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Current Topics in Medicinal Chemistry 2016In the absence of an approved and effective vaccine, topical microbicides have become the strategy of choice to provide women with the ability to prevent the sexual... (Review)
Review
In the absence of an approved and effective vaccine, topical microbicides have become the strategy of choice to provide women with the ability to prevent the sexual transmission of HIV. Topical microbicides are chemical and physical agents specifically developed and formulated for use in either the vaginal or rectal environment to prevent the sexual transmission of infectious organisms. Although a microbicide product will have many of the same properties as other anti-infective therapeutic agents, the microbicide development pathway has significant differences which reflect the complex biological environment in which the products must act. These challenges to the development of an effective microbicide are reflected in the recently released FDA Guidance document which defines the microbicide development algorithm and includes the evaluation of preclinical efficacy and toxicity, and safety and toxicology, and indicates the necessity of testing of the active pharmaceutical product as well as an optimal formulation for delivery of the microbicide product. The microbicide development algorithm requires evaluation of the potential microbicidal agent and final formulated product in assays which mimic the microenvironment of the vagina and rectum during the sexual transmission of HIV, including the evaluation of activity and cytotoxicity in the appropriate biological matrices, toxicity testing against normal vaginal flora and at standard vaginal pH, testing in ectocervical and colorectal explant tissue, and irritation studies to vaginal, rectal and penile tissue. Herein, we discuss currently accepted practices required for the development of a successful microbicide product which will prevent virus transmission in the vaginal and rectal vaults.
Topics: Anti-HIV Agents; Female; HIV; HIV Infections; Humans; Rectum; Sexual Behavior; Vagina
PubMed: 26324047
DOI: 10.2174/1568026615666150901113939 -
AIDS Patient Care and STDs Jun 2006
Topics: Anti-Infective Agents; Female; HIV; HIV Infections; Humans
PubMed: 16789859
DOI: 10.1089/apc.2006.20.448 -
CMAJ : Canadian Medical Association... Sep 2006
Topics: Anti-Infective Agents; Fund Raising; HIV Infections; Humans; Research Support as Topic
PubMed: 17001043
DOI: 10.1503/cmaj.061124 -
AIDS Patient Care and STDs Aug 2003In recent years, AIDS and sexually transmitted diseases (STDs) have become a burgeoning problem and are spreading at an alarming rate. Microbicides are being developed... (Review)
Review
In recent years, AIDS and sexually transmitted diseases (STDs) have become a burgeoning problem and are spreading at an alarming rate. Microbicides are being developed as a new therapeutic category for prevention of transmission of sexually transmitted infections (STIs) and HIV. Many of the microbicide formulations (MF) may fail to elicit a protective response either because of a lack of efficacy or inadequate formulation. Manufacturing a stable, efficacious, safe, and optimal product is the main objective of formulation development programs. Preformulation parameters (PP), as discussed in Part I of this series, influence formulation development significantly and should be considered carefully before designing a formulation strategy. Initially, based on PP and market research, a target product profile (TPP) is generated, which defines product attributes that can be normally classified as "essential" and "desirable." A complex and dynamic process begins thereafter that takes into consideration myriad factors starting from selection of delivery system, selection of excipients, compatibility study, prototype composition, selection of process and optimization, stability testing, scale up, manufacturing under good manufacturing practices (GMP), and packaging development. Prototype formulations are evaluated for several performance characteristics (e.g., dispersion behavior, bioadhesion, retention, spreading, rheology). These compositions are also subjected to biologic evaluation by various in vitro and in vivo models. Such a well-planned, well-coordinated, and well-implemented formulation development program not only accelerates overall development but also minimizes failures in subsequent clinical development studies. The objective of this review is to highlight the importance of formulation science, outline the steps involved in this process, and explore how these can be exploited for achieving optimal MF.
Topics: Administration, Intravaginal; Administration, Rectal; Anti-Infective Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Drug Delivery Systems; HIV Infections; Humans; Sexually Transmitted Diseases
PubMed: 13678540
DOI: 10.1089/108729103322277402 -
Current HIV/AIDS Reports Mar 2013Interpretation of microbicide trial results has been compromised by challenges to accurate measurement of product adherence and sexual risk behaviors. This article... (Review)
Review
Interpretation of microbicide trial results has been compromised by challenges to accurate measurement of product adherence and sexual risk behaviors. This article provides an evaluation of the methods used to measure adherence and other sensitive behaviors relevant to assessment of product safety and effectiveness in recently completed trials of vaginal and rectal microbicides. We review the strengths and limitations of existing and novel behavioral measurement strategies and provide recommendations for future trial design with the goal of facilitating the development and identification of safe and effective microbicides for HIV prevention.
Topics: Administration, Intravaginal; Anti-Infective Agents; Clinical Trials as Topic; Female; HIV Infections; Humans; Medication Adherence
PubMed: 23184582
DOI: 10.1007/s11904-012-0141-9 -
Current HIV Research Jan 2012Despite advances in the treatment of HIV infection, heterosexual transmission of HIV remains high, and vaccines to prevent HIV acquisition have been unfruitful. Vaginal... (Review)
Review
Despite advances in the treatment of HIV infection, heterosexual transmission of HIV remains high, and vaccines to prevent HIV acquisition have been unfruitful. Vaginal microbicides, on the other hand, have demonstrated considerable potential for HIV prevention, and a variety of compounds have been screened for their activity and safety as anti-HIV microbicides. Among these are the naturally occurring host defense peptides, small peptides from diverse lineages with intrinsic antiviral activity. Naturally occurring host defense peptides with anti-HIV activity are promising candidates for vaginal microbicide development. Their structural variance and accompanying mechanistic diversity provide a wide range of inhibitors whose antiviral activity can be exerted at nearly every stage of the HIV lifecycle. Additionally, peptide modification has been explored as a method for improving the anti-HIV activity of host defense peptides. Structure- and sequence-based alterations have achieved varying success in improving the potency and specificity of anti-HIV peptides. Overall, peptides have been discovered or engineered to inhibit HIV with therapeutic indices of > 1000, encouraging their advancement toward clinical trials. Here we review the naturally occurring anti-HIV host defense peptides, demonstrating their breadth of mechanistic diversity, and exploring approaches to enhance and optimize their activity in order to expedite their development as safe and effective anti-HIV vaginal microbicides.
Topics: Anti-Infective Agents, Local; Anti-Retroviral Agents; Defensins; Drug Design; HIV Infections; HIV-1; Humans; Peptides
PubMed: 22264047
DOI: 10.2174/157016212799304580 -
Trends in Microbiology Aug 2015Despite potent in vitro efficacy, most topical microbicides fail to effectively prevent HIV transmission. One reason for clinical failure may be that current microbicide...
Despite potent in vitro efficacy, most topical microbicides fail to effectively prevent HIV transmission. One reason for clinical failure may be that current microbicide testing does not reflect the environment encountered during sexual virus transmission. We discuss how preclinical microbicide development could be improved by more closely mimicking real-life conditions.
Topics: Animals; Anti-Infective Agents; Disease Models, Animal; Disease Transmission, Infectious; Drug Evaluation, Preclinical; HIV Infections; Humans; Models, Theoretical
PubMed: 26250616
DOI: 10.1016/j.tim.2015.05.001 -
HIV Clinical Trials 2001Against the backdrop of increasing numbers of HIV infections in women and the limitations of current safer sex messages, several calls have been made for the development...
PURPOSE
Against the backdrop of increasing numbers of HIV infections in women and the limitations of current safer sex messages, several calls have been made for the development of women-initiated methods of prevention as an essential component of the armamentarium to reduce women's vulnerability of acquiring infection with HIV. An effective microbicide is a critical survival tool in instances and situations where existing proven prevention strategies have failed to be adopted.
METHOD
The results of published N-9 clinical trials in terms of anti-HIV activity, safety data, and anti-sexually transmitted infection (STI) activity are discussed.
RESULTS
There is no evidence of efficacy against HIV in three clinical trials, there is scanty evidence for protection against STIs, and there is considerable evidence of dose-related adverse effects.
CONCLUSION
During this time, a vast array of potential microbicides with differing modes of action have been discovered, and some have undergone preclinical and early clinical testing. Effort, time, and resources might be better spent on advancing preclinical and clinical testing of these other candidate microbicides.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Chlamydia Infections; Chlamydia trachomatis; Female; Gonorrhea; HIV Infections; HIV-1; Humans; Neisseria gonorrhoeae; Nonoxynol; Randomized Controlled Trials as Topic; Research Design; Sexually Transmitted Diseases
PubMed: 11590526
DOI: 10.1310/5UVD-B5FL-RQAF-GDPN -
Journal of Nanobiotechnology May 2019It is essential that prophylactic drugs do not interfere with the normal function of the immune system. The use of nanoparticles as vaginal microbicides is a promising...
It is essential that prophylactic drugs do not interfere with the normal function of the immune system. The use of nanoparticles as vaginal microbicides is a promising prevention strategy against sexually transmitted infections. With that aim, our group is working with the G2-S16, a second generation carbosilane dendrimer with sulfonate groups in the periphery, which has been previously shown to be effective against HIV-1 and HSV-2 infection, and it is now on the road to clinical trials. Our objective in this new study is to assess the effects of G2-S16 on the immune barrier of the female reproductive tract. The expression of differentiation, maturation and activation markers was measured in epithelial cells, dendritic cells, M and GM macrophages, and T cells using RT-qPCR and flow cytometry. The results demonstrate that G2-S16 does not alter the natural immunity of the vagina, strongly supporting the biosafety of this dendrimer for clinical use.
Topics: Anti-Infective Agents; Biomarkers; Cell Line; Cell Survival; Dendrimers; Dendritic Cells; Epithelial Cells; Female; Gene Expression Regulation; Humans; Immune System; Macrophages; Particle Size; RNA, Messenger; Signal Transduction; Silanes; T-Lymphocytes; Vagina
PubMed: 31092246
DOI: 10.1186/s12951-019-0496-9 -
PloS One 2022Interpretation of clinical trial results testing vaginal microbicide gels for HIV prevention depends on participant adherence. Prior to the era of antiretrovirals,...
BACKGROUND
Interpretation of clinical trial results testing vaginal microbicide gels for HIV prevention depends on participant adherence. Prior to the era of antiretrovirals, microbicide trials collected adherence data via self-report, and trials typically reported trial population adherence as overall averages in primary results manuscripts. This study first sought to determine if different patterns of adherence from three trials of vaginal microbicide gels could be identified, using self-reported data and if so, how those patterns compare across trials. The second objective was to explore which individual-level factors were associated with different adherence patterns.
METHODS
Data from the following three clinical trials of vaginal microbicides were used for this study: HIV Prevention Trials Network (HPTN) 035 testing PRO 2000 and Buffergel, the Microbicides Development Programme (MDP) 301 testing PRO 2000, and the Population Council's Carraguard study, testing Carraguard gel. Latent Class Analysis (LCA) was used to identify longitudinal patterns of adherence using self-reported data about gel use. Multinomial multivariable logistic regression was used to estimate relative risk-ratios for factors which were independently associated with different latent adherence trajectories within each trial, and compared across trials.
RESULTS
Included in this analysis are 2,282 women from HPTN 035 (age 17-56 years), 6238 women from MDP 301 (age 16-75 years), and 6039 women from Carraguard (age 16-73 years). Using LCA, 3-4 different patterns of gel adherence were identified in each trial; these patterns were similar across the trials. Factors associated with adherence patterns were identified in all trials. Older age was associated with the adherence trajectory that consistently reported gel use in three trials. Participant-reported negative reaction of partners to the gel was associated with trajectories that reported less consistent adherence in two trials. A greater number of baseline-reported sex partners or sex acts was associated with trajectories which reported less consistent adherence in some trials. Trial site location was associated with membership of trajectories in all trials.
CONCLUSION
LCA was able to identify patterns of microbicide gel adherence in clinical trials that used self-reported data. Key factors associated with patterns of adherence in this study were participant age, clinical trial site location, and partner reaction to the study gel. These findings, in particular, age and perceived partner reaction to the method, are consistent with results from other clinical trials and programmatic rollout of biomedical HIV prevention methods for women in Africa. This study contributes to the body of evidence that women need more support to navigate power dynamics within their relationships with men so that they can successfully use HIV prevention methods.
Topics: Administration, Intravaginal; Adolescent; Adult; Aged; Anti-Infective Agents; Female; Gels; HIV Infections; Humans; Male; Middle Aged; Sexual Partners; Vaginal Creams, Foams, and Jellies; Young Adult
PubMed: 35551324
DOI: 10.1371/journal.pone.0267011