-
Advanced Drug Delivery Reviews Aug 2016Prevention plays an invaluable role in the fight against HIV/AIDS. The use of microbicides is considered an interesting potential approach for topical pre-exposure... (Review)
Review
Prevention plays an invaluable role in the fight against HIV/AIDS. The use of microbicides is considered an interesting potential approach for topical pre-exposure prophylaxis of HIV sexual transmission. The prospects of having an effective product available are expected to be fulfilled in the near future as driven by recent and forthcoming results of clinical trials. Different dosage forms and delivery strategies have been proposed and tested for multiple microbicide drug candidates presently at different stages of the development pipeline. One particularly interesting approach comprises the application of nanomedicine principles to the development of novel anti-HIV microbicides, but its implications to efficacy and safety are not yet fully understood. Nanotechnology-based systems, either presenting inherent anti-HIV activity or acting as drug nanocarriers, may significantly influence features such as drug solubility, stability of active payloads, drug release, interactions between active moieties and virus/cells, intracellular drug delivery, drug targeting, safety, antiviral activity, mucoadhesive behavior, drug distribution and tissue penetration, and pharmacokinetics. The present manuscript provides a comprehensive and holistic overview of these topics as relevant to the development of vaginal and rectal microbicides. In particular, recent advances pertaining inherently active microbicide nanosystems and microbicide drug nanocarriers are discussed.
Topics: Anti-Infective Agents; Drug Delivery Systems; Drug Design; Female; HIV Infections; Humans; Nanomedicine; Nanotechnology
PubMed: 26829288
DOI: 10.1016/j.addr.2016.01.017 -
Global Health, Science and Practice Apr 2022Evidence of HIV drug resistance (HIVDR) in individuals using oral pre-exposure prophylaxis (PrEP) who acquire HIV is limited to clinical trials and case studies. More...
BACKGROUND
Evidence of HIV drug resistance (HIVDR) in individuals using oral pre-exposure prophylaxis (PrEP) who acquire HIV is limited to clinical trials and case studies. More data are needed to understand the risk of HIVDR with oral PrEP during PrEP rollout. Mechanisms to collect these data vary, and are dependent on cost, scale of PrEP distribution, and in-country infrastructure for the identification, collection, and testing of samples from PrEP seroconverters.
METHODS
The Global Evaluation of Microbicide Sensitivity (GEMS) project, in collaboration with country stakeholders, initiated HIVDR monitoring among new HIV seroconverters with prior PrEP use in Eswatini, Kenya, South Africa, and Zimbabwe. Standalone protocols were developed to assess HIVDR among a national sample of PrEP users. In addition, HIVDR testing was incorporated into existing demonstration projects for key populations.
LESSONS LEARNED
Countries are supportive of conducting a time-limited evaluation of HIVDR during the early stages of PrEP rollout. As PrEP rollout expands, the need for long-term HIVDR monitoring with PrEP will need to be balanced with maintaining national HIV drug resistance surveillance for pretreatment and acquired drug resistance. Laboratory capacity is a common obstacle to setting up a monitoring system.
CONCLUSIONS
Establishing HIV resistance monitoring within PrEP programs is feasible. Approaches to drug resistance monitoring may evolve as the PrEP programs mature and expand. The methods and implementation support offered by GEMS assisted countries in developing methods to monitor for drug resistance that best fit their PrEP program needs and resources.
Topics: Anti-HIV Agents; Anti-Infective Agents; Drug Resistance; HIV Infections; Humans; Pre-Exposure Prophylaxis
PubMed: 35487541
DOI: 10.9745/GHSP-D-21-00122 -
AIDS (London, England) Nov 2016To investigate the toxicity and activity against HIV of 5-hydroxytyrosol as a potential microbicide.
OBJECTIVE
To investigate the toxicity and activity against HIV of 5-hydroxytyrosol as a potential microbicide.
DESIGN
The anti-HIV-1 activity of 5-hydroxytyrosol, a polyphenolic compound, was tested against wild-type HIV-1 and viral clones resistant to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and integrase inhibitors. In addition to its activity against founder viruses, different viral subtypes and potential synergy with tenofovir disoproxil fumarate, lamivudine and emtricitabine was also tested. 5-Hydroxytyrosol toxicity was evaluated in vivo in rabbit vaginal mucosa.
METHODS
We have cloned pol gene from drug-resistant HIV-1 isolated from infected patients and env gene from Fiebeg III/IV patients or A, C, D, E, F and G subtypes in the NL4.3-Ren backbone. 5-Hydroxytyrosol anti-HIV-1 activity was evaluated in infections of MT-2, U87-CCR5 or peripheral blood mononuclear cells preactivated with phytohemagglutinin + interleukin-2 with viruses obtained through 293T transfections. Inhibitory concentration 50% and cytotoxic concentration 50% were calculated. Synergy was analysed according to Chou and Talalay method. In-vivo toxicity was evaluated for 14 days in rabbit vaginal mucosa.
RESULTS
5-Hydroxytyrosol inhibited HIV-1 infections of recombinant or wild-type viruses in all the target cells tested. Moreover, 5-hydroxytyrosol showed similar inhibitory concentration 50% values for infections with NRTIs, NNRTIs, protease inhibitors and INIs resistant viruses; founder viruses and all the subtypes tested. Combination of 5-hydroxytyrosol with tenofovir was found to be synergistic, whereas it was additive with lamivudine and emtricitabine. In-vivo toxicity of 5-hydroxytyrosol was very low even at the highest tested doses.
CONCLUSION
5-Hydroxytyrosol displayed a broad anti-HIV-1 activity in different cells systems in the absent of in-vivo toxicity, therefore supporting its candidacy as a potential new class of microbicides.
Topics: Animals; Anti-Infective Agents; Cells, Cultured; Drug Synergism; Female; HIV-1; Human Activities; Humans; Leukocytes, Mononuclear; Microbial Sensitivity Tests; Phenylethyl Alcohol; Rabbits
PubMed: 27677167
DOI: 10.1097/QAD.0000000000001283 -
Journal of Controlled Release :... Nov 2017Sexual transmission remains one of the most significant hurdles in the fight against HIV infection. The use of vaginal or rectal microbicides has been proposed for... (Review)
Review
Sexual transmission remains one of the most significant hurdles in the fight against HIV infection. The use of vaginal or rectal microbicides has been proposed for topical pre-exposure prophylaxis but available results from clinical trials of candidate products have been, at best, less than optimal. While waiting for the first product to get regulatory approval, novel approaches are being explored in order to enhance efficacy, as well as to assure safety. Strategies involving specific delivery of antiviral agents to key players involved in the early steps of sexual transmission have the potential to help achieving such purposes. Engineering systems that allow targeting cells, tissues or other biological structures of interest may provide a way to modulate local pharmacokinetics of promising microbicide molecules and, thus, maximize protection. This concise review discusses the identification and use of potential targets for such purpose, while detailing on several examples of targeted systems engineered as potential microbicide candidates. Furthermore, remaining challenges and hints for future work in the field of targeted microbicides are addressed.
Topics: Animals; Anti-Infective Agents; Drug Delivery Systems; HIV Infections; Humans
PubMed: 28951320
DOI: 10.1016/j.jconrel.2017.09.030 -
Proceedings of the National Academy of... May 2012Vaccination and the application of a vaginal microbicide have traditionally been considered independent methods to prevent the sexual transmission of HIV-1 to women....
Vaccination and the application of a vaginal microbicide have traditionally been considered independent methods to prevent the sexual transmission of HIV-1 to women. Both techniques can be effective in macaque models, and limited efficacy has been observed in clinical trials for each. Here, we have addressed whether vaccines and microbicides can be used together to provide reinforced protection against virus challenge of rhesus macaques. In two separate experiments, four groups of animals were vaccinated with a T-cell-based adenovirus (Ad) vectored vaccine aimed at reducing postinfection viral loads and/or a partially effective dose of a vaginal microbicide aimed at blocking infection of a high-dose vaginal challenge with SIVmac251 or SHIV-162P3. In the first study, the only two protected animals were in the group that received Ad26/Ad5HVR48 vaccine vectors combined with the fusion inhibitor T-1249 as the vaginal microbicide before SIVmac251 challenge. In the second study, vaccination with Ad35/Ad26 vectors combined with the CCR5 inhibitor maraviroc as the vaginal microbicide led to significant reductions of both acquisition of infection and postinfection viral loads following SHIV-SF162P3 challenge. As expected, the vaccine by itself reduced viral loads but had no acquisition effect, whereas the microbicide had a partial acquisition effect but minimal impact on viral loads. For both measures of protective efficacy, the vaccine-microbicide combination differed more from controls than did either separate intervention. Overall, the data suggest that vaccines and microbicides are complementary techniques that may protect better when used together than separately.
Topics: AIDS Vaccines; Administration, Intravaginal; Animals; Anti-Infective Agents; CCR5 Receptor Antagonists; Cyclohexanes; Drug Therapy, Combination; Female; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Macaca mulatta; Maraviroc; RNA, Viral; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Treatment Outcome; Triazoles; Viral Load
PubMed: 22586094
DOI: 10.1073/pnas.1203183109 -
Journal of Photochemistry and... Jul 2023Cutaneous bacterial wound infections typically involve gram-positive cocci such as Staphylococcus aureus (SA) and usually become biofilm infections. Bacteria in biofilms...
Cutaneous bacterial wound infections typically involve gram-positive cocci such as Staphylococcus aureus (SA) and usually become biofilm infections. Bacteria in biofilms may be 100-1000-fold more resistant to an antibiotic than the clinical laboratory minimal inhibitory concentration (MIC) for that antibiotic, contributing to antimicrobial resistance (AMR). AMR is a growing global threat to humanity. One pathogen-antibiotic resistant combination, methicillin-resistant SA (MRSA) caused more deaths globally than any other such combination in a recent worldwide statistical review. Many wound infections are accessible to light. Antimicrobial phototherapy, and particularly antimicrobial blue light therapy (aBL) is an innovative non-antibiotic approach often overlooked as a possible alternative or adjunctive therapy to reduce antibiotic use. We therefore focused on aBL treatment of biofilm infections, especially MRSA, focusing on in vitro and ex vivo porcine skin models of bacterial biofilm infections. Since aBL is microbicidal through the generation of reactive oxygen species (ROS), we hypothesized that menadione (Vitamin K3), a multifunctional ROS generator, might enhance aBL. Our studies suggest that menadione can synergize with aBL to increase both ROS and microbicidal effects, acting as a photosensitizer as well as an ROS recycler in the treatment of biofilm infections. Vitamin K3/menadione has been given orally and intravenously worldwide to thousands of patients. We conclude that menadione/Vitamin K3 can be used as an adjunct to antimicrobial blue light therapy, increasing the effectiveness of this modality in the treatment of biofilm infections, thereby presenting a potential alternative to antibiotic therapy, to which biofilm infections are so resistant.
Topics: Humans; Vitamin K 3; Photosensitizing Agents; Reactive Oxygen Species; Anti-Bacterial Agents; Anti-Infective Agents; Methicillin-Resistant Staphylococcus aureus; Biofilms; Staphylococcal Infections; Wound Infection; Microbial Sensitivity Tests
PubMed: 37186990
DOI: 10.1016/j.jphotobiol.2023.112720 -
AIDS and Behavior May 2015The ways in which couples communicate about microbicides is likely to influence microbicide uptake and usage. We collected quantitative data about whether women in a...
The ways in which couples communicate about microbicides is likely to influence microbicide uptake and usage. We collected quantitative data about whether women in a microbicide trial discussed microbicides with their partners and explored communication about microbicides during 79 in-depth-interviews with women enrolled in the trial and 17 focus-group discussions with community members. After 4 weeks in the trial, 60 % of 1092 women had discussed microbicides with their partners; in multivariate analysis, this was associated with younger age, clinic of enrolment and not living in households that owned cattle. After 52 weeks, 84 % of women had discussed microbicides; in multivariate analysis, this was associated with not living in households that owned cattle, not living in a household that relied on the cheapest water source, allocation to 0.5 % PRO2000 gel and consistent gel adherence. Qualitative findings highlighted that women in committed relationships were expected to discuss microbicides with their partners and preferred to use microbicides with their partner's knowledge. Women had different reasons for, and ways of, discussing microbicides and these were influenced by the couple's decision-making roles. Although there was tolerance for the use of microbicides without a partner's knowledge, the women who used microbicides secretly appeared to be women who were least able to discuss microbicides. In KwaZulu-Natal, socio-cultural norms informing sexual communication are amenable to microbicide introduction.
Topics: Administration, Intravaginal; Adult; Anti-Infective Agents; Anti-Infective Agents, Local; Communication; Family Characteristics; Female; Focus Groups; HIV Infections; Humans; Interviews as Topic; Male; Middle Aged; Multivariate Analysis; Patient Acceptance of Health Care; Qualitative Research; Sexual Partners; South Africa; Truth Disclosure
PubMed: 25488170
DOI: 10.1007/s10461-014-0965-y -
AIDS Research and Human Retroviruses Aug 2017In the absence of an effective vaccine, strategies to prevent HIV transmission are urgently needed. Condomless receptive anal intercourse represents a major route of...
In the absence of an effective vaccine, strategies to prevent HIV transmission are urgently needed. Condomless receptive anal intercourse represents a major route of transmission, and efforts are being made to develop strategies, in which potent anti-HIV drugs are formulated for topical application to the rectum before sex. 5P12-RANTES is a promising candidate for such a purpose. It is an analog of the human chemokine RANTES/CCL5, which potently blocks CCR5, the principal coreceptor used by HIV to enter and infect target cells. As a protein, 5P12-RANTES is potentially vulnerable to attack by proteases in the rectal environment. In this study, we tested the stability of 5P12-RANTES on exposure to rectal lavage samples obtained from healthy volunteers, using a sensitive HIV entry inhibition assay as an indicator of stability. Varying levels of inactivating activity toward 5P12-RANTES were detected across the different lavage samples. Analysis of even the most aggressive samples indicated that protease activity in the rectal environment is unlikely to impact on the anti-HIV activity of 5P12-RANTES when applied pericoitally at the envisaged clinical dose (1 mM). This study indicates that 5P12-RANTES has adequate stability for further development as an HIV prevention drug for rectal use.
Topics: Anti-Infective Agents; Chemokines, CC; Drug Stability; Healthy Volunteers; Humans; Hydrolysis; Rectum
PubMed: 28177261
DOI: 10.1089/AID.2016.0199 -
AIDS (London, England) Oct 2011Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a strategy to develop an...
OBJECTIVE
Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a strategy to develop an effective rectal microbicide, we performed an ex-vivo preclinical evaluation to determine the efficacy and limitation of multiple combinations of reverse transcriptase inhibitors (RTIs).
DESIGN
A nucleotide, PMPA (tenofovir), a nucleoside, FTC (emtricitabine), RTIs and two nonnucleoside RTIs, UC781 and TMC120 (dapivirine), were used in double, triple and quadruple combinations against a panel of CCR5-uing and CXCR4-using clade B HIV-1 isolates and against RTI-escape variants.
METHODS
Indicator cells and colorectal tissue explants were used to assess antiviral activity of drug combinations.
RESULTS
All combinations inhibited the isolates tested in a cellular model and in colorectal explants and produced, for at least one of the compounds, a change in the dose-response curve. Double and triple combinations incrementally augmented activity, even against RTI-escape mutants, whereas quadruple combinations conferred little further advantage.
CONCLUSION
The colorectal explant model may be used to identify the best candidate molecules and their combinations at the preclinical stage. Furthermore, this study demonstrates that combinations based on RTIs with different HIV-1 inhibitory mechanisms have potential as colorectal microbicides.
Topics: Anti-HIV Agents; Anti-Infective Agents; Colon; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Male; Mucous Membrane; Rectum; Reverse Transcriptase Inhibitors; Sexual Behavior; Tissue Culture Techniques
PubMed: 21811139
DOI: 10.1097/QAD.0b013e32834b3629 -
AIDS Care Aug 2010Unless optimal adherence in microbicide clinical trials is ensured, an efficacious microbicide may be rejected after trial completion, or development of a promising...
Unless optimal adherence in microbicide clinical trials is ensured, an efficacious microbicide may be rejected after trial completion, or development of a promising microbicide may be stopped, because low adherence rates create the illusion of poor efficacy. We provide a framework with which to conceptualize and improve microbicide adherence in clinical trials, supported by a critical review of the empirical literature. The information-motivation-behavioral skills (IMB) model of microbicide adherence conceptualizes microbicide adherence in clinical trials and highlights factors that can be addressed in behavioral interventions to increase adherence in such trials. This model asserts that microbicide adherence-related information, motivation, and behavioral skills are fundamental determinants of adherent microbicide utilization. Specifically, information consists of objective facts about microbicide use (e.g., administration and dosage) as well as heuristics that facilitate use (e.g., microbicides must be used with all partners). Motivation to adhere consists of attitudes toward personal use of microbicides (e.g., evaluating the consequences of using microbicides as good or pleasant) as well as social norms that support their use (e.g., beliefs that a sexual partner approves use of microbicides). Behavioral skills consist of objective skills necessary for microbicide adherence (e.g., the ability to apply the microbicide correctly and consistently). Empirical evidence concerning microbicide acceptability and adherence to spermicides, medication, and condom use regimens support the utility of this model for understanding and promoting microbicide adherence in clinical trials.
Topics: Anti-Infective Agents; Clinical Trials as Topic; Female; HIV Infections; Humans; Information Dissemination; Male; Medication Adherence; Models, Psychological; Motivation
PubMed: 20552466
DOI: 10.1080/09540121003623719