Nonoxyl-9 can be a potent anti-viral when used infrequently, however it is not recommended as an antiviral as it tends to cause irritation to the vaginal lining, thus eliminating it's benefits and sometimes even increasing risk of STD transmission.

But whichever agent is used, it is vital that it doesn't have the side effect that brought down a once-promising product called nonoxynol-9. This surfactant, originally developed as a spermicide, was shown to destroy HIV in the lab. Because several nonoxynol-9 formulations had been on the market for decades as vaginal contraceptives, they seemed like obvious microbicide candidates.

Unfortunately, clinical trials showed that in the real world they offered no protection against HIV. If used more than about three times daily they could even increase HIV transmission. This is because nonoxynol-9 damages the mucosal layer of the vagina, leaving the underlying immune cells exposed to the virus. The rectal mucosa is damaged even more by this surfactant. To many in the field these findings came as no great surprise, because some research had already suggested nonoxynol-9 may harm epithelial cells. But the result was disappointing because, had it worked, nonoxynol-9 could have quickly been made widely available, saving many lives.

Excerpt from MICROBICIDES: A NEW APPROACH TO PREVENTING HIV AND OTHER SEXUALLY TRANSMITTED INFECTIONS by Alan Stone:

... In the Nairobi trial, the product being tested was a commercially available contraceptive sponge impregnated with 1,000 mg of nonoxynol-9. The outcome was disappointing: the product did not protect against HIV, gonorrhoea or chlamydia, and seemed to be responsible for genital ULCERS in some of the women10. Several subsequent Phase III trials of different nonoxynol-9 formulations also failed to show any benefit. These included a study in the Cameroon of a vaginal contraceptive film incorporating 70 mg of nonoxynol-9 (Ref. 12) and a trial of a contraceptive gel (known as COL-1492) containing 52.5 mg of the substance, which was carried out in several African sites13. In the latter trial, use of the surfactant was associated with a significant increase in the incidence of HIV infection. This was particularly pronounced among the women who were more frequent users of the product (mean use >3.5 times a day), and in the same group, there was a higher incidence of genital ulcers than in the equivalent placebo group. In neither trial was there an effect on gonorrhoea or chlamydia infection rates. It is unclear why the earlier safety studies with COL-1492 failed to show an excess of ulcers14, but this was probably because of their short duration and insufficient power to detect an effect of the size seen in Phase III studies. In a further study carried out in the Cameroon, a different gel containing 100 mg nonoxynol-9 also failed to protect women against the two bacterial infections (HIV was not a primary end point in this trial)15.

After the initial announcement of the COL-1492 result in 2000, several national and international bodies issued statements advising on its implications for the use of nonoxynol-9 in both stand-alone products and condom coatings. In June 2002, the World Health Organization released a report containing the recommendations of a meeting of experts who had concluded, after careful scrutiny of all the available evidence on the potential benefits and hazards of nonoxynol-9, that this substance should not be used as a microbicide (although it remains a contraceptive option for women at low risk of HIV)16. The report stresses that alternative microbicides, which are safe and effective, need to be developed as a matter of urgency.

There is insufficient information to be able to offer definitive guidance about the value of other surfactants as microbicides, although research is continuing with a number of them. For example, C31G, an equimolar mixture of the amphoteric surfactants cetyl betaine and myristamine oxide, has successfully completed a Phase I safety study (A.-M. Corner, personal communication).

Mechanism of HIV transmission

To understand why nonoxynol-9 failed to protect against HIV in the above trials, and why there is considerable optimism about the eventual success of some of the alternative microbicides that are under investigation at present, we need to consider the biological mechanism by which HIV is transmitted sexually. Potential sources of transmissible HIV are free virus particles and infected LYMPHOID CELLS in semen, in cervicovaginal secretions and in blood or other fluids present as a result of physical trauma or genital infections. The first steps in HIV infection normally involve the attachment of the virus, through the gp120 GLYCOPROTEIN on its outer membrane, to its primary receptor, CD4, on the surface of the host cell. This is followed by an interaction between a specific gp120 domain and a cellular co-receptor, which triggers a conformational change in the viral envelope that leads to fusion of the viral and host-cell membranes and entry of the viral genome into the host cell17. Two CHEMOKINE receptors on the cell surface — CCR5 and CXCR4 — serve as co-receptors for HIV, and different HIV strains tend to have a strong preference for one or the other.

The epithelium that lines the vagina and the external surface of the cervix is multilayered, and is relatively strong and durable. Beneath this is a layer of connective tissue — the lamina propria. Within these structures are several classes of lymphoid cell, including dendritic cells, macrophages, T lymphocytes and Langerhans cells (Fig. 2). Much has been written about the role of these tissues and cells in the transmission of HIV from males to females, and some aspects are controversial. (The detailed mechanism by which penile tissue becomes infected is also unclear, although there are likely to be some similarities.) A considerable body of evidence has been derived from experiments on EXPLANTS of human vaginal and cervical tissues infected with HIV in vitro, and from studies in macaque monkeys infected vaginally with the simian immunodeficiency virus (SIV). Most of the findings support the view that the primary initial sites of HIV infection are lymphoid cells in the lamina propria — dendritic cells and macrophages in particular, but possibly also T lymphocytes — that have both CD4 and the co-receptors for the virus18-20. The Langerhans cells in the genital epithelium (in contrast to those in human skin) do not seem to be as readily infectable by the incoming virus, probably because, although they express CD4, they express little of the co-receptors18. However, the possibility that they have a role in the infection process cannot be ruled out.

 


Figure 2 |  Structure of the human vaginal epithelium.  

The multilayered epithelium and the underlying connective tissue contain several types of potential target cell for HIV.

Infected dendritic cells can migrate to the local lymph nodes, where extensive HIV replication takes place, leading to generalized systemic infection. HIV particles can also attach to the surface of dendritic cells, without infecting them, through an interaction between mannose-rich residues in gp120 and specific lectins in the cell membrane, including one known as DC-SIGN. The significance of this finding is not yet clear, but it is possible that this is an important route by which non-replicating, but infectious, HIV could be carried to the lymph nodes and be presented to susceptible cells21. If so, it provides another potential target for microbicide intervention.

The non-lymphoid squamous cells, which comprise the bulk of the multilayered genital epithelium, have none of the necessary receptors for HIV and — subject to the technical limitations of the assay systems — seem to be resistant to infection18. Furthermore, these cells (unlike the cells of the epithelium that lines the gastrointestinal tract22) do not allow the virus to migrate through them by passive transcytosis. This raises the question of how HIV — whether the free virus particles or HIV-infected lymphoid cells — manages to pass through the resistant epithelial barrier. Studies in tissue explants have given rise to several proposals18, 23-25. One is that Langerhans cells and T lymphocytes in the epithelium might have the capacity to bind the virus and migrate with it to the lamina propria. However, several observations indicate that HIV can reach its subepithelial target cells only if there are physical breaches in epithelial integrity18. Clearly, such lesions will make it easier for HIV to infect cells in the lamina propria even if there are other routes through the epithelium. They can result from infection with other pathogens, from physical trauma or, as we have seen, from the use of the surfactant nonoxynol-9.

Surfactant-induced ulcers take several days to heal, so in clinical trials in populations in which sex is frequent, it is perhaps not surprising that nonoxynol-9 showed no net benefit26. Phase I studies have shown that nonoxynol-9 can also give rise to localized inflammation27, and it is likely that this also enhances the risk of HIV infection; for example, by CYTOKINE activation of potential target cells18. Moreover, nonoxynol-9 adversely affects the lactobacilli that live in the healthy vagina and whose secretion of lactic acid and hydrogen peroxide creates a second line of defence against invading pathogens27-29.

Microbicides under investigation

The problems experienced with nonoxynol-9 have focused attention on microbicides that work by different mechanisms, and which neither damage the vaginal lining nor affect the lactobacilli. Many such agents are now under investigation.

Rectal microbicides. Efforts are also being made to develop microbicides for rectal use, to combat HIV infection as a result of anal sex. This presents some difficult challenges. The rectum is an open-ended system, not a pouch like the vagina, so achieving a stable and adequate distribution of product will be problematic. Ensuring product safety will also be challenging. The epithelium that lines the rectum is not a tough, multilayered structure like the vaginal epithelium, but a single layer of columnar cells. This is easily damaged and offers little protection to the underlying lamina propria, which is rich in CD4+ macrophages and dendritic cells that are readily infectable by HIV. Nonoxynol-9 products have often been used in rectal sex. However, there are now active campaigns to ban the use of this surfactant in sex lubricants and condoms. It has been shown to enhance rectal infection by genital herpes virus in mice60 and its injurious effect on the human rectal epithelium is pronounced61.

Nonoxyl-9 as a Microbicide

AIDS 1993 Jun;7(6):797-802

The cat/feline immunodeficiency virus model for transmucosal transmission of
AIDS: nonoxynol-9 contraceptive jelly blocks transmission by an infected
cell inoculum.

Moench TR, Whaley KJ, Mandrell TD, Bishop BD, Witt CJ, Cone RA

Department of Medicine, Johns Hopkins University, Baltimore, Maryland.

OBJECTIVES: To develop an animal model to study transmucosal lentivirus
transmission, and to determine whether topical application of contraceptive
jelly can block transmission by an infected cell incoulum. DESIGN: Feline
immunodeficiency virus (FIV), a lentivirus similar to HIV, causes an
AIDS-like disease in domestic cats. HIV is transmitted primarily across
mucosal surfaces, and infected cells may be important in this transmission.
We tested the ability of FIV-infected cells to transmit infection across the
vaginal, rectal and oral mucosa of the cat, and whether a vaginal
contraceptive jelly could prevent such transmission. METHODS: An inoculum
consisting of 2 million FIV-infected primary cat T cells was administered
vaginally, rectally or orally to female cats that had received either no
pretreatment or pretreatment with a contraceptive jelly containing the
detergent nonoxynol-9 as spermicide. Transmission was detected by monitoring
recipient animals for viral antibodies and by viral cultures of blood
leukocytes. RESULTS: A single dose of the infected cell inoculum efficiently
transmitted FIV infection when delivered into the vagina or rectum (10 out
of 11 animals became infected). Pretreatment of the vagina (five animals) or
rectum (four animals) with contraceptive jelly protected all animals from
transmission by the highly infectious inoculum. CONCLUSIONS: The cat/FIV
model provides an efficient means to study transmucosal transmission of
lentivirus infections, and for assessing vaginal barrier methods that could
block transmission. One such method, nonoxynol-9 contraceptive jelly,
effectively prevents transmucosal transmission by an FIV-infected cell
inoculum.

Spermicides as Microbicides?

Commercially available spermicides have already undergone extensive safety testing, and most have been widely used. Thus, if their active ingredients were found to protect against sexually transmitted diseases (STDs), they might be promoted as vaginal microbicides much sooner than new products are likely to be available.

The active ingredients in commercially available spermicides now being tested for microbicidal activity include nonoxynol-9 (N-9), benzalkonium chloride and octoxynol9. N-9 spermicides are the only substances in advanced trials to determine antimicrobial efficacy in humans.

Developed as a contraceptive spermicide more than 40 years ago, N-9 has been available in the form of gels, foams, creams, impregnated sponges, suppositories, films and foaming tablets. It is potentially effective as a microbicide because it disrupts the outer membranes of bacteria and viruses. However, frequent N-9 use can irritate the vaginal lining, possibly allowing pathogens a way to enter the woman's bloodstream.

Some small studies suggest a modest protective effect from N-9 against gonorrhea and chlamydia. But a large, randomized, controlled FHI study in Cameroon using a low- dose (70 mg) N-9 film recommended for use with condoms indicated that N-9 did not give any additional protection against HIV, gonorrhea or chlamydia beyond that provided by condom use alone.1

Research currently is examining other N-9 doses, frequencies of use and delivery formulations (such as gel, foam, cream or suppository) to evaluate whether they can protect against microorganisms without causing vaginal irritation:

A low-dose (52.5 mg) N-9 gel, commercially available in the United States as Advantage-S, is being evaluated for its effectiveness in preventing transmission of HIV, gonorrhea and chlamydia in 1,000 to 1,500 women at high risk of HIV infection in Benin, South Africa, Thailand and Cτte d'Ivoire. This trial, sponsored by the Joint United Nations Programme on HIV/AIDS (UNAIDS), is being coordinated by the Institute of Tropical Medicine, Antwerp, Belgium, with results expected this year. 
The effectiveness of a high-dose (100 mg) N-9 gel, commercially available in the United States as Conceptrol, against male-to-female transmission of gonorrhea and chlamydia among 1,000 high-risk, Cameroonian women is being examined in a study funded by the U.S. Agency for International Development (USAID) and conducted by FHI and the Care and Health Program, a nongovernmental agency in Cameroon. The effect of the gel on HIV acquisition also will be studied, with results expected this year. 
Conceptrol's effectiveness in preventing male-to-female HIV transmission also will be evaluated in a study funded by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) to be conducted among some 4,500 HIV-negative women in Malawi and Zimbabwe. The gel's effectiveness in preventing transmission of syphilis, chlamydia, gonorrhea and trichomoniasis also will be evaluated. Study results are expected in two to three years. 
N-9 formulated into a suppository at various high-dose concentrations (greater than those commercially available) is being developed by the Program for the Topical Prevention of Conception and Disease, Advanced Care Products, and the Contraceptive Research and Development Program. N-9 delivered in this way would be expected to coat the vagina and provide longer protection as a contraceptive and, perhaps, as a microbicide. One safety trial has been completed.

Benzalkonium chloride and octoxynol-9 — both surfactants that disrupt cell membranes — are two of three active ingredients in another spermicidal substance under study, known as GEDA Plus. A safety trial among 280 healthy women found it caused little vaginal irritation.

N-9, benzalkonium chloride and sodium cholate — the three surfactants found in the F-5 gel contained in the Protectaid contraceptive sponge approved for use in Canada and Europe — are to be combined in a reformulated gel for testing as an STD microbicide. This mix of substances has been found in the laboratory to be very potent against STD pathogens. Yet, when delivered in the Protectaid sponge, the mix does not irritate the vaginal lining because only small amounts of each substance are present.

Finally, gramicidin — an active component of contraceptive gels and foams used in the former Soviet Union by millions of women over the last 40 years — shows promise as a topical microbicide. A broad-spectrum antibiotic, it inhibits STD infection. A study of gramicidin's safety and efficacy in treating symptoms of herpes infection is planned in the United States and Brazil.

— Kim Best

Reference

Roddy RE, Zekeng L, Ryan KA, et al. A controlled trial of nonoxynol 9 film to reduce male-to- female transmission of sexually transmitted diseases. N Engl J Med 1998;339(8):504-10.

Contraception 1997 Nov;56(5):329-335

Tests of vaginal microbicides in the mouse genital herpes model.

Zeitlin L, Whaley KJ, Hegarty TA, Moench TR, Cone RA

Department of Biophysics, Johns Hopkins University, Baltimore, Maryland
21218, USA.

Microbicide candidates were selected that have demonstrated activity against
sperm or sexually transmitted disease pathogens in vitro, and the efficacy
of these agents for preventing vaginal transmission of genital herpes
infection was evaluated in the progestin-treated mouse. Each agent was
delivered to the vaginas of mice approximately 20 sec prior to delivering a
highly infectious herpes simplex virus-2 inoculum. The following agents
provided significant protection: anti-HSV monoclonal antibodies III-174 and
HSV8, modified bovine beta-lactoglobulin (beta-69), carrageenan,
concanavalin A, chlorhexidine, dextran sulfate (average molecular weight
8,000 and 500,000), fucoidan, neem, nonoxynol-9, polystyrene sulfonate, and
povidone-iodine. Two agents, gramicidin and heparan sulfate, though highly
effective in vitro, were not protective in vivo at the doses tested.

Infect Dis 1993 Oct;168(4):1009-1011

Nonoxynol-9 protects mice against vaginal transmission of genital herpes
infections.

Whaley KJ, Barratt RA, Zeitlin L, Hoen TE, Cone RA

Dept. of Biophysics, Johns Hopkins University, Baltimore MD 21218.

A vaginal application of a commercially available contraceptive jelly
containing nonoxynol-9 (N9) prevented vaginal transmission of herpes simplex
virus type 2 (HSV-2) infections in the mouse. When N9 jelly was delivered to
the vagina with the virus inoculum, 20 s before inoculum, or 5 min before
inoculum, mice were completely protected from visible infection (P < .001).
Protection lasted for at least 30 min (P < .03), and significant protection
occurred even when the N9 jelly was delivered 15 min after the HSV-2
inoculum (P < .05). These results are consistent with results of studies
using N9 products in other animal models and suggest that N9-based
contraceptive products can provide significant protection against vaginal
transmission of enveloped virus infections in animals.

Am J Public Health 1998 Apr;88(4):590-596

The protective effect of condoms and nonoxynol-9 against HIV infection.

Wittkowski KM, Susser E, Dietz K

HIV Center, New York Psychiatric Institute, New York City, USA.
kmw@uni-tuebingen.de

OBJECTIVES: Whether or not spermicides can reduce the risk of human
immunodeficiency virus (HIV) transmission remains an important question for
the control of heterosexual HIV transmission. The authors provide estimates
from a reanalysis of one of the few observational studies on the efficacy of
condoms and spermicides, used separately and together, per vaginal contact.
METHODS: In this reanalysis, three different models were used to assess the
efficacy of spermicides and condoms: linear (Pearl index), exponential
(maximum likelihood), and monotonic (marginal likelihood). RESULTS: Reported
use of barrier methods among 27,432 contacts was as follows: condoms plus
nonoxynol-9, 39%; condoms alone, 25%; nonoxynol-9 alone, 24%; and
unprotected, 11%. Under all three models, the results indicate a strong
protective effect for spermicidal suppositories. The Pearl index indicated
that spermicide alone is apparently efficacious, but the efficacy per
contact cannot be quantified with this approach. Maximum likelihood
estimates for the efficacy of nonoxynol-9 alone and condoms (with or without
nonoxynol-9) were 100% (95% confidence interval [CI95] = 43%, 100%) and 92%
(95% CI95 = 79%, 100%), respectively. CONCLUSIONS: The data from this
observational study suggest that spermicides may be efficacious in reducing
the risk of HIV transmission. Published erratum appears in Am J Public
Health 1998 Jun;88(6):972

AIDS 1993 Jun;7(6):797-802

The cat/feline immunodeficiency virus model for transmucosal transmission of
AIDS: nonoxynol-9 contraceptive jelly blocks transmission by an infected
cell inoculum.

Moench TR, Whaley KJ, Mandrell TD, Bishop BD, Witt CJ, Cone RA

Department of Medicine, Johns Hopkins University, Baltimore, Maryland.

OBJECTIVES: To develop an animal model to study transmucosal lentivirus
transmission, and to determine whether topical application of contraceptive
jelly can block transmission by an infected cell incoulum. DESIGN: Feline
immunodeficiency virus (FIV), a lentivirus similar to HIV, causes an
AIDS-like disease in domestic cats. HIV is transmitted primarily across
mucosal surfaces, and infected cells may be important in this transmission.
We tested the ability of FIV-infected cells to transmit infection across the
vaginal, rectal and oral mucosa of the cat, and whether a vaginal
contraceptive jelly could prevent such transmission. METHODS: An inoculum
consisting of 2 million FIV-infected primary cat T cells was administered
vaginally, rectally or orally to female cats that had received either no
pretreatment or pretreatment with a contraceptive jelly containing the
detergent nonoxynol-9 as spermicide. Transmission was detected by monitoring
recipient animals for viral antibodies and by viral cultures of blood
leukocytes. RESULTS: A single dose of the infected cell inoculum efficiently
transmitted FIV infection when delivered into the vagina or rectum (10 out
of 11 animals became infected). Pretreatment of the vagina (five animals) or
rectum (four animals) with contraceptive jelly protected all animals from
transmission by the highly infectious inoculum. CONCLUSIONS: The cat/FIV
model provides an efficient means to study transmucosal transmission of
lentivirus infections, and for assessing vaginal barrier methods that could
block transmission. One such method, nonoxynol-9 contraceptive jelly,
effectively prevents transmucosal transmission by an FIV-infected cell
inoculum.

ACIDFORM
Contraceptive. 
Bioadhesive gel that maintains vaginal acidity.
In safety trial, combining
nonoxynol-9 (N-9) with ACIDFORM made N-9 very irritating to the vaginal lining. ACIDFORM alone soon to be tested as a contraceptive in Brazil.

These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose or cure any disease. The information contained herein is for educational purposes only. It is not medical advice and is not intended to replace the advice or attention of health care professionals.