HIV infection continues to exact a devastating toll worldwide.Advances in antiretroviral therapy have helped bring theHIV/AIDS epidemic under control in developed countries.Antiretroviral drugs, however, are not widely available inthose developing countries where HIV poses a catastrophicthreat. Effective strategies for HIV prevention are thereforecrucial to curbing the global epidemic. Vaccination, microbicideuse, and male circumcision are 3 key preventive interventions.Current research is focused on developing effective vaccinesand microbicides and on determining the extent to whichcircumcision helps prevent HIV acquisition and transmission.[Infect Med. 2008;25:63-72]
The global toll from HIV infection is steep: the joint United Nations Programme on AIDS (UNAIDS) estimates that 2.8 million deaths each year are due to HIV infection and that 38.6 million persons are living with HIV infection. In addition, UNAIDS forecasted 4.1 million new infections worldwide in 2005.1 The scope of impact establishes a clear need for improved preventive measures against HIV infection. Sub- Saharan Africa-which is home to approximately two thirds of all cases globally and where the prevalence of HIV infection among adults is about 6%-has the greatest burden.
Ideally, preventive measures should be easy, inexpensive, and continuously protective. Strategies that may help prevent infection or ameliorate HIV disease in the near future include vaccination, use of microbicides, and male circumcision.
Table 1 outlines several key challenges in HIV vaccine development.Genetic, immunological, operational, and cost hurdles stand in the way of developing an effective and practical vaccine. In the face of these challenges, the traditional paradigm of vaccine development-which holds that a candidate vaccine must achieve greater than 90% efficacy to be deemed successful-may need to be modified.2 The 4 models for a successful HIV vaccine that have been proposed are:
The US government has been supporting HIV vaccine research for nearly 25 years.3 Using an approach that led to success with other viral vaccines, early clinical trial researchers pursued development of a vaccine that elicits antibody responses to HIV envelope proteins. The first phase 3 trials using this approach- the AIDSVAX trials, sponsored by the biopharmaceuticals company VaxGen-yielded disappointing results: 5.7% of those who received the vaccine became infected with HIV compared with 5.8% of those who received placebo.4,5
More recently, 2 phase 2 test-of-concept trials of an adenovirus type 5 (Ad5)-based vaccine were stopped early when an interim analysis demonstrated no efficacy. The STEP (HVTN 502/Merck 023) trial , which was sponsored by Merck and Company and the National Institute of Allergy and Infectious Diseases, was a double-blind phase 2b placebo-controlled study conducted in North and South America, the Caribbean, and Australia using an Ad5 vector with clade B HIV inserts. It was designed to assess the safety and tolerability of the vaccine, evaluate efficacy in preventing infection, and determine the effect on disease progression in those who were infected after vaccination.
A second trial, called the Phambili trial after the Xhosa word for "move forward," used the same clade B-based adenovirus vector in South Africa (where 95% of the isolates are clade C virus) in an effort to elicit cross-clade protection.6 A modified intent-to-treat analysis of data from the STEP study revealed 24 cases of HIV infection among 741 vaccine recipients and 21 cases of HIV infection among 762 placebo recipients.7
Current efficacy trials are designed to assess outcomes by measuring HIV acquisition and markers of disease progression (viral set point 6 months after HIV acquisition). Disappointing results with vaccine candidates that elicit antibodies have prompted research into other approaches, including stimulation of cytotoxic T lymphocytes (CTLs) or a combination of CTLs and antibodies. Although unlikely to provide total protection against HIV infection, these strategies may slow disease progression.
Recent observational studies have demonstrated that the viral set point shortly after infection is a strong predictor of disease progression. A modeling study that looked at data from the Multicenter AIDS Cohort Study showed that even a small impact on the viral set point (0.5 log decrease) is associated with delay in onset of AIDS of more than 3 years. An even larger effect (1.0 log decrease in the viral set point) is associated with delay in the need for therapy of more than 2 years and theonset of AIDS of more than 8 years.8 A decrease in the set point is also associated with decreased transmission and could therefore decrease the occurrence of HIV-1 infection in a given population.
Current efficacy trials
More than 40 vaccine trials are under way. These include a large efficacy trial, with a second trial planned to begin in early 2008.9 The largest ongoing investigation to date is the RV144 trial of a CTL-based vaccine. Jointly sponsored by the US Defense Department, the NIH, and Thailand's Ministry of Health, this trial involves a recombinant canarypox vector (ALVAC vCP 1521) that is boosted by the AIDSVAX B/E product. The objectives of the trial are to evaluate both the efficacy of the vaccine candidate and the impact on disease progression. RV144 has enrolled 16,000 HIV-negative Thai volunteers (8000 in the vaccine arm and 8000 in the placebo arm), with outcomes data expected to be available in 2009.
The Partnership for AIDS Vaccine Evaluation (PAVE) 100 study will further test the hypothesis that a CTL-based product can prevent HIV acquisition or ameliorate the disease course. This study, which will enroll candidates identified by the NIH Vaccine Research Center, is a phase 2b trial testing the safety and efficacy of a multigene, multiclade vaccine regimen consisting of a 3-dose DNA prime followed by an Ad5 vector boost. The favorable immunogenicity and safety profiles of this product were recently demonstrated in phase 1 and 2a trials.10,11
The phase 2b trial will enroll participants in regions where different clades predominate-the Americas, East Africa, and Southern Africa. End points are similar to those in the aforementioned trials that looked at decreased HIV acquisition and a decrease in viral set point. PAVE 100 is expected to begin in early 2008, with data available in late 2011.
Several new products are currently in phase 1 and 2a trials. Strategies associated with these studies include new vaccine delivery methods (such as electroporation of DNA plasmids and use of novel adenovirus vectors), combination of antibody- and CTL-based vaccines, and use of novel adjuvants.9 Table 2 lists ongoing phase 2 and 3 trials.
Most global HIV-1 transmissions occur via sexual intercourse between serodiscordant couples, with the greatest burden of infections occurring among young women in developing countries.12 Women living in certain cultural milieus in these countries may be unable to negotiate condom use and thus have no way to protect themselves against infection. Until an effective vaccine becomes available, topical microbicides are the next best hope for decreasing HIV-1 infection and death among women.
Topical microbicides are generally administered vaginally. Research on whether products labeled for vaginal use may be effective when administered rectally is under way. Even a product with low efficacy, if used in 30% to 50% of exposures, might significantly decrease HIV-1 transmission rates and the burden of disease in the most vulnerable populations. 13 This promising observation has accelerated the search for microbicides that are effective against HIV, with numerous products entering phase 2 and 3 trials in recent years.
The identification of effective microbicides hinges heavily on our understanding of HIV-1 mucosal transmission. Mucosal compartments are significantly dissimilar with respect to their susceptibility to HIV-1 acquisition. Certain conditions, such as herpes simplex virus infection of the vagina and rectum, increase susceptibility to HIV-1 infection.14-16 Other inflammatory conditions, such as bacterial vaginosis and candidiasis, may increase vaginal susceptibility to infection.
Less understood are modifiable aspects of mucosal immunology that afford protection of vulnerable tissues against infection. Recent research shows that Langerhans cells, implicated in HIV-1 transmission and rapid replication following acute infection, may in fact protect against infection.17 If so, the ratio of Langerhans cells to other dendritic cell subsets in discrete mucosal compartments might influence susceptibility to HIV transmission and replication. Scientists who are involved in research and development of microbicides are assessing multiple strategies to determine how to modify the mucosal environment to minimize a person's susceptibility to HIV-1 transmission.
Mechanisms of action
Microbicides are grouped into 3 broad categories according to their mechanism of action:
Microbicides also can have contraceptive properties, making them more or less acceptable to the user, depending on fertility goals.
Products under development
An estimated 60 to 80 different microbicide products are in various stages of development, with 11 currently in clinical trials and 2 in ongoing phase 3 trials. The 2 products in phase 3 testing are Carraguard, which is being studied in South Africa, and PRO 2000, which is being studied in 4 southern African countries. Carraguard is a noncontraceptive gel consisting of a sulfated polysaccharide mixture of ?- and & kappa;-carrageenan derived from red seaweed. It has demonstrated activity as a fusion and entry inhibitor in in vitro studies.18 The safety and acceptability of the product was demonstrated in phase 2 testing among 83 Thai women.19 Phase 3 enrollment was completed in March 2007. Results are expected to be announced in early 2008.20
PRO 2000 gel, a polyanion with proven antiviral activity, has demonstrated safety and acceptability in clinical trials.21-24 The phase 3 trial is currently enrolling participants and should be completed in mid-2009.
Other products are in earlier phases of testing (Table 3).20 These products have shown promise as microbicides in vitro and have been established as safe in laboratory mod-els. Additional products are in preclinical testing while the protocol for bringing them quickly to clinical trials is being standardized.25,26
Microbicide product research has suffered several setbacks in the past few years. The 3 trials of nonoxynol- 9 use among commercial sex workers in Africa showed no efficacy in the prevention of HIV infection, with 1 trial showing a 50% higher incidence of HIV infection among those using the microbicide.27-29 These results frightened members of the HIV research and activist community and delayed future microbicide trials. Consequently, talent and resources have been diverted from microbicide research to vaccine research.30 With the development of novel approaches, research into microbicides to prevent HIV transmission has taken on new enthusiasm.
More recently, 2 phase 3 trials of C31G vaginal gel, marketed as Savvy, were halted because of poor efficacy, and 2 phase 3 trials of cellulose sulfate (CS) were stopped because of safety concerns. Although these trial discontinuations are disappointing, they demonstrate that safety monitoring and timely review of efficacy data can help preserve the safety of participants in large clinical trials while redirecting resources to more promising products.
In the Contraception Research and Development CS trial, an interim review of 35 incident HIV-1 infections revealed that CS was significantly inferior to placebo in preventing HIV-1 infection. In less than 1 week, this trial and another phase 3 CS trial conducted in Nigeria were halted.31 When reviewed, the data from the Nigerian trial suggested that the product was unlikely to demonstrate superiority to placebo.
The general consensus is that a microbicide must be readily accessible, stable in ambient conditions in tropical countries, and acceptable to both men and women to be successful. To ensure enduring efficacy, a topically applied product must be acceptableto the at-risk population. Products now undergoing testing are contained in a water-based gel, which does not necessarily provide the most acceptable or long-lasting protection. For this reason, alternative product formulations with the potential to protect for weeks or months following a single administration (eg, solid-phase films and impregnated rings) are being tested in preclinical phase 1 studies.
One of the most promising strategies for HIV prevention is male circumcision. Sexually transmitted diseases (STDs), especially ulcerative STDs, are known risk factors for HIV acquisition. Given that circumcision has been shown to reduce the rate of STDs in men, it is speculated that circumcision might reduce HIV risk indirectly. Cells that are susceptible to infection are relatively more common on the mucosal, nonkeratinizedsurface of the foreskin than on the urethra or the epithelialized shaft of the penis. Circumcision may reduce the risk of HIV infection by reducing microtrauma or abrasion of the mucosal surface of the foreskin.
Many observational studies published over the past 2 decades have suggested that circumcision has a protective effect. Most of the studies were conducted in Africa, where circumcision practice and HIV prevalence vary by tribe or ethnic group. Interpretation of any correlation observed is complicated because other behaviors or attributes that influence HIV risk may vary with circumcision practices. A recent Cochrane review considered 35 such studies, 16 in general populations and 19 in high-risk populations. (A meta-analysis could not be conducted because the studies varied by quality, design, study population, measurement of confounding variables, and method used to ascertain a person's circumcision status.)32
The proportion of studies that showed a statistically significant preventive benefit of circumcision was greater among the studies in high-risk populations than among studies in the general population. The review authors concluded that the data support proceeding with clinical trials to evaluate whether circumcision prevents HIV infection.
Randomized clinical trials.
Results from 3 randomized clinical trials of the effect of circumcision on HIV acquisition have become available within the past 2 years (Table 4). In the first trial, South African participants were randomly selected to be offered a circumcision procedure (performed by experienced local practitioners) within 1 week of the start of the trial (intervention group) or at the end of the 21-month trial (control group). Circumcision was performed at study entry for men in the intervention group; follow-up was at 3, 12, and 21 months. Participants received counseling at each visit as well as genital examination, a questionnaire (detailing sexual risk behaviors), and HIV testing. The trial was halted after a mean follow-up of 18.1 months, when an interim analysis documented a large protective effect among the intervention group- a relative risk of 0.40, or 60% protection, against HIV (P < .0001)- whereupon circumcision was then offered to the control group.33
Similar trials in Kenya and Uganda were halted when review by the data safety monitoring boards found evidence of efficacy for prevention of HIV acquisition. Although they differed slightly in design, these trials showed similar levels of efficacy, with the risk of HIV acquisition decreasing by roughly half.34,35 Adverse event (AE) reporting differed among all 3 trials; however, most documented AEs were mild to moderate. The incidence rate of AEs ranged from 1.7% to 8%. Severe AEs were only seen in the Ugandan trial, with an incidence rate of 0.2%. All AEs were managed successfully.33-35
On the basis of these data, the World Health Organization and UNAIDS have deemed male circumcision to be an effective (but not completely protective) intervention for preventing HIV acquisition and recommend that it should be recognized as an important strategy for prevention of heterosexually acquired HIV infection in men.36
Effect among MSM
Little is known about the protective potential of circumcision among men who have sex with men (MSM), for whom the primary site of infection is assumed to be the rectal mucosa. Lack of circumcision has been associated with increased risk of HIV acquisition in at least 1 study. This observational study of 3257 US men found a 1.9-fold (95% confidence interval [CI], 1.1, 3.4) increase in risk associated with lack of circumcision. 37 After adjusting for sexual practices and drug use, lack of circumcision remained associated with HIV acquisition (adjusted odds ratio, 2.0 [95% CI, 1.1, 3.7]) with a population attributable risk of 10.2%.
Effect on male-to-female transmission
Limited data exist regarding the possible effect of male circumcision on male-to-female HIV transmission. A large prospective study conducted in rural Uganda found that circumcision was associated with reduced male-to-female transmission for a subset of HIV-infected men (those with HIV RNA levels less than 50,000 copies/mL; P = .02).38,39 Recruitment into a study of the effect of circumcision among serodiscordant couples in Uganda was recently stopped40 when preliminary results showed no significant difference in HIV transmission risk between circumcised and uncircumcised HIV-infected men. The findings suggested that the risk of transmission may be increased if men who are circumcised resume sexual activity before full healing.41 Although circumcision should be provided to all men when medically indicated, currently available data do not support male circumcision as an intervention to reduce HIV transmission to women.
The HIV/AIDS epidemic has had an enormous worldwide impact. Preventing the spread of HIV and treating persons who are already infected pose tremendous challenges for public health authorities and medical researchers. The optimal approach is multidisciplinary, with dual aims of preventing the acquisition of HIV and halting its progression. International cooperation and collaborative research are essential in arresting the global spread of HIV. Vaccine development, microbicides, and male circumcision are the current strategies being explored for preventing transmission of HIV and eradicating the HIV/AIDS epidemic. Although microbicide and vaccine approaches have recently been met with disappointing news, new products continue to be developed that will add to the multidisciplinary HIV prevention approach.