Johns Hopkins Bloomberg School of Public Health: The INFO Project

Microbicides, like drugs and medical devices, must go through several stages of rigorous testing for safety and effectiveness in order to obtain approval from regulatory agencies such as the US Food and Drug Administration (US FDA). The first stages focus on safety of use and product acceptability. The final stage focuses on effectiveness—that is, the ability of a microbicide in typical use to reduce the average rates of infections when compared with control groups, as well as long-term safety and acceptability (11) (see Table 1).

If successful, one or more of the five products entering phase III clinical trials is likely to reach the market. These five products are: BufferGel®, Carraguard®, PRO 2000®, C31G, and cellulose sulfate (2, 44) (see Table 2).

A sixth product, dextrin-2-sulfate (Emmelle®), was poised to enter phase III clinical trials in 2005, but the organization running the trial, the UK Medical Research Council's Microbicides Development Programme (MDP), pulled it from the clinical trial. In a statement the organization explained that three other products of a similar type were already entering phase III clinical trials, and dextrin-2-sulfate did not prove as effective as the others in preclinical tests (78).

Most microbicides under development, including the five in phase III clinical trials, act in one or more of the following ways (44):

1. Vaginal defense enhancers boost the body’s natural defenses against infection by increasing lactobacilli or by rapidly acidifying the ejaculate, reinforcing the natural mild acidity of the vagina that inactivates both sperm and STIs. BufferGel is a vaginal defense enhancer.



2. Surfactants damage the surface membranes of disease pathogens, thereby disabling them and preventing them from causing infection. C31G is a surfactant.



3. Entry and fusion inhibitors bind to disease pathogens or to healthy cells before pathogens have a chance to invade and attach to them. Carraguard, PRO 2000, and cellulose sulfate are entry and fusion inhibitors.



4. Replication inhibitors prevent viruses from replicating in cells that they have entered. Replication inhibitors are still in preclinical studies or in phase I or phase II clinical trials. None has yet reached phase III.

Vaginal defense enhancers boost natural defenses against diseases. The vagina is normally too acidic for sperm to survive. During sexual intercourse semen, which is alkaline, neutralizes the acidity of the vagina, making it more likely that sperm—and also HIV and other pathogens—will survive. Acid-buffering microbicides make the semen acidic, which keeps the vagina acidic, thus inactivating sperm and several STI organisms, including HIV (65, 86).

BufferGel (carbomer 974P)¹, developed at Johns Hopkins University and ReProtect, Inc., a biotechnology firm, reinforces the protective vaginal acidity to kill sperm, microbes that cause some STIs, and also white blood cells infected with HIV (86, 127). Clinical trials provide some evidence that BufferGel also treats bacterial vaginosis, a condition that increases the risk of HIV infection (46, 122).

Clinical trials in India, Malawi, Thailand, Zimbabwe, and the US have found that BufferGel is nontoxic, and rates of vaginal irritation were similar to those in an earlier study of women using no vaginal product (76). In a US clinical trial most of the 48 men who completely coated the penis with BufferGel for seven consecutive nights found it acceptable and reported they would use it and not object to their partners’ use. Side effects were not significantly different from those of a placebo (114).

A phase II/III study of BufferGel is currently evaluating the contraceptive effectiveness of the substance when used with a diaphragm. A phase II/IIb HIV-prevention clinical trial will begin in late 2004 in India, Malawi, South Africa, Tanzania, the US, Zambia, and Zimbabwe to evaluate the safety and effectiveness of BufferGel and PRO 2000 in over 3,000 women (see related information below). The US National Institute of Allergy and Infectious Diseases (NIAID) and the HIV Prevention Trials Network (HPTN) are sponsoring this clinical trial (17).

Surfactants disable bacteria and viruses. Surfactants (also known as detergents) kill or disable bacteria or viruses by damaging bacterial membranes and viral envelopes (surface membranes). In this they are similar to currently available spermicides that act as surfactants, such as nonoxynol-9 (N-9) (94). Hundreds of chemicals can kill HIV, but researchers are looking for a surfactant that will not disrupt epithelial cells (the thin, protective layer of cells lining the vagina) and that has few side effects (119).

N-9 has been used for decades, before HIV appeared, as a spermicide in contraceptive foams and gels and to lubricate condoms. In lab tests N-9 rapidly and potently inactivates HIV and other STIs as well as killing sperm (25, 64, 113). Therefore, researchers had hoped that N-9 would prove to be an effective microbicide (57). Recent research, however, has found that N-9 can disrupt epithelial cells in the vagina among women who have sex several times a day, thereby increasing the risk of HIV infection (61, 101, 102, 120, 123).

In 2003 the World Health Organization (WHO) recommended that people not use N-9 for protection against HIV/AIDS or other STIs (126). There is some concern that candidate microbicides that work as detergents may have effects similar to those of N-9 on the epithelial cells in the vagina. Extended safety tests would help determine whether or not they cause similar problems (19).

C31G (Savvy®) is a microbicide developed by Biosyn, Inc. C31G is a surfactant that diffuses through cervical mucus more rapidly than N-9 and, at low concentrations,is not as toxic to vaginal cells (60). In laboratory tests C31G kills sperm cells and also kills a variety of STI pathogens, including HIV (69, 124). It does not work, however, against viruses such as human papillomavirus (HPV) that are not encased in a membrane (124).

The nonprofit research organization CONRAD, in several phase I and phase I/II clinical trials among men and women using C31G, has found that the substance is well tolerated at low doses after 3 to 14 continuous days of use (69, 74, 75). In a phase I clinical trial among women who applied C31G before sex, it significantly reduced the number of motile sperm in the vagina after sex (73).

Phase III clinical trials have begun in Ghana among more than 2,200 women to test effectiveness of C31G against HIV, and another phase III clinical trial has begun in Nigeria. Results from both studies are expected by 2007. Family Health International (FHI) is conducting these clinical trials, with funding from the US Agency for International Development (USAID) (9, 33). Additionally, a phase III clinical trial to test contraceptive effectiveness has begun in the US in over 1,000 women, funded by the US National Institute of Child Health and Human Development (21).

Entry and fusion inhibitors block pathogens. Entry and fusion inhibitors, including Carraguard, PRO 2000, and cellulose sulfate, bind to pathogens, thus preventing them from attaching to host cells, or they bind to potential host target cells, forming a protective coating that prevents pathogens from attaching. Many of these products are nonspecific blockers—that is, they act against multiple organisms, including microbes that cause HIV and other STIs (44).

Carraguard (PC-515), being developed by the Population Council, is a microbicidal gel containing carrageenan, a sulfated polysaccharide derived from seaweed. Researchers suspect that Carraguard binds to viruses, including HIV, HPV, and herpes simplex virus (HSV), thereby blocking them from sticking to healthy cells (88). Carraguard appears not to be spermicidal, however.

Carraguard is inexpensive to make (93). Another advantage is that, because carrageenan is commonly used in cosmetics, toothpastes, and food, it is expected to be safe and nontoxic when used as a microbicide. In clinical trials Carraguard is distributed in prefilled, single-dose, disposable plastic applicators. Users press a small bulb between the thumb and forefinger to squeeze out the contents of the applicator into the vagina through the elongated nozzle (93).

Preliminary data from a phase I clinical trial in Thailand found that men who applied Carraguard before sex over three months did not experience significantly more irritation than a control group of men using a placebo (59). Phase II studies among 400 HIV-negative healthy women in South Africa and among 165 such women in Thailand confirmed topical safety (that is, safety to the vaginal epithelium) (92). A phase III trial to determine the effectiveness of Carraguard in preventing HIV transmission among 6,270 women in South Africa began in March 2004 and is expected to continue for at least three years (92).

PRO 2000 (polynaphthalene sulphonate), produced by Indevus Pharmaceuticals in the US, binds to HIV and other STI pathogens, preventing them from infecting human cells. Phase I clinical trials in Belgium, South Africa, the UK, and the US have demonstrated the topical safety and acceptability of PRO 2000 in low doses, although one-third to two-thirds of women experienced mild vulval irritation or leaking of the microbicide from the vagina (77, 121). A phase I trial among 97 men found that side effects of PRO 2000 were not significantly different from those of a placebo (114). The developer may produce formulations to prevent pregnancy as well as STIs (2, 96).

A phase II/IIb HIV-prevention clinical trial involving 3,100 women in seven countries is starting in late 2004, sponsored by HPTN, to evaluate the safety and effectiveness of a low-dose of PRO 2000 and BufferGel . In addition, the MDP is planning a phase III clinical trial to begin in 2005 in Cameroon, South Africa, Tanzania, Uganda, and Zambia to test high and low doses of PRO 2000 in 12,000 women (79, 100).

Cellulose sulfate (Ushercell^TM), developed by Polydex Pharmaceuticals Ltd. in Canada, has been undergoing evaluation since the early 1990s. In laboratory and animal studies it acts against a broad range of STIs (5, 72). It also appears to have a contraceptive effect (4).

Several phase I clinical trials conducted by the Global Microbicide Project, HPTN, and WHO have demonstrated that cellulose sulfate is safe and less irritating than N-9 (72) for both women and men (70). Another phase I trial in Cameroon found that, when cellulose sulfate was compared with a nonmicrobicidal gel (KY Jelly®), there was no difference in the rates of epithelial disruption, candidiasis (yeast infection), or bacterial vaginosis or in the acceptability of the two products (20). Researchers have completed additional safety studies with similar results in India, Nigeria, and Uganda (66) and also in the US (105).

Researchers are planning phase III clinical trials to assess the effectiveness of cellulose sulfate. These trials are expected to begin in late 2004 or early 2005, involving over 2,500 women in Benin, Burkina Faso, India, Kenya, Nigeria, South Africa, and Uganda. CONRAD and FHI are conducting these studies (91, 118).

¹ Some microbicide candidates are typically known by their brand name, such as BufferGel, while others are known by their chemical agent, such as C31G. In this section each microbicide is introduced by the name most commonly used, followed by its other name, whether product or chemical, in parentheses. Thereafter, throughout the text the product is referred to by the name most commonly used. Product names are in italics, while chemicals are in roman type.