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Microbicides for Topical HIV Immunoprophylaxis: Current Status and Future Prospects

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14 May 2024

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16 May 2024

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Abstract
Microbicides, topical antiseptic agents, and a revolutionary advance in HIV prevention aim to prevent the entry of infectious agents into the human body, thus stopping the sexual transmission of HIV and other sexually transmitted diseases. Microbicides represent the promise of a new age in preventive measures against one of the world's most pressing health challenges. In addition to their direct antiviral effects during HIV transmission, microbicides also influence vaginal mucosal immunity. This article reviews microbicides by presenting different drug classifications and highlighting significant representatives from each group. It also explains their mechanisms of action and presents information about vaginal mucosal immune responses, emphasizing the critical role they play in responding to HIV during sexual transmission. For each chemical compound, the article provides a brief overview of relevant preclinical and clinical research, emphasizing their potential as microbicides.The article offers insights into the multifaceted impact of microbicides, which signify a pivotal step forward in the pursuit of effective and accessible pre-exposure prophylaxis (PrEP).
Keywords: 
Subject: Medicine and Pharmacology  -   Epidemiology and Infectious Diseases

1. Introduction

Based on the latest data of 2022, the number of people currently suffering from the human immunodeficiency virus (HIV) has reached the mark of 39 million worldwide. Despite the measures taken to prevent the spread of HIV, more than million people are being annually infected. Ever since acquired immunodeficiency syndrome (AIDS) was first clinically observed, it remains one of the main problems which humanity has faced. In 2022, approximately 630,000 people died from AIDS-related illnesses. Moreover, mortality rates are remarkably higher for young adults in developing countries reaching the highest numbers in sub-Saharan Africa [1,2].
Currently, 86% out of all HIV infected people know their HIV status and only 89% of them receive treatment. Considering the bleak statistics, detaining the spread of HIV and increasing the life expectancy should be the main intention. This, in turn, can be obtained through raising public awareness of HIV prevention methods, increasing the effectiveness and universal availability of both HIV diagnostics and active antiretroviral therapy [1,2,3,4,5].
Some studies indicate that the prophylaxis of HIV infection generated substantial economic benefits compared to those of therapy. Preventive measures can be implemented on different levels, including condom usage, voluntary medical male circumcision (VMMC) and pre-exposure prophylaxis (PrEP). Additionally, microbicides can be considered potential drugs used to combat the spread of HIV infection [6,7,8,9].
This review involves the description of some microbicides’ action mechanisms, which can help us understand their evidence base, entering a new era of HIV prophylaxis.

2. Materials and Methods

In this review, we collected information about mucosal immunity and microbicides from different groups. The aim was to describe the current state of microbicide research, highlight new drugs for PrEP (pre-exposure prophylaxis), and show where they are in clinical development and how effective their use is. We used a nonsystematic approach to search for information over a long period of time, starting with the earliest groups of microbicides and progressing to new prospective drugs that are undergoing preclinical and clinical trials. To do this, we used databases such as PubMed, Google Scholar, RePORTER and registers such as ClinicalTrials. We searched by keywords such as “HIV”, “microbicide”, “prophylaxis” and by product name. We selected randomized controlled trials and projects for this review using different combinations of these keywords. Inclusion criteria included up-to-date clinical and randomized controlled trials on different groups of microbicides used for topical immunoprophylaxis. We excluded review articles based on clinical trials, the ones that contained off topic data.
We outlined the main findings from the articles regarding the effectiveness of existing and newly developed microbicides for the most vulnerable populations. We categorized microbicides according to their mechanisms of action and the stage of development they currently exist at. The efficacy of each microbicide was compared with each other, as well as a placebo. Based on this information, we can identify the most promising areas for developing new microbicides and their potential uses.
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Figure 1. PRISMA flow diagram illustrating searches of databases and registers.
Figure 1. PRISMA flow diagram illustrating searches of databases and registers.
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3. Local Immune Response and Mucous Membranes

Most pathogens enter the body through mucous membranes, usually during ingestion, inhalation, or sexual contact, thus, overcoming not only the physical barrier, but also the immune response, organised by the mucosa-associated lymphoid tissue (MALT). In order to better understand the mechanisms of mucosal protection, let’s take a closer look at the anatomy of the female reproductive tract (FRT). The lower FRT is covered by a thick, stratified squamous epithelium. In contrast, the upper FRT is lined with simple columnar epithelium. The transformation area between two tissues contains numerous CD4+ T cells and antigen-presenting cells [10,11]. Most of the ways in which HIV enters the lower FRT involve the breach of the mucosal surface during sexual activity, ulceration caused by other sexually transmitted infections, and the direct infection of CD4+ T cells or macrophages within the epithelium. It is noteworthy that studies suggest anal intercourse to be a more significant risk factor for HIV-1 acquisition than vaginal intercourse [12]. This is explained by the presence of highly susceptible to HIV CD4+ T-cells in the distal gastrointestinal tract and their rapid depletion after the infection, so it makes sense why diarrhoea and wasting syndromes are some of the most common manifestations of the disease [13].
The process of overcoming the mucosal barrier by HIV infection includes several steps. Firstly, the selection of the virus’s genotype occurs, therefore, not all virions will be able to penetrate through the mucous membranes. For instance, B cells upon activation by mucosal dendritic cells switch the class to IgA, which can capture and inactivate viral particles that are not associated with cells [14]. Unfortunately, HIV possesses various ways of suppressing the first line of the mucosal defence. One hypothesis of an impaired humoral response relates to the impact of HIV-1 Nef on B-cell signalling and the inhibition of immunoglobulin class switching. This proposed mechanism involves the creation of actin-driven cellular conduits, that allows Nef to transit from infected macrophages and dendritic cells to uninfected germinal center B cells and accumulate there, which leads to to diminished expression of activation-induced cytidine deaminase, an essential enzyme for class switching. This process is thought to interfere with the normal functioning of B cells and their ability to mount an effective immune response [15,16] (Figure 2).
After transmission of HIV to CD4+ cells,the next step of virus selection develops, where the main role belongs to CD8+ cells, which must recognize infected cells and destroy them through the release of cytotoxic substances. However, upon close examination, it has been observed that gastrointestinal CD8+ T cells have notably lower levels of perforin and granzyme B compared to their counterparts in the blood [17]. Furthermore, two crucial transcription factors, whose expression is required for perforin expression and cytotoxicity, T-bet and Eomesodermin, are weakly expressed by rectal CD8+ T cells. Additionally, the HIV protein Nef limits detection of infected cells by cytotoxic T lymphocytes through the selective downregulation of both HLA-A and HLA-B expression, reducing the presentation of viral epitopes on the cell surface [18]. Restriction of cytotoxic response might prove beneficial to the host by limiting mucosal T-cell depletion and tissue damage. On the other hand, the inability to completely eliminate HIV-infected cells results in the failure of the second step of the virus selection [19].

4. Microbicides

Microbicides represent a potential intervention strategy for preventing HIV transmission. When applied in the vagina or rectum, these medications work to inhibit the penetration of infectious agents affecting the components of mucosal immunity.
Almost three decades ago, the concept of a topical microbicide to protect against HIV was proposed. This idea was driven by the goal of providing women with protection they can control as the majority of prevention methods available to females are subject to the control of their male partners [20]. Along with effective vaccines, microbicides (topical preexposure prophylaxis (PrEP)) and oral PrEP have the potential to accomplish this goal. Both can also serve to protect both men and women from HIV transmission during unprotected anal intercourse [21].
Modern microbicides can be divided into fast-acting drugs, designed to be applied within 1 hour before or after coitus, and drugs used to deliver the active component over a prolonged period of time. The first type includes various forms: gels, creams, ointments, lotions, tablets, aerosols, rinses and application films. These types of microbicides offer the benefit of easy application but their disadvantage is the brief duration of the active component’s effectiveness due to its rapid removal from the epithelial surface. Prolonged drugs include microbicides in forms of contraceptive sponges, intravaginal rings (IVR), uterine (cervical) caps, or enclosed in vaginal or rectal suppositories. They maintain the virucidal concentration of the active component over a greater period of time but also require mechanical installation, for which gynaecological intervention can be used [21,22].
The following groups of microbicides can be distinguished: surfactants or membrane disruptors; vaginal milieu protectors; anionic polymers; dendrimers; carbohydrate-binding proteins; HIV replication inhibitors (reverse transcriptase inhibitors).
Multi-purpose prevention technologies (MPTs) deserve special attention - these are means that provide a combination of HIV prevention, a number of sexually transmitted diseases and contraception.
For the most part, and this is evident from the research currently underway, these are advanced microbicides. Often this is a hormonal drug that acts as a contraceptive and an antiretroviral drug. Among the MPTs being developed, it is worth noting the presence of an implant form, which is injected subcutaneously and gradually releases the active substance.

4.1. Surfactants/Membrane Disruptors

Surfactants were among the first compounds to undergo clinical evaluation as topical microbicides. Well-known representatives of the first generation include nonoxynol-9 (N-9), a mixture of cetyl betaine and myristamine oxide (1.0% C31G; SAVVY) and sodium lauryl sulfate (SLS). Their action mechanism is non-specific and involves disruption of cellular and microbial membranes, which offers contraceptive activity against a wide range of pathogens. However, this could also be potentially toxic to host cells, leading to the destruction of the epithelium, vaginal irritation, inflammation, tissue infiltration by host immune cells, and alterations in vaginal flora, consequently increasing the risk of HIV infection.
The first microbicide formally tested for its efficacy in preventing HIV transmission was N-9. Phase II efficacy trial with COL-1492, a N-9 vaginal gel in female sex workers revealed that applying it more than three times per working day doubled the risk of HIV infection compared to placebo users [23]. Another phase III clinical trial represented that the use of N-9 vaginal film did not reduce the rate of new HIV infection [24]. Both of these results lead to the conclusion that it can no longer be regarded as an effective method for preventing HIV.
C31G, showing broad anti-infective activity against many bacterial and viral STD pathogens, was tested in different safety trials and was advanced to phase III clinical trial in Africa (Ghana and Nigeria) [25,26]. The Nigerian trial with SAVVY vaginal gel represented no significant differences among participants receiving SAVVY compared with those receiving placebo [27].
Sodium lauryl sulfate (SLS) was represented as a potent inhibitor of the infectivity of several enveloped (HIV-1, Herpes simplex viruses, Semliki Forest virus) and nonenveloped (papillomaviruses, reovirus, rotavirus and poliovirus) viruses because of its protein denaturing potency [28]. It was designed to function like an “invisible condom”, able to coat the vaginal wall in liquid form at room temperature and subsequently transition into a gel at body temperature. Although the results of a phase II study of 200 women in Cameroon have been pending, the interest in development of surfactants, indicating a narrow margin between effectiveness and safety, has waned.

4.2. Vaginal Milieu Protectors

Vaginal milieu protectors, another broad group of microbicides, function to preserve the acidic environment within the vaginal canal at a pH level of 4, which was shown to inactivate HIV [29]. The microbicides of this category either directly acidify or enhance the production of lactobacilli. They also serve as spermicides because the presence of semen neutralises the baseline acidity of the vagina, thereby facilitating the penetration of the virus.
Carbopol 974P (BufferGel) is one of the modern representatives of microbicides and a polymer of acrylic acid that can significantly reduce the acidity of the vaginal environment. This, in turn, demonstrates virucidal activity against HIV, as confirmed through in-vitro testing [30]. According to clinical studies conducted on female volunteers in India, Thailand, Malawi, and Zimbabwe BufferGel was proved to be safe and well tolerated by the cervicovaginal epithelium. Notably, there was a reported decrease in the prevalence of bacterial vaginosis after the first week of product use [31]. In 2009, the US National Institute of Allergy and Infectious Diseases (NIAID) discovered that repeated use of Buffer Gel led to the suppression of innate immunity. This finding prevented the product from entering the pharmaceutical market.
The Novel Intravaginal Ring as a Non-Hormonal MPT from the Population Council, whose active ingredients are copper, zinc, lactate, is also designed to optimise vaginal health and protect against STIs by increasing vaginal lactic acid concentrations. Copper IVR (Cu-IVR) from the University of California, which has a similar mechanism of action but does not offer protection against HIV, is also at an early preclinical stage. These drugs are also spermicides (inhibit sperm motility).
Additionally, in the early 21st century, attempts were made by doctors to employ lactobacilli as microbicides for stabilising vaginal pH—a remedy historically used for managing different dysbioses. However, due to the brief duration of therapeutic effects and the extended time required for lactobacilli colonies to flourish, research on microbicides based on non-genetically modified Lactobacillus sp. was subsequently discontinued.

4.3. Entry Inhibitors

The group of microbicides based on anionic polymers and dendrimers includes substances such as carrageenans, naphthalene sulfonate polymers, cellulose sulfate, nanosized dendrimers and humic acids. Action mechanism of this group involves the inhibition of viral fusion by binding to HIV surface proteins or to receptors and co-receptors of target cells.
One of the first microbicides of this group were carrageenans, a family of linear sulfated polysaccharides derived from a seaweed extract. Carrageenans are similar in structure to heparan sulfate, which is used by many microorganisms as a biochemical receptor for initial attachment to the cell membrane. Thus, carrageenans act as decoy receptors for virus fusion [22]. However, a phase III study carried out on female volunteers in South Africa from 2004 to 2007 indicated that while Carraguard gel was deemed safe for over a 2-year period of use, the occurrence of new HIV infections was comparable in both the Carraguard and placebo groups. Thus, the study did not demonstrate a statistically significant impact of carrageenans on the sexual transmission of HIV infection [32].
Other polyanionic microbicides are naphthalene sulfonate polymers PIC 024-4 and PRO 2000. PRO 2000 competes with the V3 loop of gp120 HIV-1 envelope in binding with the target cell receptor CD4 [33]. Clinical trials of PRO 2000 vaginal gel conducted on female volunteers from South Africa, Tanzania, Uganda and Zambia showed the safety of the drug, however, its effectiveness was not proven.
SPL7013 (or VivaGel® or astodrimer sodium), belonging to macromolecules with a tree-like and regularly branching structure (dendrimers) is of great interest as it is the only medication that does not contain antiretroviral (ARV) agents but yet demonstrates excellent anti-HIV potential. This medication, which initially showed its effectiveness in treating bacterial vaginosis, has already completed phase 3 clinical trials (NCT01577537), and has been registered and approved for use in more than 55 countries. In addition, the company began producing a lubricated condom and a nasal spray with the same active ingredient, which provides a moisturizing and protective barrier against respiratory viruses [34].
In the future, developments based on dendrimer-like substances, such as humic acids found ubiquitously in nature, hold promise. These substances are hyperbranched polyelectrolytes, characterized by a network of polydisperse aromatic and aliphatic structures highly substituted by carboxyl and hydroxyl groups. Humic acids, known for their low toxicity and antioxidant activity, have synthetic analogs like HS-1500 (oxyhumate), obtained through hydroquinone polymerization. Research has shown their ability to inhibit HIV in MT-2 cells [35], with effective concentrations ranging from 50-300 ng/ml and a semi-toxic concentration of 600 µg/ml.
HS-1500’s proposed mechanism involves blocking the binding of the V3 loop of gp120 to the CD4 receptor on target cells. Studies by G.K. Joone et al. demonstrated that HS-1500 enhances the proliferative effect of phytohemagglutinin on lymphocytes from HIV-infected patients [36]. This stimulative effect was also observed when administering HS-1500 to HIV-positive patients at a dose of 4 g/day for 2 weeks. The observed proliferation stimulation correlated with increased production of interleukin (IL) 2 and expression of IL-2 receptors, along with a decrease in the amount of IL-10 under the influence of HS-1500.
Another promising group may be polysaccharide-binding substances, whose representatives belong to natural peptides. The most prominent representatives are cyanovirin-N (CVN), a lectin compound derived from the cyanobacterium Nostoc ellipsosporum, and griffithsin (GRFT), derived from the red algae Griffithsia. Their mechanism of action involves the prevention of viral-host cell fusion by mannose residues on the surface of the virion. The effectiveness of these proteins against HIV infection when administered rectally and vaginally has been proven in preclinical studies [37]. The Population Council has begun to develop a vaginal insert based on this substance and 2 studies are currently at the preclinical testing stage. For the purposes of this study, GRFT has been genetically modified to produce a more stable compound less prone to oxidation, called Q-GRFT. It will be safe and suitable for use by women of any age, as well as pregnant and lactating women [38].
Peptide microbicides are promising, as it is possible to integrate the gene encoding this peptide into any microorganism. At the U.S. National Institutes of Health (NIH), research is being conducted on the potential colonisation of women’s vaginal microbiota with Lactobacillus jensenii, bacteria containing an embedded gene producing cyanovirin-N protein. Thus, this kind of microbicide will have multiple mechanisms of action: the ability to bind mannose residues on the virion surface and restore the normal vaginal flora.

4.4. HIV Replication Inhibitors

The mechanism of action of this group involves binding to the HIV-1 Reverse Transcriptase (RT) enzyme, which is responsible for the conversion of viral RNA into Proviral DNA, making viral replication impossible. One of the main distinguishing features of HIV replication inhibitors is that their active substances have already demonstrated efficacy in HIV Therapeutics. There are Nucleoside RT Inhibitors (NRTIs), or Nucleotide RT Inhibitors, which mimic endogenous nucleotides and halt the elongation of the viral DNA chain within the target cell, and Non-Nucleoside RT Inhibitors (NNRTIs), which in turn disrupt the binding of the substrate to the active site of the enzyme and have been demonstrated to bind irreversibly to RT [39]. The most famous representative of the NNRTI class is Dapivirine. Due to its irreversible binding and lipophilic properties, it may be active against both Cell-Free and Cell-Associated HIV. A vaginal gel based on dapivirine has demonstrated the ability to prevent HIV infection in humanised mice during preclinical trials [40]. The lead NRTI, in turn, is tenofovir, an adenosine monophosphate analogue. Tenofovir is converted into the active metabolite tenofovir diphosphate, which competes with deoxycytidine 5’-triphosphate for HIV-1 reverse transcriptase. It was formulated as a 1.0% vaginal gel as a microbicide composition.
Clinical trials conducted by the Centre for the AIDS Programme of Research in South Africa (CAPRISA) in July 2010 showed that tenofovir gel was 39% effective [41]. The results of third phase (FACTS-001) clinical trials indicated that peri-coital tenofovir did not prevent HIV-1 acquisition among young women at risk for HIV infection in South Africa. Microbicides from this group play a crucial role in drugs designed for pre-exposure prophylaxis, which are currently undergoing both clinical and preclinical trials.

4.4.1. Clinical Trials of Topical and oral Pre-Exposure Prophylaxis (PrEP)

In introducing drugs designed for topical pre-exposure prophylaxis (PrEP) currently undergoing clinical trials, it is essential to highlight the diverse intravaginal rings (IVRS) as notable candidates in this emerging landscape. IVRS containing only tenofovir (TFV) or TFV plus levonorgestrel (LNG), which is a contraceptive hormone, have undergone several Phase I trials conducted by CONRAD in 2016 (NCT02235662) and 2019 (NCT03279120), respectively, and have successfully met all performance benchmarks.Currently, the NCT03255915 study of intravenous administration (TDF-FTC pod-IVR) is ongoing, but participants have not been recruited yet. A Phase-IIa trial conducted in Kenya (NCT03762382) showed that TFV/LNG and TFV-containing IVRS did not adversely affect the genital microbiota and are therefore safe to use [42].
Another type of IVRS includes those containing dapivirine, an NNRTI (non-nucleoside reverse transcriptase inhibitor), which are in their final stages of development. The completed Phase 3b trial by the Microbicide Trials Network (MTN 043) affirms the safety of monthly DPV (dapivirine)-containing IVRS, particularly when used by breastfeeding women. It is worth noting that DPV IVRs have been approved by the South African Health Products Regulatory Agency (SAHPRA), for women, in March 2022. This was immediately followed by an official WHO recommendation being issued. IVRs containing DPV/LNG, which are released over a period of 90 days, underwent Phase I trials, resulting in encouraging outcomes, supporting further development of the DPV/ LNG IVR. Additionally, it is worth noting fast-dissolving inserts that are applicable for both vaginal and rectal use. They incorporate tenofovir alafenamide (TAF), a tenofovir prodrug, and elvitegravir (EVG), which is an HIV-1 integrase strand transfer inhibitor. The latter prevents the integration of HIV-1 DNA into the host DNA, thereby blocking the formation of the HIV-1 provirus [20,42,43]
These inserts have shown positive results in non-human primates, whether they are inserted vaginally hours before or after exposure to SHIV (simian human immunodeficiency virus). Additionally, in phase I trials (CONRAD 146 and MTN-039), the inserts were assessed for safety, pharmacokinetics, and pharmacodynamics. CONRAD 146 was a completed study that evaluated the TAF/EVG vaginal insert, while MTN-039 was a study focused on the rectal administration of the same and its results are expected soon. Additionally, a placebo version of this insert was assessed in two global studies: the Quatro study comparing four vaginal forms in African women and the MTN-035 (DESIRE) study comparing three rectal forms. The next step involves bringing this drug to a comprehensive multi-dose safety and pharmacokinetic study [44].
It is necessary to mention the means being developed for HIV monoprophylaxis. For example, MK-8527, a new nucleoside reverse transcriptase translocation inhibitor is being developed by Merck. This drug will be used as a once-weekly drug for treatment and as a monthly drug for PrEP. Merck had hoped that islatravir could be developed as a weekly or monthly antiretroviral, but at the higher doses needed for long-acting dosing, islatravir caused loss of lymphocytes. Currently, there are 2 trials of the drug underway. These are the MK-8527 Single-Dose Trial in HIV-1 Infected Participants (MK-8527-004) under registration number NCT05494736, taking place in Romania and South Africa, and the Safety and Pharmacokinetic Study of Oral MK-8527 QM in Participants at Low-Risk for HIV-1 Infection (MK-8527-007) under registration number NCT06045507, currently recruiting in Israel and the USA.
The first study evaluated the safety, tolerability, pharmacokinetics, and antiretroviral activity of MK-8527 in participants who had not previously received antiretroviral therapy with HIV-1 infection. The second study is a double-blind, placebo-controlled study designed to assess the safety, tolerability, and pharmacokinetics of oral MK-8527 taken once a month in participants at low risk of HIV-1 infection.
It is important to remember PrEp drugs that have been approved by the Food and Drug Administration (FDA). There are two combined drugs from Gilead: Truvada and Descovy. Descovy contains two different medicines: emtricitabine and tenofovir alafenamide. Truvada contains two different active ingredients: emtricitabine and tenofovir disoproxil fumarate. Both are used for HIV PrEP to reduce the risk of HIV infection in adults and adolescents who weigh at least 77 lb (35 kg), are HIV negative, and are at risk of getting HIV. However, the Descovy drug for PrEP is not approved for use in females at risk of infection through vaginal sex, as this use has not been studied in clinical trials [45,46].
The company ViiV Healthcare is introducing Cabotegravir in two forms - tablets and long-acting injections. Cabotegravir oral tablet (brand name: Vocabria) is used both for the short-term treatment of HIV infection in adults and adolescents 12 years of age and older who weigh at least 77 lb (35 kg) and for short-term PrEP to reduce the risk of HIV infection in adults and adolescents who weigh at least 77 lb (35 kg), are HIV negative, and are at risk of getting HIV. Long-acting injectable cabotegravir (brand name: Apretude) is used for HIV PrEP to reduce the risk of HIV infection in adults and adolescents who weigh at least 77 lb (35 kg), are HIV negative, and are at risk of getting HIV [47].
Gilead Sciences presents Lenacapavir, approved by the FDA under the brand name Sunlenca for HIV treatment. Belonging to a group of capsid inhibitors, Lenacapavir can interfere with the HIV capsid, which protects the virus’s genetic material and replication enzymes. This interference leads to disruption at various stages of the viral life cycle, preventing HIV multiplication and reducing viral load. Lenacapavir is also under investigation as a preventive measure in ongoing studies (NCT04994509 in South Africa and Uganda, and NCT04925752 in the United States, Brazil, Puerto Rico, and South Africa), with Phase 3 results pending [48]. Ongoing clinical trials are shown in Table 1.

4.4.2. Drugs in Preclinical and Early Clinical Phases

There are quite a few combined drugs undergoing preclinical and early-stage clinical development that hold potential for progressing into subsequent phases of clinical trials. We would have an easier time categorising these drugs according to their hormonal classification. Drugs of the hormonal type typically consist of a hormonal contraceptive (LNG, EE, Etonogestrel or Norelgestromin), combined with various antiretroviral drugs such as DPV, TDF, TFV or Cabotegravir and Islatravir. As mentioned earlier, these combinations serve to prevent ovulation and inhibit replication of HIV.
Another example of potential hormonal drugs involves combining contraceptive hormones with the stable analog of non-anti-retroviral anti-HIV lectins, QGRFT, which binds to the HIV envelope glycoprotein and prevents entry into target cells. Non-hormonal microbicides composed of various components primarily aim to bind or inactivate sperm, thereby preventing not only pregnancy but also transmission of HIV. Some are based on combinations of monoclonal antibodies like mAb 2C7, which mediates the killing of Neisseria gonorrhoeae or agglutinating sperm antibodies, with antiretroviral drugs, specifically TDF. Others are represented by IVR containing a fully human antibody (HCA) that has the ability to agglutinate sperm incorporated into a sustained release delivery system effectively preventing both pregnancy and transmission of HIV, but monoclonal antibodies are not the only option for future PrEP. There are other combinations of drugs like QGRFT with organic acids formulated into fast dissolving inserts that lower vaginal pH in presence of semen rendering it inactive. Other possible drugs for rendering semen infertile without harming other cells are combinations of polyphenylene and carboxymethylene (PPCM). PPCM causes premature acrosome loss in sperm and inhibits hyaluronidase, preventing sperm from fertilising an ovum [52].
Except for new combinations with a familiar delivery system, certain products have been introduced using an innovative one. This involves incorporating TFV / EFV nanoparticles (NPs) into a polymer film base (TFV / EFV NPs - in - film), enabling higher concentrations of both drugs in the genitals compared to their delivery in a liquid carrier [53]. The discussed combined microbicides, featuring groundbreaking innovations, have promising prospects. Notably, these formulations are at various stages in clinical trials, ranging from early to advanced phases and are nearing commercial viability. A significant number of candidates are undergoing clinical investigation, highlighting the potential of microbicides for future preventive applications.
As these products progress through research phases, it becomes increasingly clear that microbicides have the potential to play a critical role in preventive healthcare strategies [20,54,55,56,57]. Summary chapters are available in Table 2 and Table 3. The chemical structures of the mentioned microbicides are presented in Table 4.

5. Discussion

Microbicides play a crucial role in the fight against HIV/AIDS by providing an additional prevention tool, particularly for populations facing barriers to other existing methods such as condoms or oral PrEP. The urgent need for microbicides targeting HIV, particularly those designed for vaginal application, stems from several critical factors that underline the ongoing global efforts to curb the spread of HIV/AIDS. Globally, women bear a disproportionate burden of HIV infection, especially in sub-Saharan Africa where they account for a majority of new infections. Biological factors, such as the higher susceptibility of vaginal tissues to HIV transmission compared to penile tissues, contribute to this disparity. Vaginal microbicides offer a targeted approach to address this vulnerability by providing a protective barrier at the site of transmission, potentially reducing the risk of HIV acquisition among women. While significant progress has been made in HIV prevention, existing strategies such as condoms and oral PrEP have limitations that underscore the need for additional options. Condoms require partner cooperation and may not be consistently used, while oral PrEP may be inaccessible or unsuitable for some individuals. Vaginal microbicides offer a complementary approach that can be used discreetly and independently, filling critical gaps in the prevention toolkit and bolstering overall HIV prevention efforts.

6. Conclusion

In conclusion, the field of microbicides holds great promise for the ongoing fight against HIV infection. Recently discovered, these compounds offer a fertile ground for potential breakthroughs with numerous unexplored and unsynthesized forms. We have examined diverse classes of microbicide, dissecting their benefits and drawbacks. Our focus has narrowed down to the most promising groups of preventive agents, exploring their evolution through different phases of clinical trials. Microbicides with their multifaceted nature move from early research into the verge of being available. Within clinical trials, the extensive interest in them become apparent, revealing the nuanced promise that these agents hold for preventing HIV. Despite challenges such as optimising efficacy and distributing widely, the documented progress indicates a hopeful trajectory. Ongoing exploration and synthesis of microbicide fuel optimism for innovative solutions in HIV prevention. This field is an exciting frontier for further research and development in the global battle against HIV/AIDS.

Author Contributions

Conceptualization, Y.V.Z., V.O.P. and M.Y.S.; writing-original draft preparation, Y.V.Z., V.O.P., M.Y.S., S.O.V.; writing—review and editing, Y.V.Z., V.O.P., M.Y.S., S.O.V., E. Al-khaleefa, K.R.P., N.Y.F., D.V.S., R.V.P., O.V.M., A.A.B., N.N.Z.; visualization, M.Y.S., Y.V.Z.; supervision, Y.V.Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.

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Preprints 106442 g002
Figure 2. In the first step of selection, the virus genotype is chosen. B cells switch the class to IgA, capturing and neutralising viral particles not linked to cells. On the other hand, HIV’s Nef protein impedes the immunoglobulin class switching process, limiting the effectiveness of humoral immunity. Second step involves selection of HIV particles associated with cells. CD8+ cells identify infected CD4+ cells and eliminate them by releasing cytotoxic substances.
Figure 2. In the first step of selection, the virus genotype is chosen. B cells switch the class to IgA, capturing and neutralising viral particles not linked to cells. On the other hand, HIV’s Nef protein impedes the immunoglobulin class switching process, limiting the effectiveness of humoral immunity. Second step involves selection of HIV particles associated with cells. CD8+ cells identify infected CD4+ cells and eliminate them by releasing cytotoxic substances.
Preprints 106442 g002
Table 1. Clinical trials of pre-exposure prophylaxis currently under way.
Table 1. Clinical trials of pre-exposure prophylaxis currently under way.
Product Name Delivery method Product developer Active ingredients Hormonal type Useful links Registration number
Dapivirine + Levonorgestrel IVR Intravaginal Ring (IVR) International Partnership for Microbicides Dapivirine Levonorgestrel Hormonal [49,50] NCT05041699
MK-8527 Oral tablet Merck MK-8527 new nucleoside reverse transcriptase translocation inhibitor Non-hormonal [51] NCT05494736

NCT06045507
Lenacapavir Injectables (Subcutaneus) Gilead Lenacapavir- capsid inhibitor in combination with other antiretrovirals Non-hormonal [48] NCT04994509

NCT04925752
Table 2. Antiretroviral drugs at the preclinical and early clinical stages and their mechanisms of action.
Table 2. Antiretroviral drugs at the preclinical and early clinical stages and their mechanisms of action.
Product developer Active Ingredients Hormonal type Mechanism of Action (Meaning)
Population Council, Oak Crest Institute of Science Etonogestrel
Ethinyl Estradiol
QGRFT		 Hormonal Ovulation inhibition (pregnancy); binding to HIV envelope glycoproteins to prevent entry of HIV into target cells (QGRFT)
University of North Carolina, Chapel Hill Dapivirine
Levonorgestrel
Pritelivir		 Hormonal Antiretroviral drug + hormonal contraceptive
Auritec Pharmaceuticals Acyclovir
Dolutegravir
Etonogestrel
Ethinyl Estradiol
Rilpivirine		 Hormonal Antiretroviral drug + hormonal contraceptive
University of North Carolina, Chapel Hill Etonogestrel
Ethinyl Estradiol
Islatravir (EFdA)		 Hormonal Antiretroviral drug + hormonal contraceptive
MassBiologics
Oak Crest Institute of Science
Planet Biotechnology, Inc.
University of Massachusetts		 Monoclonal Antibodies
Tenofovir Disoproxil Fumarate (TDF)		 Non-Contraceptive mAb 2C7 mediates complement-dependent killing of Neisseria gonorrhoeae. TDF is NRTI targeting HIV infection.
Oak Crest Institute of
Science, Univ. of North Carolina, Chapel Hill		 Monoclonal Antibodies
Tenofovir Disoproxil Fumarate (TDF)		 Non-Hormonal Nucleoside analogue reverse transcriptase inhibitor (NRTI) and sperm agglutinating antibody
MUCCOMMUNE LLC HCA
Monoclonal Antibodies
VRC01 + N6		 Non-Hormonal viral neutralisation (sustained release of antibodies for non-hormonal contraception and HIV prevention)
Population Council QGRFT
Organic acids		 Non-Hormonal The selected organic acids will lower vaginal pH (pH = 3.5-4.5) in the presence of semen. The low pH inactivates sperm and bacteria. When inserted into the vagina, the FDI dissolves into a viscous gel delivering the active agents throughout the vaginal lumen to prevent sperm penetration. QGRFT is a potent non-antiretroviral (ARV) inhibitor of HIV. QGRFT binds to HIV envelope glycoproteins and prevents entry of HIV into target cells.
Magee-Women’s Research Inst. & Fndn., University of Pittsburgh 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA)
4′-Ethynyl-2-fluoro-2′-deoxyadenosine prodrug (EFdA-P)
Progestin		 Hormonal Nucleoside reverse transcriptase translocation inhibitor and progestin hormonal contraceptive
Magee-Women’s Research Inst. & Fndn., University of Pittsburgh Dapivirine
Levonorgestrel		 Hormonal Antiretroviral drug + hormonal contraceptive
Inst. For Research &
Innovation in Health (i3S), University of Porto		 Efavirenz (EFV)
Tenofovir (TFV)		 Non-Contraceptive Short-term (on-demand) protective film that dissolves on contact with vaginal fluids to deliver combination antiviral compounds
Research Triangle International (RTI) Unspecified Hormonal nucleoside reverse transcriptase inhibitor; ovulation suppression
PATH
Queen’s University Belfast		 Norelgestromin
ARV candidates under review		 Hormonal ARV + Progestin
CONRAD Cabotegravir
Levonorgestrel		 Hormonal Integrase strand-transfer inhibitor; progestin
University of North Carolina, Chapel Hill Hormonal Contraceptive
Antiretroviral (ARV)		 Hormonal Antiretroviral drug + hormonal contraceptive
Yaso Therapeutics Polyphenylene Carboxymethylene (PPCM) Non-Hormonal PPCM prevents viral binding and fusion to a host cell by attaching to and blocking key viral binding sites. It has been demonstrated that PPCM binds gB on HSV-2 and gp120 on HIV. PPCM has also shown promise against Ebola virus in vitro and gonorrhoea, in vitro and in mice. PPCM renders sperm infertile without damaging other cells.
Table 3. Antiretroviral drugs at the preclinical and early clinical stages.
Table 3. Antiretroviral drugs at the preclinical and early clinical stages.
Product Name Indications Clinical Phase Product Developer Active ingredients Hormonal type Useful links
Intravaginal ring (IVR)
90-day Pod-type Etonogestrel/Ethinyl Estradiol/QGriffithsin (EEQ) HIV, Pregnancy Preclinical – Early (Pre1) Population Council, Oak Crest Institute of Science Etonogestrel
Ethinyl Estradiol
QGRFT		 Hormonal [61]
Dapivirine + Pritelivir + Levonorgestrel 3D Printed IVR HIV, Pregnancy, HSV-2 Preclinical – Early (Pre1) University of North Carolina, Chapel Hill Dapivirine
Levonorgestrel
Pritelivir		 Hormonal [62]
Novel Intravaginal Ring as a Non-Hormonal Contraceptive Multipurpose Prevention Technology (MPT) Bacterial Vaginosis (BV)
Chlamydia
Gonorrhea
HIV
HSV-2
Pregnancy		 Pre-formulation, pre-Phase 1, Non-clinical Population Council
Queen’s University Belfast
Weill Cornell Medical College		 Copper
Zinc
Lactide		 Non-Hormonal [63]
Islatravir (EFdA) + Etonogestrel/Ethinyl Estradiol 3D Printed IVR HIV
Pregnancy		 Preclinical – Early (Pre1) University of North Carolina, Chapel Hill Etonogestrel
Ethinyl Estradiol
Islatravir (EFdA)		 Hormonal [64]
IVR. mAb
mAb 2C7 + TDF IVR HIV, Gonorrhea Preclinical – Advanced (Pre2) MassBiologics
Oak Crest Institute of Science
Planet Biotechnology, Inc.
University of Massachusetts		 Monoclonal Antibodies
Tenofovir Disoproxil Fumarate (TDF)		 Non-Contraceptive [65]
Novel mAb contraceptive + Tenofovir Disoproxil Fumarate (TDF) IVR HIV, Pregnancy Preclinical – Early (Pre1) Oak Crest Institute of
Science, Univ. of North Carolina, Chapel Hill		 Monoclonal Antibodies
Tenofovir Disoproxil Fumarate (TDF)		 Non-Hormonal [66]
Human Contraceptive Antibody (HCA) + VRC01 + N6 IVR HIV, Pregnancy Preclinical – Advanced (Pre2) MUCCOMMUNE LLC HCA
Monoclonal Antibodies
VRC01 + N6		 Non-Hormonal [67]
Non-ARV/Non-Hormonal Multi-Purpose Vaginal Ring HIV
HPV
HSV-1
HSV-2
Pregnancy		 Pre-formulation Oak Crest Institute of Science Unspecified Non-Hormonal [68]
Fast- dissolving inserts (FDIs) (Vaginal)
Non-hormonal Contraceptive Multipurpose Prevention Technology (MPT) Containing Q-Griffithsin (QGRFT) Bacterial Vaginosis (BV)
Chlamydia
Gonorrhea
HIV
HSV-2
Pregnancy		 Preclinical – Early (Pre1) Population Council QGRFT
Organic acids		 Non- Hormonal [69]
Griffithsin (GRFT) Fast-Dissolving Insert (FDI) HIV
HPV
HSV-1
HSV-2		 Pre-formulation Population Council Unspecified Non-Contraceptive [70]
Films (Vaginal)
EFdA-P + Progestin Intravaginal Film HIV, Pregnancy Early Preclinical Magee-Women’s Research Inst. & Fndn., University of Pittsburgh 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA)
4′-Ethynyl-2-fluoro-2′-deoxyadenosine prodrug (EFdA-P)
Progestin		 Hormonal [71]
Dapivirine/Levonorgestrel Extended-Release Monthly Film HIV, Pregnancy Early Preclinical Magee-Women’s Research Inst. & Fndn., University of Pittsburgh Dapivirine
Levonorgestrel		 Hormonal [72]
Tenofovir (TFV)/Efavirenz (EFV) Nanoparticles-in-film HIV, HSV-1, HSV-2 Advanced Preclinical Inst. For Research &
Innovation in Health (i3S), University of Porto		 Efavirenz (EFV)
Tenofovir (TFV)		 Non-Contraceptive [73]
Implants
Cabotegravir Pellet Implant with Levonorgestrel HIV, Pregnancy Early Preclinical CONRAD Cabotegravir
Levonorgestrel		 Hormonal [74]
Long-acting refillable nanofluidic implant (NanoMPI)- SC HIV, Pregnancy Early Preclinical University of Washington
Methodist Hospital Research Institute (HMRI)		 Etonogestrel
Islatravir (EFdA)		 Hormonal [75]
Injectables (Subcutaneus)
Cabotegravir/Levonorgestrel Long-Acting MPT Injectable HIV
Pregnancy		 Advanced Preclinical CONRAD Cabotegravir
Levonorgestrel		 Hormonal [74]
Injectable In-situ Forming Implants
Ultra-Long-Acting MPT In-situ Forming Implant (ISFI) HIV
Pregnancy		 Early Preclinical University of North Carolina, Chapel Hill Hormonal Contraceptive
Antiretroviral (ARV)		 Hormonal [76]
Gels (Vaginal / Rectal)
Yaso-GEL HIV, Pregnancy, HSV-2, HPV, Gonorrhea Advanced Preclinical Yaso Therapeutics Polyphenylene Carboxymethylene (PPCM) Non-Hormonal [77]
Oral Tablet
Dual Prevention Pill (DPP) Regimen HIV
Pregnancy		 Preclinical – Early (Pre1) Population Council
Medicines360		 Emtricitabine (FTC)
Ethinyl Estradiol (EE)
Levonorgestrel
Tenofovir Alafenamide (TAF)		 Hormonal [60]
Intravaginal Rings (Non-HIV)
Copper Intravaginal Ring (Cu-IVR) Pregnancy, HSV-2, Zika virus Early Preclinical University of California, Davis Copper Non-Hormonal [78]
Table 4. The chemical structure of microbicides.
Table 4. The chemical structure of microbicides.
Preprints 106442 i001 Preprints 106442 i002
Nonoxynol-9 (C33H60O10) C31G (C30H64N2O3)
Preprints 106442 i003 Preprints 106442 i004
Sodium lauryl sulfate (C12H25SO4Na) Carbopol 974P ( [C3H4O2]n)
Preprints 106442 i005 Preprints 106442 i006
Ϳ-Carrageenans ([C12H16O15S2 2-]n) Naftalane sulfonate polymers ([C11H9NaSO4]n)
Preprints 106442 i007 Preprints 106442 i008
Dapivirine (C20H19N5) Tenofovir (C9H14N5O4P)
Preprints 106442 i009 Preprints 106442 i010
Levonorgestrel (C21H28O2) Tenofovir alafenamide (C21H29N6O5P)
Preprints 106442 i011 Preprints 106442 i012
Elvitegravir (C23H23ClFNO5) Emtricibatine (C8H10FN3O3S)
Preprints 106442 i013 Preprints 106442 i014
Tenofovir disoproxil fumarate (C23H34N5O14P) Cabotegravir (C19H17F2N3O5)
Preprints 106442 i015
Islatravir (C12H12FN5O3)
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