Approximately 40 million people are currently living with HIV worldwide, almost 5 million of whom were infected in 2005. In addition to expanding the availability of antiretroviral (ARV) treatment in developing countries, the scale of the epidemic requires the continued promotion of available prevention tools and the exploration of a range of novel technologies. Research and development are ongoing for several promising new prevention strategies, including male circumcision, microbicides, pre-exposure prophylaxis, and preventive HIV vaccines. Efforts also continue to promote known strategies, including prevention of sexually transmitted infections (STIs). In many cases, the methods in development are initially expected to have partial efficacy and are intended to be used in conjunction with male condoms. In addition, no one method can meet the needs of all individuals; therefore, a range of complementary prevention tools will be needed to stem the epidemic.

Sexually Transmitted Infections

The spread of HIV is thought to be accelerated by the relationship between HIV and STIs. The presence of an STI may increase the infectiousness of an HIV-positive individual as well as enhance susceptibility to HIV infection among those who are HIV-negative.

Ulcerative STIs -- chancroid, herpes, and syphilis -- can increase viral shedding of HIV, generally from the ulcer itself. Ulcers may also bleed during intercourse, which in turn can increase HIV transmission. Susceptibility to HIV can be intensified in the presence of an ulcerative STI, either through mucosal disruption or through an increase in the presence or activation of cells susceptible to HIV. Susceptibility may be further increased by interactions between viral STIs and HIV.

Inflammatory STIs -- chlamydia, gonorrhea, and trichomoniasis -- can also enhance HIV infectiousness by increasing viral shedding. Susceptibility to HIV can be increased among HIV-negative women by proliferation of HIV-susceptible cells resulting from infection from non-ulcerative STIs. HIV replication may also be facilitated through an interaction between chlamydia and selected white blood cells.

The relationship between HIV and sexually-transmitted types of human papillomavirus (HPV) is complex. Coinfection with HPV and HIV is frequent, an occurrence that is likely a result of common risk factors as well as an increase in susceptibility to HPV among HIV-positive individuals. The converse may also be true: the risk of acquiring HIV may be increased by HPV infection. Additional research is needed to further define the association between HPV and HIV and the potential impact of HPV infection on HIV transmission.

Condoms can reduce the risk of contracting many STIs. Studies have shown decreased rates of gonorrhea, chlamydia, herpes simplex virus type 2, and syphilis among those who use condoms consistently. The reduction in STIs that would result from increased condom use could reduce HIV incidence.

Bacterial Vaginosis

Bacterial vaginosis (BV), sometimes referred to by the general term "vaginitis," is one of the most common infections of the female reproductive tract and may play a role in increasing the susceptibility of women to HIV infection. BV, which occurs in up to 25% of women, refers to a drop in the levels of lactobacilli (bacteria that help to protect the vagina). BV, unlike many other STIs, is common among women having sex with women.

BV and STIs commonly occur together, but researchers are unsure as to why. One theory is that acquiring an STI is linked to low levels of lactobacilli. Some data support the use of condoms in preventing BV, but due to the uncertainty of its cause and its high prevalence in areas where the risk of HIV infection is also high, further research is needed to consider if interventions to control BV can be useful as an HIV prevention method in women worldwide.

Male Circumcision

It is possible that male circumcision could play a significant role in reducing the spread of HIV infection in hard-hit areas such as sub-Saharan Africa. In 1986, the first report that suggested that circumcision may offer a degree of protection from HIV infection was published. In the years following, numerous observational studies and meta-analyses were conducted, with the former suggesting that areas with the highest HIV prevalence -- namely Eastern and Southern Africa -- were also areas where most men are not circumcised. A meta-analysis revealed an association between circumcision and lowered HIV risk among men in sub-Saharan Africa -- 21 of the 27 studies reviewed demonstrated a reduction in HIV risk among circumcised men. But due to the lack of experimental data, a causal relationship between circumcision and HIV prevention could not be established. It was also unclear, based on the observational studies, whether HIV infection rates were greater in high prevalence areas due to low rates of circumcision or because of behavioral differences between the circumcised and the uncircumcised groups.

In the first randomized clinical trial assessing whether circumcision can reduce the risk of HIV infection, researchers found circumcision to have a 60% protective effect. Of more than 3,000 men who were followed for an average of a year and a half, 20 members of the intervention group and 49 of the control group acquired HIV during the trial. This means that the intervention (circumcision at the beginning of the trial) prevented six out of ten HIV infections during the study, suggesting that men who have been circumcised have less of a likelihood of acquiring HIV when having sex with HIV-positive female partners. The data from this first clinical trial seem to indicate that in regions with high HIV prevalence, circumcision could reduce men's risk of becoming infected. Different cultures have various views about circumcision, and implementing this potential HIV prevention method on a large scale could be difficult. Since data from the first trial seem to indicate that circumcision is partially protective, circumcised men will still need to use condoms. Programs that promote circumcision for HIV prevention will need to include a condom education component.

Microbicides

Microbicides are substances intended to reduce sexual transmission of HIV or STIs when applied topically to the vagina. A number are currently in development. A microbicide could be formulated as a gel or cream; film; suppository; pre-loaded diaphragm or cervical cap; or slow-release sponge or vaginal ring. Some formulations would be applied prior to each act of intercourse, while others might be worn by the woman continuously to provide protection for a longer period of time. Some microbicides might be contraceptive; others would allow women to become pregnant while simultaneously offering protection from HIV. An ideal microbicide would also be acceptable to a variety of men and women in different cultures.

Microbicides would provide a much-needed woman-controlled method of HIV prevention. As the HIV epidemic progresses, women and girls are increasingly affected. Between 2003 and 2005, the number of women living with HIV increased by 1 million to a total of 17.5 million worldwide. In sub-Saharan Africa, 57% of HIV-positive adults are women. Moreover, women -- particularly young women -- are biologically more susceptible to HIV and STIs than men. When combined with the persistence of gender inequality, economic disparities, and violence, this increased biological risk further reduces women's ability to protect themselves from HIV. Microbicides, which could be used with or without a partner's knowledge, would provide a prevention option for women that they could control.

Microbicides could prevent transmission of HIV through several mechanisms of action. Membrane disruptive agents (surfactants) kill or inactivate viruses or bacteria by disrupting their outer membranes. Vaginal defense enhancers boost vaginal immunity and maintain the protective acidic pH of the vagina. Entry/fusion inhibitors disrupt the process of attachment, binding, and fusion between HIV and host cells -- by targeting either the viral envelope or host cell receptors and co-receptors. Replication inhibitors prevent the virus from spreading to other cells and/or interrupt the viral replication process by inhibiting reverse transcription. Microbicides may also reduce susceptibility to HIV by providing a physical barrier to infection and supplying lubrication during intercourse to reduce the risk of epithelial disruption. As microbicides with a single active ingredient or mechanism of action are unlikely to offer complete protection, combination microbicides are being explored as a means of increasing efficacy.

There are currently 14 microbicide candidate products in preclinical development and 15 in clinical development. Ten of the products in clinical development are in early-stage trials (Phase 1, 1/2, or 2) and five products are in more advanced trials (Phase 2/2B or 3). These late-stage trials, spanning 12 countries, will enroll nearly 30,000 participants. One of the five products in late-stage trials is a membrane disruptive agent (Savvy), one is a vaginal defense enhancer (BufferGel), and three are entry/fusion inhibitors (Carraguard, cellulose sulfate, and PRO 2000). Replication inhibitors are in early-stage trials, (Tenofovir/PMPA gel, TMC120, and UC-781). Each of the microbicides in late-stage trials is expected to have partial efficacy, which means they should be used with condoms. A 60% efficacious microbicide could avert 2.5 million HIV infections over 3 years if used in 73 lower-income countries.

The development of rectal microbicides is at a much earlier stage than vaginal microbicides, partly because the environments of the rectum and vagina are markedly different. Early research is being conducted to find markers that could be used to study the safety of rectal microbicides. Studies are also being done to determine the acceptability, when used rectally, of different volumes of a gel that is similar to potential microbicides. Given the differences in the tissues and structures of the vagina and rectum, more research is needed to assess the potential of microbicides for rectal use.

Preventive HIV Vaccines

An increasing number of organizations have become involved in vaccine research and development, and the number of vaccines in clinical testing has grown substantially over the past five years. This growth, however, has occurred in the context of significant challenges.

Early vaccine candidates sought to elicit a humoral immune response, aiming to produce neutralizing antibodies, leading to viral clearance after exposure. For a variety of reasons, induction of this type of immunity has proven difficult. VaxGen's candidate vaccine AIDSVAX, which employs recombinant gp120 proteins to induce an antibody-mediated immune response, was shown to be ineffective in Phase 3 trials conducted in the United States and Thailand.

Recent research has focused increasingly on cell-mediated immunity. There are currently more than 30 products in early-stage trials taking place in 19 countries, the majority of which aim to elicit a cellular immune response. The products in development employ a range of strategies, including vector-based vaccines, lipopeptide vaccines, DNA vaccines, and recombinant protein vaccines. A large-scale trial of Aventis Pasteur's candidate vaccine ALVAC vCP1521, which uses a canarypox vector, was recently begun in Thailand and should produce results within five years. AIDSVAX is being used as a booster in this trial.

Despite the promising growth of vaccines in the pipeline, significant challenges persist, and cell-mediated immunity -- on which the vast majority of current candidates rely -- is unlikely to confer complete protection, but rather will lower transmission risk or slow disease progression by controlling viral replication. To speed the development of an effective vaccine, the pipeline may need to be evaluated and diversified. The differences in HIV types, or clades, around the world adds complexity, since a vaccine that is effective in producing an immune response to one clade may not have the same efficacy against another clade. These factors, and others, pose substantial challenges to the development of an effective HIV vaccine.

Barrier Methods

The female condom has been shown in laboratory studies to be impermeable to STIs, including HIV. Epidemiological studies have demonstrated that the effectiveness of female condoms in preventing STIs is most likely comparable to that offered by male condoms. While the cost of a female condom is significantly higher than the cost of a male condom, female condoms are available and have been found to be acceptable to both men and women in diverse settings. As a woman-initiated method of protection, the female condom provides another option for women at risk for HIV infection.

While all studies to date have been observational, evidence suggests that diaphragms are protective against STIs. Randomized controlled trials examining the effectiveness of diaphragms for prevention of HIV and non-HIV STIs are currently being conducted. Since the cervix is a principal entry site for STIs, including HIV, other cervical barriers including cervical caps may offer additional prevention options. To increase effectiveness, physical barrier methods could be used in combination with chemical barriers, such as microbicides.

Pre-Exposure Prophylaxis

Pre-exposure prophylaxis (PREP) involves the provision of antiretrovirals to high-risk individuals prior to HIV exposure in order to reduce the risk of becoming infected. PREP is distinct from post-exposure prophylaxis, which refers to the provision of ARVs to lower the risk of infection after a possible exposure. PREP -- if found to be safe and effective -- would provide a convenient method of HIV prevention for high-risk individuals in situations where they are unable or unlikely to use other methods. A desirable formulation would be potent and non-toxic, would not bring about resistance, and could be given as a once-daily formulation.

Clinical trials have begun to determine whether tenofovir (TDF), when used as PREP, is a safe and effective method of prevention, but some trials have met with resistance. TDF trials in Cambodia, Cameroon, Malawi, and Nigeria were stopped after activists and community members raised a variety of concerns. Additional trials are planned or currently underway in Botswana, Ghana, Peru, Thailand, and the United States. But the controversy emphasized that clinical trials of new prevention methods will need to strike a careful balance between the urgent need to find new tools, and the ethical need to protect participants. Such trials will need to include the community in the earliest planning stages if they are to be successful.

Conclusion

While no technology is anticipated to be the "silver bullet" of HIV prevention, the variety of methods in development has the potential to affect the HIV epidemic in a comprehensive manner. As partial effectiveness is likely to remain a concern even beyond the success of any prevention technology currently in development, employing methods such as condoms remains important.

Betsy Finley and Carolyn Plescia are Writer/Research Associates at the Alliance for Microbicide Development.