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  Table of Contents  
REVIEW ARTICLE
Year : 2012  |  Volume : 33  |  Issue : 2  |  Page : 81-90
 

Microbicides and HIV: A Review and an update


1 Department of Skin VD, Medical College, Vadodara, Gujarat, India
2 STI, National Technical Support Unit, National AIDS Control Organization, Ministry of Heath and Family Welfare, New Delhi, India

Date of Web Publication9-Oct-2012

Correspondence Address:
Smriti Naswa
Department of Skin-VD, Medical College and SSG Hospital, Vadodara 390 007, Gujarat
India
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Source of Support: None, Conflict of Interest: None


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   Abstract 

HIV is a pandemic which has continually posed challenges to the scientific society in large and to medical fraternity in particular in terms of treatment as well as prevention. The treatment is lifelong suppressive than curative; hence the importance has always been to prevention strategies. The strategies like abstinence, monogamy and consistent condom use have various societal and behavioural issues and HIV vaccine is still not at the horizon. In such a scenario, pre-exposure prophylaxis (PrEP) and microbicides have emerged as newer options of prevention. Microbicides are referred to as topical PrEP. They are compounds that can be applied inside the vagina or rectum to protect against sexually transmitted infections (STIs) including HIV. Microbicides can be vaginal and rectal and can be formulated as gels, foams, rings, hydrogels, silicone elastomer gels, diaphragm, quick-dissolve polyvinyl alcohol based films, and bioadhesive vaginal tablets. The microbicides have been divided into various categories based on where they disrupt the pathway of sexual transmission of HIV. The article highlights the classes of microbicides and various trials conducted on them. It also enumerates various approaches in pipeline like antimicrobial peptides, aptamers, flavonoids, small interfering RNAs and DNAs, and bioengineered lactic acid bacilli.


Keywords: HIV, microbicides, trials


How to cite this article:
Naswa S, Marfatia Y S, Prasad T. Microbicides and HIV: A Review and an update. Indian J Sex Transm Dis 2012;33:81-90

How to cite this URL:
Naswa S, Marfatia Y S, Prasad T. Microbicides and HIV: A Review and an update. Indian J Sex Transm Dis [serial online] 2012 [cited 2019 Nov 22];33:81-90. Available from: http://www.ijstd.org/text.asp?2012/33/2/81/102098



   Introduction Top


HIV continues to elude all the scientific efforts to find an effective preventive strategy.

Globally, the toll of people living with HIV has risen to 33.3 million. The HIV pandemic began in 1980s and since then the virus has infected more than 60 million people and nearly 30 million people have died of HIV-related causes. Approximately 2.7 million people were newly infected with HIV in 2010 - amounting to more than 7,000 every day. The number of new infections continues to outstrip advances in treatment; for every person starting HIV treatment, there are two new infections. [1],[2] Besides, latest NACO and UNAIDS estimates have revealed that approximately 2.5 million people with HIV are in in India accounting for roughly half of Asia's HIV burden. [3]

Need for rectal microbicides- Worldwide, men who have sex with men (MSM) are 19 times more likely to be infected with HIV than the general population. The HIV epidemic has begun to stabilize in many countries, but it still continues to affect MSM disproportionately. Unprotected anal sex is the main cause of the HIV epidemic among this population. In addition to this, 5-10% of world's population engages itself in anal sex. [2]

Despite the knowledge of successful HIV prevention strategies including ABC- abstinence, be faithful, condom use, and reduction in the number of sexual partners, and early diagnosis and treatment of sexually transmitted infections - HIV continues to pervade developing countries (especially among women) at an alarming rate. [4]

Currently available HIV prevention techniques are often not feasible to practice for many women who live in resource poor settings. [4]

Strategies to prevent sexual transmission of HIV include consistent and correct usage of condoms,vaccines, systemic pre-exposure prophylaxis (PrEP), male circumcision and topical prophylaxis with microbicides.

  • Despite more than two decades of HIV-1 vaccine research, there is still no efficacious HIV-1 vaccine, with scepticism regarding its short and long-term feasibility;
  • There are rapid advances being made in field of PrEP, but there are concerns regarding issues like toxicities associated with long-term exposure to antiretroviral agents, risk for selecting resistant viral variants, cost, access, and adherence, apart from moral and ethical dilemmas;
  • Male circumcision is still lacking the global appeal;
  • In this setting, microbicide research has gathered momentum. [5] Microbicides have the ability to greatly empower women, which, unlike male or female condoms, are a potential preventive option that women of any social, economic, cultural or religious background can easily use to control acquisition of HIV and do not require the cooperation, consent or even knowledge of the partner. [4]


An unexplored promise- preventing HIV by protecting the cervix and rectum

It is well known that receptive partner whether through vaginal or anal intercourse has more likelihood of acquiring sexually transmitted infections (STI) including HIV compared to insertive partner. The per-act risk of acquisition of HIV is more in receptive vaginal intercourse (0.15-1.01%) than insertive (0.01 to 0.1%) and still higher in anal intercourse (receptive- 0.50% and insertive- 0.065%). [6] The gamut of such sexual relationships worldwide centres the brunt of infection to women and MSM.

Worldwide, nearly half of all individuals living with HIV are women, who acquire the HIV largely by heterosexual exposure. Being receptive partners, women are twice as likely as their male partners to acquire HIV during sex. [7] Many women, because of limited economic options and gender inequality, cannot reliably negotiate sexual encounters and safe sex practices like use of condoms, leaving them vulnerable to unwanted pregnancy and sexually transmitted infections (STIs), including HIV. The need of the hour, thus are female driven protective measures. Similarly, MSM continue to be disproportionately affected by HIV. With clinical deployment of a safe and effective HIV vaccine still likely to be years away, topical microbicide formulations that are applied vaginally or rectally are receiving increasing attention as another strategy for HIV prevention. [8]

Host factors affecting sexual transmission of HIV- factors important in devising microbicide strategies

Female factors- A shield against HIV

The intact multilayered squamous epithelium in the vagina and ectocervix provides the first line of defense and physical barrier against HIV. Disruption of this barrier (due to cervical ectopy, acute infection and genital ulcer disease) enhances acquisition of HIV. In addition, vaginal flora, vaginal acidic pH, mucus, and genital tract secretions are believed to play important roles in host defence. [5]

The cervical mucus coats endocervix making it resistant to infection by cell associated and cell free virus. Also, the mucus contains antiviral proteins like secretory leucocyte protease inhibitor, and high levels of natural ligands to CXCR4 and CCR5 which might block HIV-1 binding to CD4+ Tcells. Mimicking or augmenting these natural ligands is a proposed mechanism of microbicide development. [8]

Vaginal epithelial cells have limited permeability to particles greater than 30 nm (HIV virion is 80-100 nm). However, HIV enters the superficial layers of the squamous epithelium by diffusing across a concentration gradient (mechanism known as "transmigration", responsible for transmission of HIV from semen to vaginal epithelial cells) and gets sequestered their surface; and later infects CD4+ helper cells, Langerhans cells, dendritic cells, macrophages, and small Ki67 negative T cells (activated cells returning to resting state) found in mucosal epithelium. [3],[8]

Lactic acid (LA) produced by lactobacilli in vagina of healthy women is known to inhibit/inactivate bacteria causing bacterial vaginosis and HSV. L-LA is less toxic than D-LA. A study by Conza et al., has found that L-LA is virucidal for HIV and this is because of a viral protein target in LA and not due to acid (lactate anion) alone. The inactivation with L-LA was found to be rapid, irreversible and more potent than lactate anion. The other advantages like maintenance of its virucidal activity in presence of seminal plasma and activity against broad spectrum of HIV strains (CCR5, CXCR4, and dual tropic) make lactic acid a promising microbicide. [9]

Male factors and HIV transmission

Male circumcision is protective with circumcision decreasing the risk of female-to-male HIV transmission by 50-76%. [8]

Semen and seminal plasma proteins interfere with the antiviral activity of several microbicides and may impair female host defences or enhance HIV infectivity. [5] Patel S et al., found that seminal plasma interfered with the activity of PRO 2000 and of cellulose sulphate against HSV-2, increasing by 100-fold the concentration of drug required to inhibit 90% of viral plaque formation. [10]

SEVI- Semen contains abundant amounts of prostatic acid phosphatase (PAP) fragments which form amyloid fibrils. These fibrils are termed as semen-derived enhancer of virus infection (SEVI). They capture HIV virions and promote their attachment to target cells, thereby enhancing the infectious virus titer by several folds. In a study by Munch et al., (which used multiple cell lines isolated from whole blood), physiological concentrations of SEVI amplified HIV infection (of both R5 and X4 tropic HIV-1) of T cells and macrophages. [11] While Allen S et al., noted a difference using human cervical explants model, where SEVI had differential behaviour in ecto and endocervical mucosa. SEVI inhibited the penetration of epithelium by HIV in ectocervix and increased the penetration in endocervix. [12]

CD4 independent mechanisms of HIV transmission- new avenues and targets for microbicide development

There are two kinds of cells coming in contact with HIV during heterosexual transmission- CD4dependent cells (endo- and ecto-cervical cells) and CD4 independent cells (sperm and vaginal epithelial cells). A study by Bandivdekar et al., in India has shown the presence of hMR (human Mannose Receptor) on sperm as well as vaginal epithelial cells. This is a 160kDa protein to which cell free HIV as well as gp120 binds specifically binds. The differential expression of hMR determines risk of sexual transmission of HIV, signified by less than 10% of the vaginal epithelial cells of HIV negative serodiscordant females showing presence of hMR. [13]

HLA type

Variations in human leukocyte antigen (HLA) are found in all individuals. In a study conducted in Mumbai, India, among serodiscordant couples, few alleles were observed exclusively either in HIV positive or negative spouse. Reactions to candidate microbicides reflect polymorphic action of vaginal or rectal cells due to variation in HLA. Thus, the synthesis of microbicides should be done taken into consideration HLA polymorphism so that they can withstand the host rejection leading to HIV prevention. [14]

Anal sex

According to some estimates, the risk of becoming infected with HIV through anal sex is 20 times greater than vaginal sex because the rectal lining is thinner (only one cell thick) and much more fragile than the lining of the vagina. [2],[15] The subepithelial lamina propria of rectum contains many cell types to which HIV-1 specifically binds. Rectal lymphoid follicles contain specialized M cells (microfold cells), which bind and present HIV-1 to underlying lymphoid tissue. [8] [Figure 1]
Figure 1: Thickness of rectal and vaginal mucosa [15]

Click here to view


Using sexual lubricant products (lubes) during receptive anal intercourse is a common practice among both men and women, which increase the likelihood of STI transmission through mucosal irritation. [16]

Microbicides- topical chemical barriers against HIV/STD

Microbicides are now being referred to as topical PrEP. [17],[18]

Topical microbicides have been proposed as agents to break the chain of transmission in sexually transmitted infections by providing chemical, biological, and/or physical barriers to infection by blocking and/or inactivating pathogens at the mucosal surface where infection can occur. [19]

These are compounds that can be applied inside the vagina or rectum to protect against sexually transmitted infections (STIs) including HIV. Microbicides may or may not have spermicidal activity (contraceptive effect). At present, an effective microbicide is not available. [2],[4]

An advantage of microbicides over male and female condoms is that they are expected to interfere less with intimacy and sexual pleasure, and be more discrete. [20]

History of microbicides

The idea for a microbicide-like product was first proposed more than 20 years ago by reproductive health specialists and advocates who recognized the need for female-controlled HIV prevention methods. One of the first products considered were the nonoxynol-9 (N-9) and similar detergent based spermicides were prophylactic contraceptives for HIV/AIDS; but they used to cause lesions in vaginal and cervical epithelia leading women more vulnerable to HIV infection. Hence there use as microbicides was abandoned. [21] Other first generation microbicides that included products intended to strengthen natural defenses in the vagina or create a barrier to protect target cells in the vagina also proved unsuccessful. [22] The recent CAPRISA 004 trial, in which a 39% reduction in HIV acquisition was observed in women who applied 1% tenofovir gel before and after sex, was considered as a major milestone in the field. [18]

Types of Microbicides

Microbicides can be vaginal or rectal.

Microbicide delivery systems- Microbicides can be formulated as gels, foams, rings, hydrogels, [23] silicone elastomer gels, [24] diaphragm, quick-dissolve polyvinyl alcohol based films, [25] and bioadhesive vaginal tablets [26] (emtricitabine and tenofovir can be used). Tablets are advantageous because they are relatively inexpensive, easy to manufacture, and they avoid the waste product associated with use of vaginal gel applicators [Figure 2].
Figure 2: Microbicides[22]

Click here to view


Intra-Vaginal rings (IVR) are considered to improve adherence and eliminate the need to be applied on daily basis (extended release rings e.g. 28 days). Controlled release polymeric materials used to prepare IVR include silicone elastomers, ethylene-vinyl-acetate copolymers (EVAc) and polyurethanes (PUs). PUs, unlike other two have water swellable properties rendering them effective in controlled release of most microbicide drugs like tenofovir which are too lipophilic or too hydrophilic to reach potentially therapeutic release rates. [27],[28]

Classification of microbicides

The agents developed in earlier years were surfactants and acidifying agents acting non-specifically on membranes (viral/host) or creating a hostile environment in the genital tract for viral transmission. Later compounds that target specific viral-host cell interactions were used. More than 10 reverse transcriptase inhibitors and 16 entry inhibitor agents have been investigated in microbicide trials. [8]

Topical microbicides are grouped into five classes of agents, based on where they disrupt the pathway of sexual transmission of HIV. These classes include [8] [Table 1].
Table 1: Salient features of various classes of microbicides[8]

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  • Surfactants/membrane disruptors,
  • Vaginal milieu protectors,
  • Viral entry inhibitors,
  • Reverse transcriptase inhibitors,
  • Group whose mechanism is unknown.


Clinical trials on microbicides [22]

A review of preclinical and clinical research from 1966 to 2008 on the development of microbicides formulated to prevent vaginal HIV transmission by Cutler B et al., yielded 118 studies: 73 preclinical and 45 clinical. [8]

Various trials are on-going in several parts of world including India (like MTN 005 and Sex Workers study). [31]

The current and past trials include those on first generation products like PRO gel, buffer gel, carraguard, cellulose sulphate (namely MDP 301, HPTN 035, Savvy etc); tenofovir gel for vaginal use (CAPRISA 004 and 008, VOICE, FACTS 001 etc.); monthly usable vaginal rings (ASPIRE, The Ring study); and rectal microbicides (RMP 01, RMP 02, MTN 007). [15]

Newer advances and approaches in pipeline

The field of microbicides discovery is fast growing. Newer and newer microbicides acting on various steps of HIV infection is being developed and tested for suitability of human use. Few of the latest approaches are highlighted in [Table 2].
Table 2: Newer advances and approaches in pipeline

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Issues related to microbicides

The use and approval of microbicides on one hand will lead to a preventive strategy towards STI/HIV which is female controlled, but on other hand might lead to disinhibition and increase in high risk sexual activity.

Microbicides also known as topical PrEP (pre-exposure prophylaxis) is a form of chemoprophylaxis against HIV and hence the long-term toxicities, risk compensation, and virologic resistance are some of the key issues before large scale usage of microbicides.

Acceptance of microbicides and its correlation with adherence towards them is based on many social and behavioural factors. Characteristics making microbicides acceptable in the HPTN 035 trial were protection against HIV/STIs, ease of use, no sexual interruption, and increase in sexual pleasure; while those decreasing acceptance were the failure to remember to use the product and messiness during sex. [46] While acceptance were based on the lubricant qualities and perceived protective benefits, adherence and consistent use were more dependent on contextual and partner-related factors. Adherence was more with casual partners than primary partners in 6% cellulose sulphate gel phase III clinical trial among high-risk women in Africa and India; because of less risk of inconvenience, or fear of partner disapproval. [47]

How cost-effective would these microbicides be?

Using mathematical modelling, Verguet et al., interpreted a scenario using a microbicide gel with 55% efficacy, 30% adherence and a price per use of $0.51 and $2.23 for the South African and American public sectors respectively. If such a microbicide is used for one year, it would be cost-effective in South Africa with high HIV load, while would not beso in developed, low HIV load country USA (with cost exceeding that of anti-retroviral therapy in USA). [48]

Microbicide clinical trials face scientifically and ethically complex issues, such as the choice of placebo gel, the potential for viral resistance, and the inclusion of HIV-infected participants. [8]

Any kind of prevention strategy should also have a strong background of counselling services to sustain its prevention benefits.


   Conclusion Top


The idea of microbicides has been there since more than two decades and more and more novel concepts are being developed to eventually find a preventive strategy towards HIV which is available, feasible, safe, cost-effective; and scientifically, culturally, socially and ethically acceptable. Increasing knowledge regarding pathomechanisms of HIV infection is leading to development of specific microbicides with likelihood of increased efficacy. The microbicide trials have led to certain challenges, new information and essential lessons; all of which should help in development of an effective HIV preventive microbicide in near future.

 
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    Figures

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