The global HIV epidemic and the continuing need for effective preventive interventions
Joint United Nations Programme on HIV/AIDS (UNAIDS) and WHO have estimated that worldwide the number of people living with HIV has increased from 29 million in 2001 to 33.4 million in 2008, while the annual number of new infections has decreased from 3.2 to 2.7 million during the same period . The increased prevalence of HIV infection has been recorded in all regions of the world and this can be attributed partly to improvements in the longevity of HIV-infected people as a result of increased access to antiretroviral treatment (ART). The incidence of HIV infection appears to have declined in sub-Saharan Africa, Asia, Oceania and Europe, whereas it has stabilized or slightly increased in Latin America, North America, the Caribbean, the Middle East and North Africa.
Despite evidence of declining incidence in many parts of the world and increasing access to ART, HIV infection remains a major public health problem, especially in low-income and middle-income countries. According to WHO, United Nations Children's Fund (UNICEF) and UNAIDS, more than 4 million HIV-infected adults and children were receiving ART in low-income and middle-income countries at the end of 2008 . Overall coverage in these countries was low, however, with only 42% of the 9.5 million people in need of these life-saving drugs actually receiving them. Thus, the majority of people currently in need of treatment remain untreated, especially in the high-prevalence countries of sub-Saharan Africa. As the number of people who meet the criteria for initiation of ART continues to rise, particularly following the recent revision of guidelines to recommend initiation of treatment at higher CD4 cell counts , ART programmes will find it increasingly difficult to extend coverage and sustain provision of treatment services to all patients who need them. Moreover, it is estimated that there are more than two new HIV infections for every new patient who is started on treatment . For the HIV epidemic to be brought under control, there is an urgent need for the expansion of ART services, while at the same time, HIV prevention efforts are strengthened in order to reduce the number of new HIV infections and the pool of HIV-infected patients who will need treatment in the future. Scaling up known effective interventions while searching for new prevention methods of proven effectiveness must remain a major global public health priority.
The search for effective preventive interventions
Even before the causative agent of AIDS was discovered, it was established that it must be an infectious agent that was transmitted through sexual intercourse. This led health authorities and organizations of men who have sex with men (MSM) in industrialized countries to recommend sexual behaviour change, including use of condoms, as a strategy to stem the spread of the new disease . The discovery of the HIV virus in 1983 raised hopes that the development of a vaccine might be possible. It is now more than 25 years since this important discovery was reported and yet we still do not have an effective vaccine. Since the first cases of AIDS were described, many studies have been conducted on the epidemiology of HIV infection and risk factors for the acquisition of HIV. These studies have allowed us to identify modifiable risk factors for HIV acquisition and this has been the basis for the development of a number of preventive interventions that have been tested in randomized controlled trials (RCTs).
Sexual intercourse is the main mode of HIV transmission among adults globally and is the focus of this supplement. We now understand that the sexual transmission of HIV in a population is determined by a range of factors that influence the rate of sexual contact between infected and uninfected partners and the probability of transmission during a specific sexual encounter. Patterns of sexual behaviour are key determinants of the rate of sexual contact between HIV-discordant partners. These include rates of sexual partner change and characteristics of sexual networks including choice of partners and concurrency of partnerships. The probability of transmission during a single sex act depends on the type of sexual activity (including use or nonuse of condoms), the infectiousness of the infected partner and the susceptibility of the uninfected partner. A number of biological factors have been identified that influence the efficiency of transmission, including HIV viral load, stage of HIV disease, sexually transmitted infections (STIs) and other genital infections and male circumcision [5–7]. Although biological and behavioural factors are important proximal risk factors for HIV transmission, they are in turn influenced by a complex array of underlying factors including societal and cultural norms, sex-based inequality and socioeconomic variables. A comprehensive understanding of the proximal biomedical and behavioural risk factors, as well as distal contextual factors is required in order to develop effective HIV preventive interventions.
Increasing awareness of the infection and promotion of sexual behaviour change among groups at high risk and in the general population have been a major focus of public health programmes developed to control the epidemic. As part of these efforts, use of condoms is recommended as a means of HIV prevention. Although no RCTs have been conducted to measure the effectiveness of male condoms, studies of discordant couples indicate that consistent use of the male condom is approximately 80% effective in preventing heterosexual transmission of HIV . Although promotion of safer sexual practices, including consistent condom use, remains a key component of HIV control programmes, there is still limited evidence of which specific intervention approaches are most successful in changing behaviour, and to date, no RCTs of behavioural interventions have been able to demonstrate a significant impact on HIV incidence.
Improved understanding of factors influencing the probability of sexual transmission of HIV has helped to identify other potential interventions and subsequently test their effectiveness in rigorously conducted RCTs. Control of other STIs has been shown in one RCT to reduce the incidence of HIV infection, but other trials have failed to find an effect of improved STI treatment on HIV spread. Male circumcision is so far the only intervention that has been shown to be effective in reducing the risk of HIV acquisition in multiple RCTs, showing 50–60% protection in all three trials that have tested this intervention.
Studies of the epidemiology of HIV have also highlighted the increased vulnerability of women to HIV infection. Although the male condom is highly effective in preventing the sexual transmission of HIV, in many settings, women have little negotiating power to use a condom and protect themselves against HIV. This has led to the development of microbicides, products in various formulations which women could insert in the vagina in order to reduce the probability of acquiring HIV infection during sexual intercourse. Several RCTs of candidate microbicides have been conducted, but so far no product has been found to be effective in reducing HIV transmission. Hopes are high that the next generation of microbicides, which include antiretroviral compounds, will be more successful.
Antiretroviral drugs entered the HIV prevention field more than 15 years ago with the trials of prophylactic treatment for the prevention of mother-to-child transmission and a case–control study of the effectiveness of occupational postexposure prophylaxis. New uses of antiretroviral drugs in HIV prevention include preexposure prophylaxis (PrEP) and the test and treat strategy. Trials of PrEP are ongoing, whereas the test and treat strategy is in the early stages of development.
Lastly, in the past few years, there has been a growing realization that successful control of the spread of HIV might be achieved by using a combination of preventive interventions that are tailored to the specific needs of the target population. Combination prevention is hotly discussed, but so far there are very few empirical data and the evaluation of combination prevention will pose significant challenges.
HIV prevention at the cross-roads
In a recent systematic review which summarized the results of RCTs of 39 interventions to prevent sexual transmission of HIV, 33 trials failed to show either a positive or negative effect on HIV acquisition . It is clearly disappointing that the overwhelming majority of trials showed ‘flat’ results. The majority of flat results were reported in trials of vaginal microbicides (33.3%), STI treatment (24.2%) and behavioural interventions (21.2%). In examining the results of such trials, we clearly need to explore possible reasons for the large proportion of trials showing flat results and to consider whether these findings have implications for the design and conduct of future HIV prevention trials.
The main objective of this special journal supplement is to review the evidence base on the different approaches to prevention of sexual transmission of HIV among adults. Following this introductory note, there are seven review articles which will discuss the following main areas of HIV prevention research:
1. Behavioural interventions;
2. STI control for HIV prevention;
3. use of ART for HIV prevention;
4. topical microbicides;
5. HIV vaccines;
6. male circumcision;
7. combination prevention.
For each review article, the authors were requested to address the following questions and issues:
1. Brief review of the intervention approach or approaches.
2. Summary of the results of past trials and other studies.
3. Discussion of ongoing and planned studies.
4. Perspectives on outstanding questions, methodological challenges and future research needs.
The final article in this supplement draws together some of the key messages from the seven review articles and seeks to learn the lessons of past failures and successes in the field and to discuss what we should be doing the same and what we should be doing differently in the years to come.
Most of the lead authors of these review articles were keynote speakers at a special scientific symposium entitled ‘HIV Prevention – Where Now?’, held in Mwanza, Tanzania, from 14–16 July 2009. The main objectives of the symposium were to bring together leading African scientists and researchers from other parts of the world to review existing knowledge about HIV prevention, to review past successes and failures in HIV prevention research and to discuss future research directions and methods including the role of RCTs in research on HIV prevention. The symposium also provided an opportunity to celebrate the official opening of the new Mwanza Intervention Trials Unit (MITU) which has been established on the campus of the Tanzanian National Institute for Medical Research (NIMR) Mwanza Centre. The new unit in Mwanza represents an important new resource for clinical trials in Africa.
It is fitting that this symposium, bringing together many of the world's leading HIV prevention scientists, was held in the location of the first trial to demonstrate the impact of a preventive intervention on HIV incidence in the general adult population  20 years after the commencement of that trial. We hope that this supplement will provide a valuable contribution to the debate on the role of trials in HIV prevention and help to set the scene for research leading to a larger armamentarium of effective prevention tools in the next 10–20 years.
We would like to thank the Tanzania AIDS Commission, UK Medical Research Council and International Partnership on Microbicides for their generous financial support for the symposium and the publication of this special supplement. We are also grateful to NIMR Mwanza Centre under the leadership of our colleague John Changalucha for its long-term support for the collaborative HIV research programme between NIMR, LSHTM and AMREF in Mwanza and for hosting this symposium. Special thanks go to Jacqueline Jackson and her administrative team for organizing the symposium so efficiently and to all the participants for their active engagement in the discussions.
Conflicts of Interest: None.
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