|
 |
| REVIEW ARTICLE |
|
| Year : 2018 | Volume
: 17
| Issue : 2 | Page : 49-57 |
|
|
Nanotechnology and the future of condoms in the prevention of sexually transmitted infections
Clarence S Yah1, Geoffrey S Simate2, Percy Hlangothi3, Benesh M Somai4
1 Implementation Science Unit, Wits Reproductive Health and HIV Institute (Wits RHI), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; Department of Biochemistry and Microbiology, Nelson Mandela University, Port Elizabeth, South Africa
2 School of Chemical and Metallurgical Engineering, University of the Witwatersrand, Johannesburg, South Africa
3 Centre for Rubber Science and Technology, Nelson Mandela University, Port Elizabeth, South Africa
4 Department of Biochemistry and Microbiology, Nelson Mandela University, Port Elizabeth, South Africa
| Date of Web Publication | 13-Mar-2018 |
Correspondence Address:
Dr. Clarence S Yah
Wits Reproductive Health and HIV Institute, University of the Witwatersrand, P/Bag 3, Wits 2050, Johannesburg
South Africa
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/aam.aam_32_17
 Abstract | | |
Objective: The human immunodeficiency virus (HIV) is among the utmost destructive viruses humankind has ever faced in almost four decades. It carries with it profound socioeconomic and public health implications. Unfortunately, there is, currently, no effective cure for HIV infections. This review discusses the various types of condoms, microbicides, and the potential use of nanoparticle-coated condoms as a means of diminishing the risk of HIV transmission and sexually transmitted infections (STIs) during sexual intercourse. Methods: We identified 153 articles from 1989 to 2015 indexed in various journal platforms, reports, and magazines. Using the PRISMA guidelines as proxy in performing the research review process, only 53 articles were selected. Ideally, articles that failed to describe the nature and types of condoms, condom failures, nanoparticle-coated condoms, microbicides, and HIV prevention were excluded. Results and Discussion: In general, it has been shown that antiretroviral therapy (ART) currently available can only limit transmission and acquisition of HIV strains. Apart from ART treatment, the use of condoms has been identified globally as a cost-effective intervention for reducing the spread of HIV and other STIs. However, while condoms are supposed to be effective, reliable, and easy to use, research has shown that they are attributable to 20% failures including breakages. Nevertheless, other studies have shown that coating condoms with nanoparticles is an important and effective method for reducing condom breakage and HIV/STI transmission during sexual intercourse. Conclusions: A review of literature cited in this paper has shown that nanotechnology-based condom systems have the potential to prevent the spread of HIV and STIs. Furthermore, the antimicrobial nature of some nanoparticles could provide a safe and efficient way to disrupt and/or inactivate different STIs – including viral, bacterial, and fungal diseases.
| Abstract in French | | |
Objectif: Le virus d'immunodéficience acquise (VIH) est l'un des virus les plus destructeurs auquel l'humanité toute entière a eu à faire face durant ces quatre décennies. Loin d'être un sujet de santé publique à prendre à la légère, il traine dans son sillage des profondes conséquences socio-économiques. Malheureusement, il n'ya pas de traitement effectif à ce jour contre les infections liées au VIH. Cette revue fait donc un bref étalage des différents types de condoms, de microbicides et de l'utilisation des condoms enrobés de nanoparticules comme méthodes de prévention de la transmission du VIH et des maladies sexuellement transmissibles (MST) pendant les rapports sexuels. Méthode: Nous avons identifié153 articles datant de 1989 à 2015 et indexés dans plusieurs plateformes de revues scientifiques et de rapports. Utilisant les indications de PRISMA comme proxy dans le processus de recherche, seulement 53 articles ont été sélectionnés. Ceux qui n'ont pas traité de la nature et des types de condoms, de l'échec de l'utilisation des condoms, des condoms enrobés de nanoparticules, des microbicides et de la prévention du VIH ont été exclus. Résultat et Discussion: Dans l'ensemble, il a été démontré que la thérapie antirétrovirale (TAR) disponible présentement limite uniquement la transmission des souches de VIH. En plus des traitements par TAR, l'utilisation des condoms a été reconnue de façon globale comme méthode appropriée et efficace de réduction de la dissémination du VIH et des MST. Cependant, nonobstant le fait que les condoms soient considérés comme moyens effectifs, fiables, efficaces et faciles à utiliser, il a été démontré par les chercheurs que 20% des cas d'échecs sont attribués à la déchirure des condoms. Néanmoins, aucune étude n'a démontré que les condoms enrobés de nanoparticules offrent une meilleure option face aux déchirures et à la réduction de la transmission du VIH et des MST lors des rapports sexuels. Conclusion: La revue de littérature citée dans cet article a démontré que les condoms enrobés de nanoparticules ont le potentiel de prévenir la dissémination du VIH et des MST. Dans le même ordre d'idée, la nature antimicrobienne de certaines nanoparticules pourrait contribuer efficacement et sûrement à éliminer les différentes MST y compris celles d'origine virale, bactérienne ou fongique.
Mots clés: Thérapie antirétrovirale, condom, syndrome d'immunodéficience acquise /infection sexuellement transmissible, microbicide, nano-composites antimicrobiens, prévention Keywords: Antiretroviral therapy, condom, human immunodeficiency syndrome/sexually transmitted infection, microbicide, nanocomposite-antimicrobial condoms, prevention
How to cite this article:
Yah CS, Simate GS, Hlangothi P, Somai BM. Nanotechnology and the future of condoms in the prevention of sexually transmitted infections
. Ann Afr Med 2018;17:49-57 |
How to cite this URL:
Yah CS, Simate GS, Hlangothi P, Somai BM. Nanotechnology and the future of condoms in the prevention of sexually transmitted infections
. Ann Afr Med [serial online] 2018 [cited 2023 Mar 28];17:49-57. Available from: https://www.annalsafrmed.org/text.asp?2018/17/2/49/227177 |
| Introduction | |  |
The human immunodeficiency virus (HIV) and sexually transmitted infections (STIs) constitute major global health burdens, especially in Sub-Saharan Africa where life expectancy has fallen because of HIV and HIV-related diseases.[1] Unfortunately, there is, currently, no effective cure for HIV infections. Antiretroviral therapy (ART) including preexposure prophylaxis (PrEP) and postexposure prophylaxis (PEP), currently available, can only limit transmission and acquisition of HIV strains. However, apart from ART treatment used in reducing the burden of HIV, community engagement, system strengthening, individual-centered behavioral change, advocacy, counseling, and promotion of the use of condoms have been identified globally as cost-effective interventions for reducing the spread of HIV and other STIs.[2] In particular, HIV counseling and testing (HCT) and the use of condoms have been scaled up globally, especially in settings with elevated HIV incidences.[1]
Although HCT and the use of condoms, male circumcision [3],[4],[5],[6],[7] combined with community education, health care/promotion delivery systems-centered approaches, and advocacy strategies enhance behavioral changes [8] that improve health-care quality of HIV and STIs' acquisition and transmission, the HIV epidemic persists.[9] This is largely due to condom-breakage/slippage, noncompliance, and nonadherence to ART medications.[10] In fact, earlier meta-analysis findings by Weller and Davis [11] showed that condoms are 87% effective in preventing pregnancy and provide only approximately 69% of HIV transmission risk reduction. However, their efficacy is much lower than 69% during sexual intercourse. Other studies indicate that the efficiency and efficacy of using condoms depend on condom use, health promotion, and individual lifestyle behavior.[12] Some of the factors that have influenced poor condom uptake and eroded their efficacy stem from structural factors such as gender inequality, stigma, discrimination, partner interest, poverty, length of relationships, and the extent of partner trust.[13],[14],[15],[16],[17],[18],[19],[20],[21]
The failure and incorrect use of condom have had serious and devastating effects, especially in terms of HIV and STIs acquisition, transmission, and other related health consequences including premature pregnancies.[1] Therefore, innovative ideas are needed to improve condoms properties and usage. It is believed that condom innovations are a key to the adoption and sustained uptake that can eventually have an impact on HIV and other STIs transmission during sexual intercourse.[15]
Previous research studies with respect to innovative approaches indicate that antimicrobial nanoparticle-coated condoms have great qualities of nonspecific broad-spectrum antimicrobial properties against viruses, bacteria, and fungi.[16] In addition to preventing HIV transmission, they potentially destroy secreted HIV and other STIs in anal and vaginal fluid during sexual activities, thus reducing HIV and STIs transmission.[15],[16] The antimicrobial nanoparticle-coated condoms, thus, perform a dual role of preventing HIV and other STIs' transmissions, including inactivating the infectiousness of HIV and other STIs pathogens.[16] These antimicrobial broad-spectrum properties are due to the vast physiochemical properties of the nanoparticles imparted onto the condom and also the slow release of antimicrobial agents, thus maintaining a sustained action.[17] For example, silver nanoparticle (AgNP)-coated antimicrobial condoms have extensive physiochemical properties that impart broad-spectrum nonspecific antimicrobial actions that are antiviral, antibacterial, and antifungal.[15],[16]
As already stated, the spread of HIV and the risk factors associated with its transmission have continued to escalate due to the limited prevention methods.[18],[19],[20] Therefore, the absence of a complete cure underscores the need for universally acceptable and innovative alternative prevention approaches that would augment current treatments such as the use of AgNP-coated antimicrobial condoms. Although general topics on condoms and some of the innovations have been extensively studied as noted already, a comprehensive review that analyzes and compares such studies is not available. Therefore, this paper brings together data derived from a number of distinct studies and critically analyzes it in terms of the various types of condoms, microbicides, and the potential use of nanoparticle-coated condoms as a means of diminishing the risk of HIV transmission and STIs during sexual intercourse.
| Methods | | |
Research strategy
The strategy for writing this article was guided by the research question that a condom which is the common and easily accessible intercourse (anal and vagina) prevention method against STIs and HIV may not be as effective as described in basic research. This is due to the fact that body fluid and other oily substances decrease the tensile strength of condoms by 90% in less than a minute [21] when stretched resulting in slippage and breakages (burst).[21],[22] Based on these premises, the study team was instituted comprising epidemiologists, microbiologists, chemists, chemical engineers, and bio-nanotechnologists so as to critically analyze the ongoing research by the team on the improvement of condom properties using nanoparticles. To do this, we reviewed articles, reports, and magazines in relation to HIV/STIs prevention with respect to condoms, nanotechnology including microbicides, and ART.
Extraction processes and selection criteria
We reviewed and analyzed articles on the types of condoms (1989–2015), condom failure, slippage and condom breakage/burst (1994–2016), and condoms coupled with nanoparticles that enhanced HIV/STIs prevention (2010–2015) indexed in various journal platforms, reports, and magazines. We used the PRISMA guidelines as proxy to perform the research review process [23] using key search words such as “types of condoms,” “condom failure,” “condom usage and breakage/burst,” “condom slippage and breakage/burst,” “nanotechnology and condom,” and “microbicides and HIV prevention.” The following indexing sources were used to identify the relevant articles for the study: PubMed, Science Direct, Google Scholar, MeSH PsycInfo, and SCOPUS. The articles were then synthesized and screened. Ideally, articles that failed to describe nature and types of condoms, condom failures, nanoparticle-coated condoms, microbicides, microbicides, and HIV prevention were excluded as shown in [Figure 1]. In general, there were 153 articles identified from 1989 to 2015. Of the 153 studies, only 53 were selected. | Figure 1: Identification and screening of articles used for fostering condoms in preventing human immunodeficiency syndrome and sexually transmitted infection
Click here to view |
CSY conceptualized and designed the study. CSY and GSS independently collected and reviewed various articles. CSY and GSS wrote the draft article while BMS and PH consolidated and reviewed the article. CSY, GSS, and BM gave input in the nanotechnology and condom latex section while CSY and BM discussed and analyzed the ART and microbicide sections.
| Results and Discussion | | |
Condom
Condoms are physical barriers worn on the penis or inserted into the vagina/anus depending on the type; they are designed to prevent transmission and acquisition of STIs, including HIV.[24] In addition, they are used to guard against female pregnancy resulting from sexual intercourse.[25],[26],[27],[28],[29] These condoms are composed of materials that are compatible to the body.[30] The common available condoms include lambskin or sheepskin, latex, polyurethane, and polyisoprene condoms.[29] These condoms exist in various types, sizes, colors, and flavors and all perform the same function, i.e., preventing HIV and other STIs transmission and unwanted pregnancies. Most of these condoms are easily available with relatively minimal toxicity and site effect.[31]
The condoms were formerly designed solely for effective prevention of HIV and other STIs transmission during sexual intercourse.[32] In this regard, the main function of the condom is to prevent the deposition of semen into the anus or vagina during sexual intercourse.[24],[31] Similarly, the condom provides another vital function, i.e., pregnancy prevention.[24] Because of this singular important function, the notion of condom use has removed the perception that contraception is a feminine activity.
Due to the advent of HIV infections, several condom designs that encourage their acceptability during sexual intercourse are currently available and more are under development. Each design is aimed at improvement, boosting the usage and reduction of STIs and HIV transmission during sexual intercourse.[24] For example, some condoms are designed with an erectogenic compound coated on the internal surfaces that counter male impotency and erectile dysfunction during sexual intercourse.[33] The erectogenic condoms help give sustain firm erection, as well as prevent condom slippage.[33] In another study, Kiser [34] developed a molecular gel condom that is liquid at room temperature but when inserted into the vagina coats the vagina walls while reverting to liquid gel form when in contact with semen. This gel condom has antiviral properties that protect women and their unborn babies against HIV infection during labor and delivery.[34]
With regard to the introduction of nanotechnology in condoms, some condoms are coated with spermicidal lubricant and antimicrobial agents to improve their functions.[15],[27] The main construct of any condom today is its efficacy and efficiency as an HIV and other STIs prevention tool during sexual intercourse.[11] Reports from related studies show that the male condom, if used correctly and consistently, will provide 80%–90% effectiveness in reducing HIV and other STIs [11],[35],[36],[37],[38] while the female condom will provide 94%–97% HIV and other STIs risk reduction.[36] However, the failure of condoms to protect against HIV and other STIs transmission frequently results from incorrect or inconsistent condom use, including condom breakage, leakage, and slippage during sexual intercourse.[15],[39],[40],[41] With a single misuse of the condom, the risk is as high as when having unprotected sex.[41]
Assuming that condom is 85%[15] efficient in protecting HIV transmission during intercourse and taking into account that >35 million people are infected with HIV worldwide and also assuming that all the HIV-infected individuals acquired HIV via sexual intercourse, by default, approximately 30 million (0.85 × 35,000,000) people may have been prevented from HIV acquisition if condom was effectively used. The remaining 15%(35-30 million) equating to 5 million people would have been due to condom failures.
A study by Sparrow and Lavill [41] shows that condoms can break, slip, and leak depending on a number of factors. A family planning study showed 410 (10.9%) instances of condom breakage, slippage, and leakage out of 3754 episodes of condom usage.[41] In a similar study in Sri Lanka, 44.7% of female sex workers (FSWs) reported condom breakage in their female sex work professional career.[42] In addition, a randomized control trial conducted by Walsh et al.[42] to determine the efficacy of nonlatex and latex condoms in pregnancy reduction and HIV infection found nonlatex condom exhibiting higher percentage (4.0%) rate of breakage and slippage when compared to latex condoms (1.3%), especially for early condom users. This indicates that the reliability of condom in HIV and pregnancy prevention is not 100% efficient. The factors associated with condom breakage and slippage are varied ranging from dryness, vigorous sex and tearing,[41] and use of oil-based lubricants.[21]
Mineral oil-based lubricants such as body and hand lotions, Vaseline, and other petroleum jelly products weaken latex condoms, decreasing the tensile strength of the condom by 90% in 1 min,[21] thus enhancing condom breakage.[21] Furthermore, studies show that on average, “heat ejaculation” during sexual intercourse usually last approximately 2 min globally.[21] Thus, the longer the exposure of a latex condom to body lotion lubricants during sexual intercourse activities, the more likely the rapid deterioration of tensile strength, development of pores, breakage, and increased risk of HIV and other STIs transmission or unwanted pregnancies. On the other hand, the safe use of water and silver-based lubricants can prevent condom breakage and the acquisition of HIV and other STIs.[24] However, the cost and limited availability of water and silver-based lubricants in developing countries limit affordability, scale up and uptake, adoption, sustainability, and implementation. Furthermore, during sexual intercourse activity, only a single use of a condom is recommended.[24]
Lambskin condom
Lambskin condoms are composed of a natural material made mostly from lamb or sheepskin and intestines.[43] These lambskin condoms, although more expensive when compared to other types of condoms, provide a more natural sensation during sexual activities.[44] They are preferred by individuals who have an allergic reaction to latex condoms.[43] Lambskin condoms can prevent pregnancy but are less effective in combating STI organisms during sexual intercourse.[45] This is because lambskin condoms have large pores capable of allowing STI organisms through.[46] These pores can measure up to 1500 nm in diameter and are ten times larger than the diameter of the HIV and 25 times larger than the hepatitis B virus.[44]
Latex condoms
Latex condoms are made from sulfonated polymer and are commonly available and very effective in preventing infection from STI organisms (including viruses) and unwanted pregnancy.[44] They are impermeable and provide the best HIV protection if correctly used.[29] These latex condoms are made in a variety of sizes, colors, flavors, and textures. According to the Centers for Disease Control and Prevention, latex condoms, if properly used, provide the most effective method of preventing all STIs and pregnancy.[24] For example, findings by Steiner et al.[47] showed that latex condoms are 100% effective in preventing pregnancy. In the same study, a cohort of 300 women relying on the male latex condom as a means of contraception were followed up for one menstrual cycle while reporting for sexual intercourse episodes. The results showed that none of the women who participated in the study reported any episode of pregnancy.[47] In a similar study, earlier randomized findings among 805 monogamous men by Frezieres et al.[48] had compared frequency of breakage and slippage of polyurethane and latex condoms during sexual intercourse for over 6 months. The findings showed that the frequency of breakage and slippage was 8.5% for polyurethane and 1.6% for latex condoms.[48] The participants acknowledged more satisfaction with the latex condom when compared to the polyurethane condom.[24] This is why public health authorities have implemented a variety of interventions to escalate the use of latex condoms in all settings so as to prevent HIV transmission.[24] Although the latex condom demonstrates high degree of protection against genital fluid HIV and other STIs, the exact impact has been difficult to quantify epidemiologically because of the numerous challenges and difficulties to observe and measure behavior activities that occur during sexual/intercourse activities.[29] Other challenges may include the likely development of allergies resulting from latex condom use.[15],[29] Other limitations include the weakening of the latex condom and reduction of its strength due to exposure to oil lubricants, as well as mineral oil, vegetable oil, petroleum jelly products,[21] and when in contact with intravaginal antifungal preparations during sexual intercourse.[49]
Polyurethane condoms
Polyurethane nonlatex condoms are synthesized from nonartificial materials and are polyvinyl/plastic in nature. They are effective for the prevention of pregnancy and STIs [29],[44],[50] but less effective than latex condoms.[49] Most female condoms are made of polyurethane sheaths which are usually inserted 8 h before commencement of the sexual act.[51] The polyurethane sheath condom is efficacious in providing protection against infection and transmission of all STIs such as chlamydia, gonorrhea, chancroid, trichomoniasis syphilis, genital herpes, and human papillomavirus (HPV).[24] The polyurethane condom can be donned in either direction and is usually packaged with a silicone-based lubricant. The nipple-tipped polyurethane condoms are packaged with a silicone-based lubricant.[29] Polyurethane condoms are preferred by those who are allergic to latex condoms.[29],[52] However, the rate of polyurethane condom breakage is higher when compared to latex condoms. Some of the nonlatex condoms have breakage rates during use ranging from 2.64 (95% confidence interval [CI]: 1.6–4.3) to 4.95 (95% CI: 3.7–6.8).[29] In a randomized clinical trial by Frezieres et al.,[48] it was found that polyurethane condom breakage and slippage over a period of 6 months was 8.5% among a cohort of 805 monogamous participants in the study.
Polyethylene condoms
The polyethylene condom is a light-weighted condom that can withstand very high temperatures. When subjected to ultra violet light, the polyethylene condom remains stable; in addition, it does not deteriorate when stored for long periods of time.[53] It is odorless and looks transparent in nature with very limited allergic reactions when compared to other condom types. However, this condom has limited elasticity when compared to latex condoms.[24] It is effective in preventing the transmission of HIV and STIs and also guards against unwanted pregnancy.[24]
Polyisoprene condoms
Polyisoprene condoms are nonlatex, clinically tested [54] thin and flexible condoms that provide a useful alternative for users who have allergic reactions when employing latex condoms.[55] These condoms feel like natural rubber and are very comfortable with a very low allergic reaction.[55],[56] They are likely to be more costly than polyurethane and latex condoms but are less expensive than lambskin condoms. Polyisoprene condoms provide an effective prophylactic to pregnancy and STIs such as gonorrhea, chlamydia, herpes, HIV, HPV, and syphilis.[55]
Microbicides and nanotechnology
Microbicides are vaginal or rectal antimicrobial gels that are used to prevent STIs.[57],[58] Several clinical trials have shown microbicides' potential prevention of STIs, including HIV as well as pregnancy.[5],[58],[59] They come in various types including gels, creams, films, sponges, and suppositories all containing active antimicrobial agents.[57],[59] They are usually inserted before intercourse [57] and some of them are formulated with a nanotechnology background, especially the Viva Gel ™ (SPL7013).[5] The SPL7013 is functionalized with dendrimer that offers anti-HIV and anti-herpes simplex virus (HSV) activity, with a well-tolerated minimal in vitro and in vivo health effect.[5] The limitation of microbicides is that they are target specific; however, broad-spectrum microbicides can provide a wide range of antimicrobial activities.[58] Condoms on the other hand can provide protection likely to all types of STIs.[24]
The application of nanotechnology provides a wide range of support, including targeted, slow and sustained release of vaginal microbicides.[5] The combination of nanoparticles with microbicides and condom usage will provide extra prevention of STIs and other related health consequences. Without condoms, microbicides can offer both primary protection but in conjunction with condoms they can provide back-up protection if a condom breaks, leaks, or slips off during sexual activities.[57],[59]
Antiretroviral therapy and human immunodeficiency syndrome prevention
The WHO and the International AIDS Society have proposed the administration of ART to all HIV-positive individuals irrespective of CD4 cell count.[60] This is because ART compliance indicates significant reduction in viral load suppression including level of infectiousness and transmission by 96%.[61] Similarly, high ART coverage has shown significant reduction in the reproductive number (Ro) to <1.[62],[63] However, the need to take ARTs daily has prompted ART fatigue, ART failure/noncompliance, as well as nonadherence and uptake.[54],[64],[65] Apparently, this has hampered ART ineffectiveness resulting into the emergence of ART-resistant strains and health complications in some settings.[66]
Moreover, despite the need of HIV-infected individuals to receive an optimal standard of care, there are also serious constraints hampering treatment including limited access to effective ART care in Sub-Saharan Africa.[1] Second, patients defaulting on ARTs treatment have reported serious side effects and other complications of the liver; in addition, renal, glucose, lipid, cardiovascular, and bone disease problems have also been reported.[64],[67] Studies show that tolerable and sustained ART treatment plays an essential role in the maximizing and suppression of proviral DNA and plasma viral loads,[68],[69] as well as improvement of immunological depressed functions and the reduction of HIV-related infections and mortality.[5],[68],[69]
Improved ART adherence with viral load copies of <400/ml to <50/ml has been shown to reduce HIV transmission by 90% among serodiscordant partners.[47],[70] However, this does not mean that the person does not have HIV. The person still has HIV and is liable to transmit HIV with less risk. The success is based on treatment as prevention which is a function of treating all HIV positive on ART irrespective of CD4 counts.[66] According to modeling findings by Williams and Gouws,[62] HIV transmission can be reduced by 90% if >90% of people know their status and 90% of HIV positives are placed on ART and 90% have viral load reduction. Therefore, novel and effective combination package of HIV treatment strategies including prevention, biomedical, behavioral, and structural interventions if adapted can play a significant role in HIV reduction and elimination.[9] The new ART cascade for elimination of HIV infections includes the followings:
- Provision of ART to all infected with HIV irrespective of CD4 count [71],[72]
- Provision of PrEP to prevent those who are at risk of HIV such as FSW, men who have sex with men, people who inject drugs and other vulnerable groups deem necessary [71],[72]
- Provision of PEP to all exposed to risk of HIV acquisition within 72 h of exposure if they are HIV negative within the specified period of 72 h.[71],[72]
This has invigorated the need for a better consensus to enhance current methods and develop alternative and more easily available interventions that will reduce the HIV epidemics associated with sexual intercourse. Indeed, this can help stem HIV epidemic which is such a huge burden devastating Sub-Saharan Africa, the most affected region.[1] Reports from the Division of Acquired Immunodeficiency Syndrome show that over 25 different types of ART drugs have been approved to date, ranging from single to fixed dose triple combinations and generic formulations with daily dosing of one or more pills. However, none of these ARTs have provided a total cure for HIV.[19],[20]
Condom and nanotechnology
Nanotechnology/nanomaterials are another new emerging field with unique physicochemical properties that have the potential to improve the limitations of biomedical applications including those with antimicrobial and drug delivery properties.[73],[74] The disruptions of pathogens' infectivity through the broad-spectrum activities of nanoparticles with antimicrobial properties can play a significant role in decreasing infectious contact, chain transmission, and spread of diseases, including STIs. The development of nanocomposite stable condoms coated with antimicrobials that are able to sustain, augment, and inactivate mucosal surfaces from sustaining HIV and STIs during (anal/vaginal) sexual intercourse activities has opened up another dimension of molecular prevention of STIs. These nanoparticle antimicrobials are functionalized on the condoms in such a way that they cannot be washed by mucosal surfaces of anal or vagina secretions but provide a sustained release at the mucosal surfaces during usage.[15],[75] The nanotechnology condom may be another innovation that will greatly overtake the mechanical suppression of HIV and augment ART outcomes in mucosal surfaces of anal and vaginal secretions. The reinforcement of the condom by coating with stable antimicrobial nanoparticles may play a significant role in reducing condom breakage and slippage during sexual activities. There are reports [76] that nanoparticles, including those consisting of carbon nanotubes, have demonstrated excellent antimicrobial, elastic, mechanical, and reinforcement polymer nanocomposite properties.[77]
Nanoparticles such as gold, quantum dots, silver, zinc, iron, platinum, magnesium oxide, titanium, and copper have the potential to be used in various biomedical applications of drug delivery, and antimicrobial and diagnostic tests applications.[73],[76],[77],[78],[79] Among these silver nanoparticles [15] and to a lesser extent, gold [79] and carbon nanotubes [76] have received greater attention as antimicrobial agents. In addition, AgNPs have been demonstrated to bind to HIV-CD4 sites, thereby preventing HIV-CD4-mediated fusion, and thus disrupting viral replication processes.[80] The development of antimicrobial nanoparticles-coated condom as indicated in [Figure 2] will provide additional protection against STIs. For example, AgNPs-coated polyurethane condom has been developed by Mohammed Fayaz et al.[15] with no significant effect on human HeLa and C8166 T-cell lines. Their findings showed that these condoms can effectively destroy HIV-1 and HSV-1/2.[15] The AgNPs were shown to inhibit HIV-1 and HSV-1/2, together with bacteria and fungi, thereby providing another line of microbial defense. The AgNP-coated polyurethane condom therefore provides multiprotection: it ensures disruption of the infectivity of the STI pathogen and prevention of both attachment to CD4 cells and transmission of HIV on mucosal surfaces during sexual intercourse.[15],[60],[80] These findings thus indicate that this emerging field of nanoparticle-coated condoms can augment and overcome the current treatment limitations regarding some STIs on mucosal surfaces during sexual intercourse. | Figure 2: The biohybrid scheme of an antimicrobial nanoparticle condom composite. The figure describes a simple illustration of silver nanoparticle condom-polymer hybrid in producing a potent broad-spectrum antimicrobial silver nanoparticle condom[82]
Click here to view |
Other studies show that natural rubber latex has features that can be manipulated and blended with nanoparticles, improving the physiochemical properties for biomedical application.[81] Guidelli et al.[81] blended wound dressing natural rubber latex with 30 nm AgNPs and found that the AgNPs were gradually released from the rubber latex into the wound, thus “potentiating” and augmenting the healing of the wound.[82] The healing process was facilitated by the broad-spectrum antimicrobial action of AgNPs, in combination with the angiogenic properties of the latex material.[81],[82],[83] The natural rubber latex is under development for biomedical materials such as condoms, surgical gloves, and for hospital protective “wears.”[84] Actually, the benefits of the biohybrid latex condom nanoparticles can play an essential role in the prevention of STI and HIV via mucosal surfaces during sexual intercourse. The use of bio-hybrid-condom nanoparticles in the prevention of STIs and HIV can thus play a vital role in augmenting and complementing ART treatment as a preventative measure during sexual intercourse. [Figure 1] demonstrates a schematic synthesis of antimicrobial nanoparticle condoms.[85]
| Conclusions | | |
Since the inception of the HIV epidemic almost 4 decades ago, more than 78 million people have been infected; over 39 million deaths and currently over 35 million people are living with the HIV globally.[1] This review has shown that the spread of anal and vaginal HIV/STIs disease can be reduced depending on access to the right information regarding the required type of condoms, rightful condom use, sustained ART uptake, and the requisite behavioral changes. Furthermore, recent research studies have shown that the use of targeted and universal approaches in condom promotion and the reinforcement of condoms with antimicrobial nanoparticles can reduce the burden of STI and HIV on mucosal surfaces during vaginal and anal sexual intercourse.[85] It is also advisable that when there is a diagnosis of HIV, ART should be initiated as per local national guidelines and this should apply to all the people who have acute infections and are willing to start their ART treatment. When a person is on ART, various types of preventions and safer barrier methods, including condom use and regular counseling, should also be administered.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | UNAIDS. The Gap Report. Geneva: UNAIDS; September, 2014.  |
| 2. | El-Sadr WM, Serwadda DM, Sista N, Cohen MS. HIV prevention: Great achievements, more challenges ahead. J Acquir Immune Defic Syndr 2013;63 Suppl 2:S115-6. |
| 3. | Johnson KE, Quinn TC. Update on male circumcision: Prevention success and challenges ahead. Curr Infect Dis Rep 2008;10:243-51. |
| 4. | |
| 5. | Rupp R, Rosenthal SL, Stanberry LR. VivaGel (SPL7013 gel): A candidate dendrimer – Microbicide for the prevention of HIV and HSV infection. Int J Nanomedicine 2007;2:561-6. |
| 6. | Sánchez J, Sal Y Rosas VG, Hughes JP, Baeten JM, Fuchs J, Buchbinder SP, et al. Male circumcision and risk of HIV acquisition among MSM. AIDS 2011;25:519-23. |
| 7. | Doerner R, McKeown E, Nelson S, Anderson J, Low N, Elford J, et al. Circumcision and HIV infection among men who have sex with men in Britain: The insertive sexual role. Arch Sex Behav 2013;42:1319-26. |
| 8. | Yah CS, Tambo E, Khayeka-Wandabwa C, Ngogang JY. Impact of telemonitoring approaches on integrated HIV and TB diagnosis and treatment interventions in sub-saharan Africa: A scoping review. Health Promot Perspect 2017;7:60-65. |
| 9. | McNaghten A, Kearns R, Siegler AJ, Phaswana-Mafuya N, Bekker LG, Stephenson R, et al. Sibanye methods for prevention packages program project protocol: Pilot study of HIV prevention interventions for men who have sex with men in South Africa. JMIR Res Protoc 2014;3:e55. |
| 10. | Griffin R, Snook WD, Hoff GL, Cai J, Russell J. Failure to embrace the barrier/condom use message. J Assoc Nurses AIDS Care 2006;17:24-9. |
| 11. | Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. Cochrane Database Syst Rev 2002;1:CD003255. |
| 12. | Garcia-Retamero R, Cokely ET. Simple but powerful health messages for increasing condom use in young adults. J Sex Res 2015;52:30-42. |
| 13. | Mantell JE, Smit JA, Beksinska M, Scorgie F, Milford C, Balch E, et al. Everywhere you go, everyone is saying condom, condom. But are they being used consistently? Reflections of South African male students about male and female condom use. Health Educ Res 2011;26:859-71. |
| 14. | Adefuye AS, Kennedy SB, Amuwo S, Nolen S, Sayad JV. Condom use among young African American men: Implications for planning interventions. J Health Dispar Res Pract 2014;7:104-20. |
| 15. | Mohammed Fayaz A, Ao Z, Girilal M, Chen L, Xiao X, Kalaichelvan P, et al. Inactivation of microbial infectiousness by silver nanoparticles-coated condom: A new approach to inhibit HIV- and HSV-transmitted infection. Int J Nanomedicine 2012;7:5007-18. |
| 16. | Walsh TL, Frezieres RG, Peacock K, Nelson AL, Clark VA, Bernstein L. Evaluation of the efficacy of non latex condom: Results from a randomized, controlled clinical trial. Perspect Sex Reprod Health 2003;35:79-86. |
| 17. | Jain J, Arora S, Rajwade JM, Omray P, Khandelwal S, Paknikar KM, et al. Silver nanoparticles in therapeutics: Development of an antimicrobial gel formulation for topical use. Mol Pharm 2009;6:1388-401. |
| 18. | Needle R, Fu J, Beyrer C, Loo V, Abdul-Quader AS, McIntyre JA, et al. PEPFAR's evolving HIV prevention approaches for key populations – People who inject drugs, men who have sex with men, and sex workers: Progress, challenges, and opportunities. J Acquir Immune Defic Syndr 2012;60 Suppl 3:S145-51. |
| 19. | Gandhi M, Gandhi RT. Single-pill combination regimens for treatment of HIV-1 infection. N Engl J Med 2014;371:248-59. |
| 20. | AIDSinfo. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. AIDSinfo 3/16/2015. Available: http://aidsinfo.nih.gov/guidelines [Last assessed on 2015 Oct 12]. |
| 21. | Voeller B, Coulson AH, Bernstein GS, Nakamura RM. Mineral oil lubricants cause rapid deterioration of latex condoms. Contraception 1989;39:95-102. |
| 22. | Bagnol B, Mariano E. Vaginal practices: Eroticism and implications for women's health and condom use in Mozambique. Cult Health Sex 2008;10:573-85. |
| 23. | Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med 2009;151:264-9, W64. |
| 24. | Centers for Disease Control and Prevention (CDC). Condoms and STDs Fact Sheet for Public Health Personnel. Atlanta, GA: Center for Disease Control and Prevention; 2011. Available from: http://www.cdcgov/condomeffectiveness/latexhtm. [Last accessed on 2015 Mar 12]. |
| 25. | Workowskin KA, Berman SM. Sexually Transmitted Diseases Treatment Guidelines, 2006. Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention; 2006. |
| 26. | Wilkinson D, Tholandi M, Ramjee G, Rutherford GW. Nonoxynol-9 spermicide for prevention of vaginally acquired HIV and other sexually transmitted infections: Systematic review and meta-analysis of randomised controlled trials including more than 5000 women. Lancet Infect Dis 2002;2:613-7. |
| 27. | Handley MA, Reingold AL, Shiboski S, Padian NS. Incidence of acute urinary tract infection in young women and use of male condoms with and without nonoxynol-9 spermicides. Epidemiology 2002;13:431-6. |
| 28. | Whaley AL, Winfield EB. Correlates of African American college students' condom use to prevent pregnancy, STDs, or both outcomes. J Natl Med Assoc 2003;95:702-9. |
| 29. | Gallo MF, Grimes DA, Lopez LM, Schulz KF. Non-latex versus latex male condoms for contraception. Cochrane Database Syst Rev 2006;2:CD003550. |
| 30. | Staab RS, Allendale NJ. Condoms for Beneficial Agents Delivery US Patent No 20070175484 A1; 2007. |
| 31. | Mathew V, Bantwal G. Male contraception. Indian J Endocrinol Metab 2012;16:910-7. |
| 32. | Ditmore M, Neth C. Unsafe condoms and other unsafe sex accessories. Reprod Health Matters 2006;14:171-3. |
| 33. | Kemp CA, Hampshire GB. Condom with an Erectogenic Composition Patent No 6,840,244; 2015. |
| 34. | |
| 35. | Hearst N, Chen S. Condoms for AIDS Prevention in the Developing World: A Review of the Scientific Literature University of California; 2003. |
| 36. | Pinkerton SD, Abramson PR. Effectiveness of condoms in preventing HIV transmission. Soc Sci Med 1997;44:1303-12. |
| 37. | Holmes KK, Levine R, Weaver M. Effectiveness of condoms in preventing sexually transmitted infections. Bull World Health Organ 2004;82:454-61. |
| 38. | Trussell J, Sturgen K, Strickler J, Dominik R. Comparative contraceptive efficacy of the female condom and other barrier methods. Fam Plann Perspect 1994;26:66-72. |
| 39. | Frezieres RG, Walsh TL, Nelson AL, Clark VA, Coulson AH. Breakage and acceptability of a polyurethane condom: A randomized, controlled study. Fam Plann Perspect 1998;30:73-8. |
| 40. | Yarber WL, Graham CA, Sanders SA, Crosby RA. Correlates of condom breakage and slippage among university undergraduates. Int J STD AIDS 2004;15:467-72. |
| 41. | Sparrow MJ, Lavill K. Breakage and slippage of condoms in family planning clients. Contraception 1994;50:117-29. |
| 42. | Jayawardena H. Use of unsafe condoms and unsafe use of good condoms. Reproductive Health Matters 2007;15:192. |
| 43. | Forsyth AD, Carey MP, Fuqua RW. Evaluation of the validity of the condom use self-efficacy scale (CUSES) in young men using two behavioral simulations. Health Psychol 1997;16:175-8. |
| 44. | Workowski KA, Berman S. Sexually Transmitted Diseases Treatment Guidelines, 2010. Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Atlanta, GA 30333; 2010. |
| 45. | Carey MP, Carey KB, Weinhardt LS, Gordon CM. Behavioral risk for HIV infection among adults with a severe and persistent mental illness: Patterns and psychological antecedents. Community Ment Health J 1997;33:133-42. |
| 46. | Lytle CD, Carney PG, Vohra S, Cyr WH, Bockstahler LE. Virus leakage through natural membrane condoms. Sex Transm Dis 1990;17:58-62. |
| 47. | Steiner MJ, Taylor DJ, Feldblum PJ, Wheeless AJ. How well do male latex condoms work? Pregnancy outcome during one menstrual cycle of use. Contraception 2000;62:315-9. |
| 48. | Frezieres RG, Walsh TL, Nelson AL, Clark VA, Coulson AH. Evaluation of the efficacy of a polyurethane condom: Results from a randomized, controlled clinical trial. Fam Plann Perspect 1999;31:81-7. |
| 49. | Rosen AD, Rosen T. Study of condom integrity after brief exposure to over-the-counter vaginal preparations. South Med J 1999;92:305-7. |
| 50. | French PP, Latka M, Gollub EL, Rogers C, Hoover DR, Stein ZA, et al. Use-effectiveness of the female versus male condom in preventing sexually transmitted disease in women. Sex Transm Dis 2003;30:433-9. |
| 51. | Drew WL, Blair M, Miner RC, Conant M. Evaluation of the virus permeability of a new condom for women. Sex Transm Dis 1990;17:110-2. |
| 52. | Zhao R, Wu JQ, Li YY, Zhou Y, Ji HL, Li YR, et al. Efficacy of a combined contraceptive regimen consisting of condoms and emergency contraception pills. BMC Public Health 2014;14:354. |
| 53. | Legge NR, Mowbray RC. TPE condoms impervious to ozone levels that damage NR latex condoms. Rubber World 1994;211:43. |
| 54. | Palosuo T, Mäkinen-Kiljunen S, Alenius H, Reunala T, Yip E, Turjanmaa K. Measurement of natural rubber latex allergen levels in medical gloves by allergen-specific IgE-ELISA inhibition, RAST inhibition, and skin prick test. Allergy 1998;53:59-67. |
| 55. | Carey RF, Herman WA, Retta SM, Rinaldi JE, Herman BA, Athey TW. Effectiveness of latex condoms as a barrier to human immunodeficiency virus-sized particles under conditions of simulated use. Sex Transm Dis 1992;19:230-4. |
| 56. | Patel VL, Gutnik LA, Yoskowitz NA, O'sullivan LF, Kaufman DR. Patterns of reasoning and decision making about condom use by urban college students. AIDS Care 2006;18:918-30. |
| 57. | Boyapalle S, Mohapatra S, Mohapatra S. Nanotechnology applications to HIV vaccines and microbicides. J Glob Infect Dis 2012;4:62-8. |
| 58. | Singh O, Garg T, Rath G, Goyal AK. Microbicides for the treatment of sexually transmitted HIV infections. J Pharm (Cairo) 2014;2014:352425. |
| 59. | Foss AM, Vickerman PT, Heise L, Watts CH. Shifts in condom use following microbicide introduction: Should we be concerned? AIDS 2003;17:1227-37. |
| 60. | Thompson MA, Aberg JA, Hoy JF, Telenti A, Benson C, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA 2012;308:387-402. |
| 61. | Williams BG, Dye C. Put Your Money Where Your Model Is: ART for the Prevention and Treatment of HIV/AIDS CROI: 17 th Conference on Retroviruses and Opportunistic Infections San Francisco, United States of America; 2010. |
| 62. | |
| 63. | |
| 64. | Günthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, et al. Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA panel. JAMA 2014;312:410-25. |
| 65. | Charania MR, Marshall KJ, Lyles CM, Crepaz N, Kay LS, Koenig LJ, et al. Identification of evidence-based interventions for promoting HIV medication adherence: Findings from a systematic review of U.S.-based studies, 1996-2011. AIDS Behav 2014;18:646-60. |
| 66. | World Health Organization (WHO). Antiretroviral Treatment as Prevention (TasP) of HIV and TB: 2012 Update WHO/HIV/201212. Geneva: World Health Organization; 2012. |
| 67. | Reust CE. Common adverse effects of antiretroviral therapy for HIV disease. Am Fam Physician 2011;83:1443-51. |
| 68. | Wyl Vv, Gianella S, Fischer M, Niederoest B, Kuster H, Battegay M, et al. Early antiretroviral therapy during primary HIV-1 infection results in a transient reduction of the viral setpoint upon treatment interruption. PLoS One 2011;6:e27463. |
| 69. | Hocqueloux L, Avettand-Fènoël V, Jacquot S, Prazuck T, Legac E, Mélard A, et al. Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts. J Antimicrob Chemother 2013;68:1169-78. |
| 70. | Attia S, Egger M, Müller M, Zwahlen M, Low N. Sexual transmission of HIV according to viral load and antiretroviral therapy: Systematic review and meta-analysis. AIDS 2009;23:1397-404. |
| 71. | Maksud I, Fernandes NM, Filgueiras SL. Technologies for HIV prevention and care: Challenges for health services. Rev Bras Epidemiol 2015;18 Suppl 1:104-19. |
| 72. | Grant RM, Smith DK. Integrating antiretroviral strategies for human immunodeficiency virus prevention: Post- and pre-exposure prophylaxis and early treatment. Open Forum Infect Dis 2015;2:ofv126. |
| 73. | Blanco-Andujar C, Tung LD, Thanh NT. Synthesis of nanoparticles for biomedical applications. Annu Rep Prog Chem Sect A 2010;106:553-68. |
| 74. | Simate GS, Yah CS. The use of carbon nanotubes in medical applications – Is it a success story? Occup Med Health Aff 2014;2:146-7. |
| 75. | Haider A, Kang IK. Preparation of silver nanoparticles and their industrial and biomedical applications: A comprehensive review. Adv Mater Sci Eng 2015;2015:ID 165257. |
| 76. | Venkatesan J, Jayakumar R, Mohandas A, Bhatnagar I, Kim SK. Antimicrobial activity of chitosan-carbon nanotube hydrogels. Materials (Basel) 2014;7:3946-955. |
| 77. | Gupta AK, Harsha SP. Analysis of mechanical properties of carbon nanotube reinforced polymer composites using continuum mechanics approach. Procedia Mater Sci 2014;6:18-25. |
| 78. | Sunitha A, Rimal IR, Sweetly G, Sornalekshmi S, Arsula R, Praseetha PK. Evaluation of antimicrobial activity of biosynthesized iron and silver Nanoparticles using the fungi Fusarium oxysporum and Actinomycetes sp on human pathogens. Nano Biomed Eng 2013;5:39-45. |
| 79. | Addae E, Dong X, McCoy E, Yang C, Chen W, Yang L, et al. Investigation of antimicrobial activity of photothermal therapeutic gold/copper sulfide core/shell nanoparticles to bacterial spores and cells. J Biol Eng 2014;8:11. |
| 80. | Lara HH, Ayala-Nuñez NV, Ixtepan-Turrent L, Rodriguez-Padilla C. Mode of antiviral action of silver nanoparticles against HIV-1. J Nanobiotechnology 2010;8:1. |
| 81. | Guidelli EJ, Kinoshita A, Ramos AP, Baffa O. Silver nanoparticles delivery system based on natural rubber latex membranes. J Nanopart Res 2013;15:1536. |
| 82. | Tian J, Wong KK, Ho CM, Lok CN, Yu WY, Che CM, et al. Topical delivery of silver nanoparticles promotes wound healing. ChemMedChem 2007;2:129-36. |
| 83. | Mendonça RJ, Maurício VB, Teixeira Lde B, Lachat JJ, Coutinho-Netto J. Increased vascular permeability, angiogenesis and wound healing induced by the serum of natural latex of the rubber tree Hevea brasiliensis. Phytother Res 2010;24:764-8. |
| 84. | Hasma H, Othman AB, Fauzi MS. Barrier integrity of punctured gloves: NR superior to vinyl and nitrile. J Rubb Res 2003;6:9. |
| 85. | Yah CS, Simate GS. Nanoparticles as potential new generation broad spectrum antimicrobial agents. Daru 2015;23:43. |
[Figure 1], [Figure 2]
| This article has been cited by | | 1 |
Establishing a prediction model for recurrence of condyloma acuminatum |
|
| Mengyun Zhan, Zhenzhen Tong, Song Chen, Yu Miao, Yun Yang | | European Journal of Medical Research. 2022; 27(1) | | [Pubmed] | [DOI] | | | 2 |
RIVERSIDE MEN'S KNOWLEDGE AND WAYS OF ACTING REGARDING CONDOM USE |
|
| Elen Petean Parmejiani, Ana Beatriz Azevedo Queiroz, Mônica Pereira Lima Cunha, Ana Luiza de Oliveira Carvalho, Gabriela Silva dos Santos, Juliana da Fonsêca Bezerra, Edilene Macedo Cordeiro Figueiredo, Clenilda Aparecida dos Santos | | Texto & Contexto - Enfermagem. 2022; 31 | | [Pubmed] | [DOI] | | | 3 |
SABERES E MODOS DE AGIR DE HOMENS RIBEIRINHOS SOBRE O USO DE PRESERVATIVO |
|
| Elen Petean Parmejiani, Ana Beatriz Azevedo Queiroz, Mônica Pereira Lima Cunha, Ana Luiza de Oliveira Carvalho, Gabriela Silva dos Santos, Juliana da Fonsêca Bezerra, Edilene Macedo Cordeiro Figueiredo, Clenilda Aparecida dos Santos | | Texto & Contexto - Enfermagem. 2022; 31 | | [Pubmed] | [DOI] | | | 4 |
The Factors Determining the Skin Penetration and Cellular Uptake of Nanocarriers: New Hope for Clinical Development |
|
| Afsaneh Farjami, Sara Salatin, Samira Jafari, Mohammad Mahmoudian, Mitra Jelvehgari | | Current Pharmaceutical Design. 2021; 27(42): 4315 | | [Pubmed] | [DOI] | | | 5 |
Engineered nanoparticle bio-conjugates toxicity screening: The xCELLigence cells viability impact |
|
| Clarence S Yah, Geoffrey S. Simate | | BioImpacts. 2020; 10(3): 195 | | [Pubmed] | [DOI] | | | 6 |
Preparation and characterization of a novel thermosensitive and bioadhesive cephalexin nanohydrogel: a promising platform for topical antibacterial delivery |
|
| Sara Salatin, Farzaneh Lotfipour, Mitra Jelvehgari | | Expert Opinion on Drug Delivery. 2020; 17(6): 881 | | [Pubmed] | [DOI] | |
|
 |
|
|
|
