bodyNatural polymers such as arginine, chitosan, dextrin, polysaccharides, poly (glycolic acid), poly (lactic acid), and hyaluronic acid have been treated for polymeric drug delivery systems. Synthetic polymers such as poly (2-hydroxyethyl methacrylate), poly(N-isopropyl acrylamide)s, poly(ethylenimine)s, dendritic polymers, biodegradable and bio-absorbable polymers have been also discussed for polymeric drug delivery. Targeting polymeric drug delivery, biomimetic and bio-related polymeric systems, and drug-free macromolecular therapeutics have also treated for polymeric drug delivery. In polymeric gene delivery systems, virial vectors and non-virial vectors for gene delivery have briefly analyzed. The systems of non-virial vectors for gene delivery are polyethylenimine derivatives, polyethylenimine copolymers, and polyethylenimine conjugated bio-reducible polymers, and the systems of virial vectors are DNA conjugates and RNA conjugates for gene delivery.ConclusionThe development of polymeric drug delivery systems that have based on natural and synthetic polymers are rapidly emerging to pharmaceutical fields. The fruitful progresses have made in the application of biocompatible and bio-related copolymers and dendrimers to cancer treatment, including their use as delivery systems for potent anticancer drugs. Combining perspectives from the synthetic and biological fields will provide a new paradigm for the design of polymeric drug and gene delivery systems.

Crossing Barriers From blood-to-brain and academia-to-industry

Cardiovascular disease in HIV-positive patients

Part I: Pharmacological Considerations for Drug Delivery Systems in Cancer Medicine Systemically Administered Drugs Reginald B. Ewesuedo and Mark J. Ratain Regional Administration of Antineoplastic Drugs Maurie Markman Theoretical Analyses and Simulations of Anticancer Drug Delivery Ardith W. El-Kareh and Timothy W. Secomb Part II: Technologies Available for Use in Cancer Drug Delivery Systems Biopolymers for Parenteral Drug Delivery in Cancer Treatment Wolfgang Friess Hydrogels in Cancer Drug Delivery Systems Sung-Joo Hwang, Namjin Baek, Haesun Park, and Kinam Park Microparticle Drug Delivery Systems Duane T. Birnbaum and Lisa Brannon-Peppas Polyethylene Glycol Conjugation of Protein and Small Molecule Drugs: Past, Present, and Future Robert G. L. Shorr, Michael Bentley, Simon Zhsao, Richard Parker, and Brendan Whittle Emulsions As Anticancer Delivery Systems S. Esmail Tabibi Part III. Current Applications: Products Approved or in Advanced Clinical Development Liposomal Drug Delivery Systems for Cancer Therapy Daryl C. Drummond, Dmitri Kirpotin, Christopher C. Benz, John W. Park, and Keelung Hong Gliadel(R): A New Method for the Treatment of Malignant Brain Tumors Francesco DiMeco, Henry Brem, Jon D. Weingart, and Alessandro Olivi Intralesional Chemotherapy with Injectable Collagen Gel Formulations Elaine K. Orenberg Sustained-Release Drug Delivery with DepoFoam Sankaram B. Mantripragada and Stephen B. Howell Cancer Vaccines Susanne Osanto Part IV. Future Directions: Novel Cancer Drug Targets and Delivery Systems Gene Therapy of Cancer Susanne Osanto Progress in Antisense Technology Stanley T. Crooke Tumor Vaccines Francesco M. Marincola Diagnosis and Treatment of HumanDisease Using Telomerase As a Novel Target Lynne W. Elmore and Shawn E. Holt Index

The development of biomaterials to treat, repair, or reconstruct the human body is an increasingly important component of materials research. Collaboration between materials researchers and their industrial and clinical partners is essential for the development of this complex field. To demonstrate the importance of these interactions, two articles in this issue focus on advances in biomaterials relating to the use of colloidal systems for transport, drug delivery, and other medical applications. These articles were coordinated by Dominique Muster (Université Louis Pasteur, Strasbourg) and Franz Burny (Hôpital Erasme, Brussels). The following is the second of these two articles.There are two important objectives in drug delivery research. The first is to maximize the effectiveness of drugs by increasing the amount of drug reaching the target tissue while sparing other tissues the deleterious effects of the drug. The second is to control the release of a drug, so that the period of optimal drug concentration in the target tissue is maximized. A numbe r of different Systems have been investigated to achieve these objectives, including soluble polymeric delivery Systems and a range of colloidal drug delivery forms such as liposomes, emulsions, micelles, microcapsules, microparticles, and nanoparticles. This article focuses on polymeric materials for the production of micro- or nanoparticle Systems for dru g delivery by injection, and their characterization and Performance in vivo.Colloidal particles have a number of advantages as drug delivery Systems; they are easy to prepare, have the potential for high drug loading, and release of the drug can be controlled. However, without surface modification, colloidal particles are difficult to target because they are directed largely to the liver and spieen after intravenous injection. The reasons for this can be found in the context of the body's defenses. In order to protect against disease, the body has a complex System to ensure that invading microorganisms are identified and neutralized at the earliest possible opportunity. Most parasitic or invading organisms which pose a threat are particulate in form, and thus any colloidal drug delivery System will have to evade detection by these mechanisms in order to reach its target.

(See the major article by Abbas et al on pages 224–34.) The development of, and globlal access to, effective antiretroviral medications revolutionized human immunodeficiency virus type 1 (HIV-1) care. In addition to their important life-saving treatment benefits, antiretrovirals have recently been demonstrated to be highly efficacious for HIV-1 prevention as well, when used as antiretroviral therapy (ART) to reduce the infectiousness of HIV-1–infected persons and pre-exposure prophylaxis (PrEP) for uninfected persons who have ongoing HIV-1 exposure. Antiretroviral-based prevention, both ART and PrEP, are among the most promising strategies for reducing the number of new HIV-1 infections globally. Consequently, policymakers are weighing the costs, benefits, and risks of public health implementation of ART and PrEP for HIV-1 prevention. One potential risk of both ART and PrEP is the selection and transmission of HIV-1 variants that are resistant to one or more antiretroviral medications, which can result in HIV-1 treatment failure with associated morbidity and mortality and increased costs (of more complex second- and third-line treatment regimens); thus, there has been considerable speculation about the potential risks of resistance from both ART and PrEP. In this issue of the Journal of Infectious Diseases, Abbas et al present a mathematical model to estimate the number of HIV-1 infections averted and the number of acquired and transmitted HIV-1 cases of resistance in a setting similar to South Africa and under several scenarios about coverage of ART and PrEP [1]. For PrEP, the authors assumed use of combination emtricitabine-tenofovir, for which efficacy has been demonstrated [2–4]. For ART, the authors modeled first-line regimens containing the same antiretrovirals and assumed that second-line drugs were not available, given limited availability of second-line medications in many resource-limited settings. A number of additional scenarios were analyzed, including having ART initiation at CD4 lymphocyte cell counts at either <200 or <350 cells/µL, reflecting evolving international guidelines on clinical benefits of earlier ART initiation, and allowing for “inappropriate” PrEP use by persons that are already infected with HIV-1, either through PrEP initiation occurring during unrecognized seronegative acute HIV-1 infection or PrEP initiation by persons with undocumented, chronic HIV-1 infection, which could occur if HIV-1 testing is not conducted prior to initiation or through “black market” availability of PrEP. The authors used optimistic scenarios for ART retention and PrEP effectiveness; notably, the model assumed general distribution of PrEP rather than risk-targeted delivery. Not surprisingly, the results of this mathematical modeling article underscore that population-level coverage and effectiveness (which is dependent on adherence) are the main determinants of the number of infections averted with both ART and PrEP, and that implementation of a combination of ART and PrEP prevents more infections in a population than a program that delivers exclusively either ART or PrEP. More interestingly, the model analysis also suggests that HIV-1 drug resistance in a population would be largely driven by ART, not PrEP, in all scenarios modeled, as a result of insufficient ART adherence or lack of viral load monitoring in ART programs, leading to selection of resistant variants during incomplete viral suppression. The model also finds that the population prevalence of resistance as a direct result of PrEP may be very low and that the greatest resistance risks related to PrEP would be from inappropriate use by persons already HIV-1 infected, rather than from PrEP being prescribed for HIV-1 prevention, even anticipating inadvertent prescribing for persons with unrecognized acute HIV-1 infection. What do these findings mean for potential implementation of PrEP for HIV-1 prevention? First, these results directly address the often-voiced concern that PrEP will lead to substantial HIV resistance in populations. Instead, because high PrEP adherence prevents most HIV-1 infections, it is unlikely to select for resistant variants, although low PrEP adherence does not prevent infection; the model presented by Abbas et al suggests that substantial population-level resistance is unlikely. Moreover, even with optimistic assumptions about ART continuation rates, the amount of resistance generated from ART failure greatly exceeds the resistance selected by PrEP. Indeed, emerging evidence from Africa has demonstrated increasing resistance accompanying ART roll-out over the past decade [5–7]. Nevertheless, if persons on PrEP alternated between periods of good and poor adherence in patterns that increased the risk of them becoming HIV-1 infected and then taking PrEP, the risk of resistance could be greater than predicted in this model. Implementation of PrEP will require ongoing complementary strategies to ensure high quality HIV-1 testing, reduce HIV-1 risk, and maximize PrEP-taking. A second message from the Abbas et al model is the importance of HIV-1 testing before PrEP initiation to avoid inadvertent exposure for an HIV-1–infected person to what is effectively suboptimal mono- or dual-agent ART. The model assumed that 2.5% of persons with undiagnosed chronic HIV-1 infection would initiate PrEP each year, which is arguably very high. Nevertheless, the model alerts us to the importance of strategies to monitor quality HIV-1 testing and PrEP pharmacovigilance during this period where PrEP is moving from efficacy trials to implementation. Third, a highly intuitive finding of the model is that less drug resistance could result if ART and PrEP regimens were used that did not include the same antiretroviral agents. The completed, first-generation PrEP trials used tenofovir, alone or in combination with emtricitabine, resting on the substantial body of clinical safety and experience with these agents for testing PrEP as a novel HIV-1 prevention strategy. New PrEP agents are in development, but their use would not be routine for several years. While, hypothetically, it is preferable to utilize PrEP regimens that do not overlap with antiretrovirals used for treatment, there is also a cost of inaction—missing the opportunity to prevent new HIV-1 infections with demonstrated effective tenofovir-based PrEP while waiting for new safe and effective PrEP regimens to be identified. While providing some new insights, there are also limitations to the Abbas et al model. For ART, the key benefit that was not included in this model was its health impact in terms of saving lives. As the primary benefit of ART is to prolong life, and the primary problem of resistance is the loss of efficacy of ART, this is an important gap in the model. For PrEP, a critical operational factor for maximizing impact in terms of infections averted will be “prioritization,” in which age, gender, and risk behaviors are incorporated into risk assessments for potential PrEP users to maximize the likelihood that PrEP is provided to those most at risk of HIV-1 infection. To optimally use resources for PrEP, programs will need to prioritize those who are at highest risk of HIV-1 acquisition and are motivated to take PrEP. Whereas the authors of the present model used a coverage level of 30% of the general population and included those that did not adhere to PrEP well, other models have suggested that if PrEP delivery programs can target delivery to those at greater HIV-1 risk and achieve higher adherence in a prioritized population, by reducing the total number of new HIV-1 infections, PrEP could even reduce the prevalence of drug resistance [8]. Thus, the complex mathematical model developed by Abbas et al helps identify some of the next steps for mathematical models and needs for empiric data to clarify policy considerations and implementation priorities for antiretroviral-based HIV-1 prevention through ART and PrEP. For both PrEP and ART for HIV-1 prevention, adherence is key to effectiveness. For ART, the result is adherence over a lifetime, or until a cure is available. Expanding implementation of ART for HIV-1 prevention will include persons initiating at higher CD4 lymphocyte counts and earlier in their disease course before they have experienced symptoms, and they may face heightened adherence challenges. PrEP adherence has different challenges than ART, namely requiring persons without HIV-1 to perceive their own risk sufficiently to initiate and adhere to PrEP. Thus, PrEP needs to be delivered in a different model than ART, as it is not a commitment to life-long medications, but specially directed to individuals during life periods of highest risk. While much can be learned from the Abbas et al model about the potential for generation and spread of HIV-1 antiretroviral resistance related to ART and PrEP, equally important is what this model can teach us about the public health impact of these prevention strategies. The authors have moved the discussions about PrEP forward from modeling simply the number of drug resistance cases with their public health perspective in which they present the ratio of cumulative HIV-1 infections averted to prevalent HIV-1 drug resistance, which puts the deleterious effect of drug resistance into context with the benefits of HIV-1 infection prevention. This model clearly demonstrates that both ART and PrEP, particularly when rolled out together, offer the potential for substantial HIV-1 prevention. Recognizing the potential risks of PrEP and ART, including antiretroviral resistance, is critical for developing mitigating strategies, because the potential benefits of these new prevention strategies are substantial and there is real public health risk in not implementing tools that we know work.

Knowledge and Use of Preexposure and Postexposure Prophylaxis Among Attendees of Minority Gay Pride Events, 2005 Through 2006