Vaccines

Report released at AIDS 2012 calls for sustained funding of HIV prevention research to achieve our collective vision of zero new HIV infections

Washington DC (23 July 2012) – A decade of unprecedented investment in HIV prevention research has led to major scientific breakthroughs in vaccines, microbicides, voluntary medical male circumcision, treatment as prevention and pre-exposure prophylaxis, or PrEP, but sustained financing will be needed to capitalize on these breakthroughs to deliver new options that can help end the AIDS pandemic, according to a new report released today at the XIX International AIDS Conference in Washington, DC.

The new report, Investing to End the AIDS Epidemic: A New Era for HIV Prevention Research & Development, tracks investment in prevention research in 2011 and looks back at a decade of tremendous growth in funding, despite sometimes uncertain prospects for some HIV prevention options. Yet the authors note that capitalizing on recent breakthroughs in the field and ensuring a pipeline of new next generation products will require sustained and flexible investments from a range of donors in the coming years.

The eighth annual report from the HIV Vaccines and Microbicides Resource Tracking Working Group shows that funders invested a total of US$1.24 billion in research and development (R&D) for six key prevention options: preventive HIV vaccines, microbicides, PrEP using antiretroviral drugs, treatment as prevention, prevention of vertical transmission and operations research related to medical male circumcision. This investment is down slightly from the US$1.27 billion invested in 2010 for these six research areas. Investments in vaccine and microbicide R&D decreased in 2011, though decreases for microbicide R&D were attributed to funding disbursement cycles and did not represent declines as compared with past investments.

“This is a critical time. We now have 8 million people on antiretroviral treatment and we are seeing reductions in new HIV infections, even in the most affected communities. But it is not enough to think that HIV is a disease that can be managed with pills. HIV has to be brought to an end and funding shortfalls must not become the roadblocks that prevent us from achieving our goals,” said Michel Sidibé, Executive Director of the Joint United Nations Programme on HIV/AIDS, (UNAIDS).

“Recent advances toward the development of a preventive HIV vaccine have fueled optimism within the AIDS vaccine field. Researchers around the world are now working to build on this progress to develop next-generation vaccine candidates and advance the most promising of these candidates toward large-scale efficacy trials,” said Margaret McGlynn, IAVI President & CEO.  “I am more optimistic now than ever before that the development of a preventive AIDS vaccine is within reach. However, in order to build on this recent progress it is critical that we sustain financial commitment and support for HIV vaccine R&D.”

In the past two years, beginning with results from the landmark CAPRISA 004 microbicide trial announced at the last International AIDS Conference, we have seen tremendous breakthroughs in antiretroviral-based prevention, including TDF/FTC (Truvada) as daily oral PrEP, which was approved by the US Food and Drug Administration as a new prevention option last week, and the HPTN 052 treatment as prevention study which provided evidence that early treatment of HIV-positive people may also protect their HIV-negative partners.

Analyses completed in the past year have unveiled crucial clues as to how the candidate in the RV144 HIV vaccine trial provided protection against HIV. In addition, recent advances in identifying and characterizing broadly neutralizing antibodies to HIV are informing potentially powerful new vaccine candidates.

For microbicides, Phase III clinical trials are underway that could provide the results needed to license and deliver marketable products, including 1 % tenofovir gel and vaginal rings that could offer women protection for a month, two months or longer—and might eventually combine an antiretroviral drug with a contraceptive hormone to provide dual protection. Additional PrEP trials are looking at different drugs and less-than-daily dosing that might be easier for people to adhere to.

Recent positive results underscore the importance of preparing for success and capitalizing on areas of progress and promise. The prevention field continues to need funding structures that can adapt quickly and are sufficiently generous to allow for rapid expansion in the event of positive outcomes.

Indeed, the HIV prevention research field is facing a new and exciting era with many new HIV prevention options becoming available, including female condoms, voluntary medical male circumcision, antiretroviral treatment as prevention and PrEP.  The report notes that additional funding will be needed to effectively roll out all available options, which represents an investment opportunity for countries heavily impacted by HIV, particularly emerging economies.

As the rallying cry to end AIDS is heard this week from policymakers, researchers, funders and advocates gathered in Washington, DC, and as we work together to craft a response to AIDS, the Working Group notes that research to develop and roll out new prevention options is a vital component for success and must be appropriately funded.

“For the first time, the end of the AIDS epidemic is within reach,” said Mitchell Warren, Executive Director of AVAC. “New prevention options – voluntary medical male circumcision, PrEP, treatment as prevention, microbicides and eventually vaccines – will play a critical role in reducing the cycle of new infections.  The past decade has been a period of increasing investment in HIV prevention R&D and has yielded unprecedented success. With sustained and flexible funding, the future of HIV prevention research will be even more promising.”

The report is available online at: www.hivresourcetracking.org.

Credit: UNAIDS

There is broad scientific consensus that getting to zero new HIV infections will require an HIV vaccine. Modelling shows that even a partially effective HIV vaccine can save many lives and dollars over time.

Although a vaccine to prevent HIV could be the tool to quicken the pace to reach the end of AIDS, the quest for an effective vaccine has until now proved elusive. The very nature and variety of the human immunodeficiency virus has meant that it has resisted most attempts to quell its spread and scientists and vaccinologists the world over are focusing efforts on finding solutions.

Exciting recent developments in HIV vaccine research are instilling hope around finding an effective vaccine. In 2009, results from a trial in Thailand—RV144—showed a 31.2% vaccine efficacy in preventing HIV infections. Although only modestly protective, the results instilled new hope that an HIV vaccine could be found and made available for populations around the world most in need of a vaccine.

The results represented a significant scientific advance, and were the first demonstration that a vaccine can prevent HIV infection in a general adult population. It was a discovery of great importance and has been followed by more encouraging data in the last couple of years.

Data presented in the past year has been presented on the protective immune responses that were stimulated by the Thai vaccine trial.  Trials are now planned to see if an RV144-like regimen will protect against a strain of HIV infection found in South Africa and against HIV acquisition by people at higher risk of exposure, specifically men who have sex with men.

UNAIDS and the US Centers for Disease Control worked closely with modelling teams to estimate the impact of the RV144 regimen in different countries and with different populations and found that 10% of infections could be prevented if the same 31% efficacy was found in people who receive the vaccine. This shows that a modestly effective HIV vaccine could add to the prevention toolbox of partially effective methods, hastening the decline of the HIV epidemic.

These and other advances in HIV vaccine development—including the design of new tools and technologies for vaccine delivery—have boosted optimism in the field about the prospects for the development of a safe and effective AIDS vaccine.

However, early data from the HIV Vaccines and Microbicides Resource Tracking Working Group is showing that a downturn in HIV vaccine funding that began in 2008 continued through 2011. The quest for effective HIV vaccines is a long-term investment in both the product (vaccines) and in the people who will develop, produce, market and support them. Investments in research and trials are essential and can bring benefits far beyond the AIDS field.

The need for a vaccine to prevent HIV is clear. Today, as we commemorate World AIDS Vaccine Day, there are in excess of 34 million people living with HIV, and every day more than 7000 people are becoming newly infected with the virus. Although a vaccine may not provide the magic bullet to end the AIDS epidemic, it would provide an additional tool to add to the robust package of HIV prevention options which are now available.

UNAIDS will continue to work with multiple partners––scientific communities, national and international AIDS research agencies, the pharmaceutical industry, private foundations, member states, and affected communities––to push the HIV vaccine agenda forward and ensure that the quest for a safe and effective HIV vaccine continues.

UNAIDS Executive Director Michel Sidibé at the press conference of the 2009 AIDS Vaccine Conference. Paris, 19 October 2009. Credit: UNAIDS

The yearly AIDS Vaccine Conference opened in Paris today. High on the agenda are discussions on the progress made in vaccine development and implications of trial results for the future. In a keynote address to the conference, UNAIDS Executive Director Mr Michel Sidibé said access and affordability were the first challenges towards building an effective AIDS response.

Mr Sidibé spoke about positive developments related to the AIDS vaccine research field. The recent results in Thailand have given hope to the many scientists who are working on finding a safe and highly effective HIV vaccine. These efforts demonstrate the vigour and momentum of the collective global effort to deliver on the promise of AIDS vaccines, said Mr Sidibé.

The UNAIDS Head also spoke of the challenge in creating conducive conditions for massive uptake of an effective AIDS vaccine. Antiretroviral treatment has been around since 1996, but real access to treatment only came about after public pressure put on world leaders – as a result the prices of medicines came down giving millions of people living with HIV in developing countries access to treatment.

Today, AIDS activists are repeating these efforts to reduce prices, this time for second line antiretroviral medicines.

“A ready to use vaccine against HIV could be more than a decade away, but when it does become available, it needs to be financed as a public good that is accessible for all,” Mr Sidibé said, “Meanwhile we have to redouble our combination HIV prevention efforts to stop the continuing tide of new HIV infections.”

AIDS Vaccine 2009 will bring together established and young research scientists, with clinicians, epidemiologists and public health experts aimed at sharing experience and scientific advances and enhancing collaborations.

The first AIDS Vaccine Conference, organized by the Global HIV Vaccine Enterprise, was held in Paris in the year 2000 with the aim of advancing the field of HIV vaccine research through discussion, exchange and learning. The annual meeting is now seen as the leading forum for exchange of scientific information relating to the difficult challenge of developing an effective vaccine against HIV. It will conclude on 22 October.

By Michel Sidibé, Executive Director, Joint United Nations Programme on HIV/AIDS (UNAIDS) Geneva, Switzerland

The promise of a vaccine against HIV has got one step closer. Results from the largest vaccine trial ever conducted show a modest but encouraging 31% efficacy in preventing new HIV infections in Thailand. This has vindicated thousands of scientists and volunteers who have been hoping that a safe and highly effective HIV vaccine is possible.
 

This news comes at a time when the movement to achieve universal access to HIV prevention and treatment is gaining momentum. Today more than 4 million people living with HIV are receiving antiretroviral treatment and fewer babies are being born with HIV.  With less than half the people who need treatment having access and with each day more people becoming infected with HIV than are started on treatment, we are mortgaging our future. But we are also exposing a fundamental social injustice—between the privileged and the forsaken—a divide we can bridge. 

An acceptable vaccine is not yet ready, but let us prepare today for tomorrow. Let us learn from the lessons of the AIDS response thus far.  

The first challenge is access and affordability. Antiretroviral treatment has been around since 1996, but real access to treatment began only when public pressure was put on world leaders and the prices of medicines came down. Today, AIDS activists are repeating these efforts to reduce prices, this time for second line antiretroviral medicines. It is unacceptable that 98% of pregnant women in developed countries are able to access HIV prophylaxis to stop transmission to their babies when little more than 33% in developing countries can do so.

The news coincides with this week’s United Nations General Assembly. During which the Secretary-General reminded us of “our commitment to equity” and where I appealed to many Heads of State who are committed to promoting equity to place equity in the AIDS response high on their list. We must not allow cost to deter people from access to a vaccine.

The second challenge is creating the conditions for massive uptake of an effective vaccine. Time and again, women and girls are unable to make independent decisions about their health and education. Many men and women do not come forward to take an HIV test for fear of stigma and discrimination. People without a voice—sex workers and their clients, injecting drug users and men who have sex with men—are often excluded from health and social welfare programmes. We look to civil society to continue to break down the barriers to vaccine uptake.

The third challenge is in creating health systems capable of delivering the vaccine. Currently clinics are geared towards immunizing infants and young children. The largest benefits of an HIV vaccine will likely accrue from vaccinating the present cohort of young people and those at higher risk of HIV exposure. A failure to reach adolescents will represent another failure to break the back of the epidemic.

There is no time for complacency in our efforts to stop new HIV infections. The world needs a strong HIV prevention campaign that is evidence-informed and grounded in human rights. It is high time to end discrimination, bad laws, and harmful social norms that fuel HIV transmission.

As scientists and world leaders absorb the implications of the Thai study results in the coming weeks they must be mindful of these challenges. A “ready to use” vaccine is years—perhaps decades away, but when it does become available, it ought to be financed as a public good that is accessible for all. How else can we reasonably expect to put an end to this epidemic?

Geneva, 24 September 2009 – The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) are optimistic about the results, announced today, of the largest ever HIV vaccine clinical trial held to date.

The study results, representing a significant scientific advance, are the first demonstration that a vaccine can prevent HIV infection in a general adult population and are of great importance.

The two UN agencies congratulate both the principal investigators, sponsors and the trial volunteers who have made this encouraging result possible.

The RV144 HIV vaccine study results, revealing a 31.2% vaccine efficacy in preventing HIV infections are characterized as modestly protective. However, these results have instilled new hope in the HIV vaccine research field and promise that a safe and highly effective HIV vaccine may become available  for  populations throughout the world who are most in need of such a vaccine. No vaccine safety issues were observed in the trial.

Much more work, though, has to be done by the principal investigators and a large group of international collaborators to analyse the trial data, understand the protective mechanism, determine the duration of protection, and map next steps. Licensure at this point in time may not be possible solely on the basis of this study's results, and it remains to be seen if the two specific vaccine components in this particular regimen would be applicable to other parts of the world with diverse host genetic backgrounds and different HIV subtypes driving different regional sub-epidemics. Once an HIV vaccine does become available, it will need to be universally accessible by all persons at risk.

In addition, early HIV vaccines with modest levels of efficacy would most likely have to be used as complementary tools in combination with strategies to promote changes in behavioural and social norms, promotion of correct and consistent condom use, access to safe injection equipment, as well as male circumcision.

The Phase III trial, involving 16 395 adult male and female volunteers in Thailand, was a test- of-concept of a novel HIV vaccine regimen with two different candidate vaccines developed by Sanofi-Pasteur and the non-profit organization Global Solutions for Infectious Diseases. The trial was performed by the Thai Ministry of Public Health, sponsored by the United States Army Surgeon General and received funding from the United States National Institute for Allergy and Infectious Diseases and the United States Army Medical Research and Materiel Command, Department of Defense. 

WHO and UNAIDS began supportive work for this trial 18 years ago, in 1991, when Thailand was recommended as one of the WHO-sponsored countries in preparation for HIV vaccine trials and the development of the National AIDS Vaccine Plan. In particular, WHO and UNAIDS through their HIV Vaccine Advisory Committee (VAC) provided continuous technical guidance and advice for review, approval and implementation of the RV144 trial protocol. In 2006, VAC performed an external evaluation of the trial examining various ethical and community-related issues: this evaluation showed that the trial was being conducted at the highest scientific and ethical standards and with active community participation.

Moreover, WHO and UNAIDS, in collaboration with partners, such as the Global HIV Vaccine Enterprise have jointly developed numerous policy documents relating to access to care and treatment for trial participants, design and purpose of test of concept HIV vaccine trials as well as scientific parameters.

WHO and UNAIDS will work with the global HIV stakeholder community to further understand and resolve a range of questions related to the potential introduction of an HIV vaccine of moderate protective efficacy. This includes additional, in-depth trials in different populations with diverse host and virus genetic backgrounds.

Until a highly effective HIV vaccine becomes available UNAIDS and WHO underline the importance of effective and proven HIV prevention methods for all people. A comprehensive HIV prevention package includes, but is not limited to, behavioural interventions to reduce sexual risk practices, including correct and consistent male and female condom use, early and effective treatment for sexually transmitted infections, male circumcision in high HIV prevalence settings, harm reduction for injecting drug users, post-exposure prophylaxis with antiretroviral drugs, and interventions to prevent HIV transmission in health care settings. 

18 month old baby in Baragwanath Hospital, Soweto, South Africa
Credit: UNAIDS/L. Gubb

Bacille Calmette-Guérin, or BCG, is one of the most widely given vaccines globally and is safe in people with healthy immune systems. WHO recently published further research on the finding that this standard tuberculosis vaccine has a higher risk of causing death in babies living with HIV.

Given the severity of these risks, WHO recommends not vaccinating babies with HIV and delaying vaccination for those whose HIV status is unknown but who have signs or symptoms consistent with HIV infection.

This recommendation came in 2007 and poses several challenges to weak health systems around the world.

It underscores the need for more widespread testing of HIV in babies and pregnant mothers. Clinical symptoms of HIV infection typically occur after 3 months of age but in some countries babies are routinely vaccinated with BCG at birth.

UNAIDS calls for scaling up access to and use of quality services for the prevention of mother-to-child transmission as well as integrated delivery of services for HIV and tuberculosis.

“A selective BCG vaccination policy in HIV-exposed infants will require high uptake of maternal HIV testing, strengthened prevention of mother-to-child transmission services, and better integration of TB and HIV programmes,” said Dr Catherine Hankins, UNAIDS Chief Scientific Adviser in HIV this Week scientific blog.

The results of a three-year study in South Africa were published in the July edition of the journal Bulletin of the WHO. They confirm earlier research which led WHO in 2007 to change BCG vaccination policy for babies. The WHO Global Advisory Committee on Vaccine Safety and the Strategic Advisory Group of Experts TB and HIV experts then published Revised BCG vaccination guidelines for infants at risk for HIV infection.

“This paper gives better information on the risk of generalized BCG infection in HIV infected children and strongly reinforces the need to find better ways to prevent TB in infants (who are most at risk of dying from TB) and for diagnosing HIV in infants,” said Dr Alasdair Reid, UNAIDS TB Adviser.

15th Conference on Retroviruses
and Opportunistic Infections took place in
Boston 4-6 February 2008. Credit: CROI

The annual Conference on Retroviruses and Opportunistic Infections (CROI) began in 1994 as a small meeting of scientists studying HIV and clinicians treating people with HIV. It is now one of the most important annual HIV gatherings and provides a forum for basic scientists, clinical investigators, and global health researchers to present, discuss, and critique their investigations into the epidemiology and biology of human retroviruses and the diseases they produce.

The 15th CROI concluded in Boston on 6 February and while announced trial results were not encouraging, many significant topics were discussed. The absence of a scientific breakthrough in HIV vaccine development underscores the need to scale-up existing prevention and treatment strategies.

HSV-2 trial - No observed reduction in risk

Disappointing results were announced from trials to see if ongoing treatment of the virus that causes herpes in humans, herpes simplex virus type 2 (HSV-2), would reduce the risk of HIV transmission. HIV-negative people with HSV-2 were asked to take medication to suppress outbreaks of herpes. However, the trial results showed no difference in rates of HIV infection between individuals who had taken the medication and those who hadn’t.

Scientific data shows a link between HSV-2 infection and susceptibility to acquiring HIV infection and there are other on-going trials exploring different aspects of this link, so researchers remain cautiously hopeful about this avenue of research.

Male circumcision

Previously-released data from the studies of male circumcision in Uganda which were stopped in December 2006 were presented by trial investigator Maria Wawer. One trial explored whether circumcising a HIV-positive man reduced the risk of HIV transmission to his HIV-negative female partner. Results showed a trend towards increased HIV transmission from men to their female partners. This trend was more notable, although still not statistically significant, when the men resumed sex before their wound had healed completely.

While this data is not new, its presentation at CROI gave an opportunity for discussion and analysis of its implications. Advocates stressed the necessity for all male circumcision programmes to directly address women’s increased vulnerability to infection by sex with a recently-circumcised, HIV-positive man.

UNAIDS Chief Scientific Adviser Dr Catherine Hankins said, “This underlines the importance of considering male circumcision as part of a comprehensive prevention package which includes couple counselling and post-surgery advice involving both partners. Couples should consider a mutual commitment to abstinence until the wound is healed completely.”

UNAIDS guidelines recommend that all men undergoing male circumcision should be clearly instructed and supported to abstain from sexual intercourse until certified wound healing, which normally can take up to six weeks, to avoid increasing the risk of both acquiring and transmitting HIV.

Most importantly, individuals must understand that male circumcision does not afford complete protection against HIV infection and that it must not replace other prevention strategies such as correct and consistent use of male and female condoms, reduction in the number of sexual partners, avoidance of penetration, and treatment of sexually transmitted infections.

Vaccines

Last September there was a disappointing failure in Merck’s adenovirus- based HIV vaccine candidate. The consensus from experts at CROI was that it was important for scientists to go back to the drawing board of basic science to get a better understanding of the workings of the virus and the responses of the human immune system. There was a call for increased investment into basic scientific research and less emphasis on expensive clinical trials, although clearly both are needed.

There is a growing acceptance that the search for the elusive HIV vaccine is set to continue for some time. This underscores the need to scale-up existing prevention and treatment strategies and highlights the importance of improving people’s access to sexual health information, access to HIV testing and counselling services and to male and female condoms.

Other interesting topics under discussion at CROI included improved screening for TB, ensuring adequate representation of women in HIV trials, aging and AIDS, and paediatric and adolescent HIV care.

Meeting at UNAIDS in Geneva, health experts said
that cultural and social barriers can still stop women
taking part in HIV trials in sufficient numbers, while
too little is known about the effects of biological
differences between the sexes in such areas as the
impact of HIV drugs.

Women and adolescent girls are on the frontline in the AIDS epidemic but getting them the special treatments, HIV prevention strategies and protection they need will require a varied, multi-disciplined response -- medical, social and economic, health specialists agreed.

Meeting at UNAIDS in Geneva, health experts from international agencies, non-governmental organisations (NGOs), research institutions and the private sector, said that cultural and social barriers can still stop women taking part in HIV trials in sufficient numbers, while too little is known about the effects of biological differences between the sexes in such areas as the impact of HIV drugs.

Winding up the first of two days of discussions on Monday 10 December, Kristan Schoultz, Director of the Global Coalition on Women and AIDS, said delegates had made a thorough review of the challenges and difficulties and the moment had come to start putting forward proposals for solutions.

“I think we have determined some of the challenges we face, (now) we need to tease out of this a way forward,” she said.

The route lay beyond a strict interpretation of the conference’s theme – “Making HIV Trials Work for Women and Girl Adolescents” -- and should include economic and social changes to address background factors such as poverty and empowerment.

“We need to highlight the difference between sex
and gender differences. Gender also brings in
social, cultural and economic issues as opposed to
the straight biological issues,” said Geeta Rao Gupta,
President, the International Center for Research on
Women (ICRW).

“We need to highlight the difference between sex and gender differences. Gender also brings in social, cultural and economic issues as opposed to the straight biological issues,” said Geeta Rao Gupta, President, the International Center for Research on Women (ICRW).

Although women account for some 50% of people infected with HIV worldwide, in sub-Saharan Africa the figure is around 60% and amongst some ethnic minorities in developed countries women also account for a disproportionate percentage. In parts of southern Africa, girl adolescents are some four times more likely to become infected with HIV than males of the same age.

For years after AIDS was first recognized in the early 1980s, medical research continued to be largely male orientated. Clinical trials involving women of child-bearing age had been banned in the United States in the late 1970s, in part because of the thalidomide scandals, and the restriction was not lifted until the early 1990s. In addition, the epidemic was initially thought largely a disease affecting men who had sex with men.

“The current research emphasis being put on microbicides for women is an illustration of the way in which priorities have changed,” said Roberta Jean Black, tropical microbicides team leader of the U.S. National Institutes of Health.

“The current research emphasis being put on
microbicides for women is an illustration of the way
in which priorities have changed,” said Roberta
Jean Black, tropical microbicides team leader of
the U.S. National Institutes of Health.

“Some of these inequalities simply represented misunderstandings of the disease and its evolution…We have responded successfully but the work is not done,” she added.

“The existing strategy was not designed with the percentage (of women) in mind. This is an iniquitous state of affairs,” declared Julie McHugh, company group chairman, virology, Tibotec.

More needs to be known about the progress of HIV in women.

“We are looking for answers for women. We now have women in menopause with HIV and we do not know anything about it,” said Heidi Nass, Director, Education and Policy Advocacy, Health HIV Care Program, University of Wisconsin. “We have seen the list (of things to do) a million times, it would be really nice to come out with action,” she added.

Gaps in understanding

There are many gaps in our understanding of HIV and how it evolves in women and the difference that gender can make, participants agreed. For example, CD4 tends to be higher in women, yet there appears to be no significant impact on the progress of the disease.

Most trials are not designed to detect sex
differences. “We are relying on safety trials from the
(rich, developed) north, and carried out on men,”
said Catherine Hankins, Chief Scientific Adviser to
UNAIDS.

But the difference can lead to delays in the timing of treatment for women. When it comes to mother-to-child-transmission (MTCT), this can have the unfortunate result that women who are not deemed sick, and are therefore not treated, are far more likely to infect their children than those who were inside the treatment threshold.

Most trials are not designed to detect sex differences. “We are relying on safety trials from the (rich, developed) north, and carried out on men,” said Catherine Hankins, Chief Scientific Adviser to UNAIDS.

There are also indications that some treatments have significant toxicity for women. Nevirapine, for example, can produce rashes and hepatic complaints. Toxicity can be one reason why women tend to abandon trials more often than men and is another area in which more research is needed.

Biologically different

Even if there are no side effects, it is possible that existing treatments may not be the best possible way of tackling HIV in women. Women are biologically different, so they need specific research.

Women in poorer countries can face a host of barriers to taking part in clinical trials. They may fear it will suggest that they are ill and lead to them being stigmatised, they could need permission from their partners or family – most people at risk are in long-term partnerships -- and they may not want to use contraception or they may fear for their future fertility.

Male circumcision provides no protection for women, although there could be secondary benefits for women, but more needs to be learned.

Difficult considerations

The whole question of trials for adolescents was thick with difficulties. Even a standard definition of what constitutes an adolescent is difficult to establish.

“Communities are very sensitive about involving young girls in trials for fear that they are promoting sexual activity,” said Gita Ramjee, Director, HIV/AIDS Lead Programme and HIV Prevention Research Unit, South African Medical Research Council.

Summing up the changes needed to help women and adolescent girls, Isabelle de Zoysa, senior adviser on HIV/AIDS at the World Health Organisation said: “We are looking how we move through gender unbiased, through gender sensitive to gender transforming.”

The conference, ‘Making HIV Trials Work for Women and Adolescent Girls’, takes place in Geneva on 10 – 11 December 2007. The meeting is co-sponsored by UNAIDS, the Global Coalition on Women and AIDS, the International Centre for Research on Women (ICRW), and Tibotec.

In the first of a special three-part web series, www.unaids.org looks at the state of research into new HIV prevention technologies, the ethical debates around the issue, and the steps that have been taken to answer the concerns. The question of HIV trials, and in particular the involvement of women and adolescent girls in them, will be the subject of a two-day conference being hosted by UNAIDS in Geneva December 10-11.

Nearly three decades after AIDS began ringing global alarm bells, no vaccine is in sight and medical advances are still urgently needed. Some significant progress has been seen – biomedical prevention modalities which have been proven highly effective in randomised controlled trials, such as prevention of mother-to-child transmission and male circumcision for HIV risk reduction— still have suboptimal coverage in the most affected countries. Concerted efforts are underway to expand access to these two HIV prevention tools, however nevertheless, the prevention ‘tool box’ needs to be expanded to provide people with additional choices, particularly for prevention of sexual transmission of HIV.

But medical breakthroughs in such a complex disease not only take time—seeking them also poses special practical and, perhaps more critically, ethical problems because of the inevitable need for testing eventually to be done on humans. In recent years, there has been criticism from activist and human rights campaigners about perceived failings in the organisation of human trials. Argument has focused on suggestions of insufficient involvement of local communities in the low- and middle-income countries chosen as sites for testing in the decisions that surround trials, or on the alleged inadequacy of information or guarantees for volunteers taking part in them.

The often very public disputes that ensue have led UNAIDS and other international organisations involved in the AIDS response to refine guidelines for the ethical conduct of human trials.

Need as great as ever

According to the latest data released by UNAIDS and WHO, nearly 7,000 people are newly infected with HIV every day, while the daily death toll from AIDS stands at nearly 6,000 per day, putting it in the top rank of global killers. In sub-Saharan Africa, home to 22.5 million people living with HIV (68% of the global total), AIDS is the primary cause of premature death. Although scientists have succeeded in developing drugs that can prolong the lives of those living with HIV, only a minority of people in need of treatment in developing and middle-income countries has access to it.

Since their launch in 1996, antiretroviral drugs (ARVs) have revolutionised the treatment of HIV-related illness and prolonged and improved the quality of life for people living with HIV in countries where they are available and affordable. But in poorer countries, and particularly in sub-Saharan Africa, where women and adolescent girls make up 61% of the population living with HIV, the cost of drugs remains a huge deterrent to their use, and this is particularly so of second line drugs which people need once first line regimens are no longer as effective for them. “Halting the spread of HIV remains an imperative as each new infection translates into eventual treatment demand. Finding ways to slow HIV transmission is a top research priority,” said UNAIDS Chief Scientific Adviser, Catherine Hankins. “Speeding the search for a biomedical breakthrough to complement changes in social norms and behaviours remains urgent.”

The International Aids Vaccine Initiative (IAVI) estimates that— conservatively—an effective HIV preventive vaccine could avoid almost 1-in-5 of a projected 150 million new infections – that is 30 million – in coming decades. A highly effective vaccine could prevent 70 million infections in 15 years, it says. Modelling of the potential impact of male circumcision in sub-Saharan Africa suggests that male circumcision could avert 2 million new HIV infections and 300,000 deaths over the next ten years and avert a further 3.7 million new HIV infections and 2.7 million deaths in the decade thereafter.

Trials underway

There are currently some 50 vaccine trials underway, or scheduled, in a record number of over 30 countries, ranging from the United States to Uganda. Much of the cutting-edge research is being carried out in Asia and Africa, where most of the new HIV infections are occurring. But the announcement in September 2007 of the discontinuation of a leading HIV Merck vaccine candidate being tested in trials underlines how difficult this type of research and development is and shows just how far there is still to go before a vaccine becomes available.

There are many other prevention strategies undergoing human testing. These include vaginal microbicides, pre-exposure prophylaxis (PrEP), suppression of herpes simplex 2 infection and treating the infected partner in serodiscordant couples to see if it reduces HIV transmission.

Vaginal microbicides come in the form of creams, gels, suppositories, films, sponges or rings that release anti-HIV microbicide over time and could afford protection against other sexually transmitted diseases. If spermicidal, they might also be used for preventing unintended pregnancy. The ideal product would be odourless and colourless. As such, microbicides could increase the options for women who find it difficult or impossible to persuade their partners to use a condom. PrEP is another experimental prevention strategy which is being tried out in many parts of the world. It consists of anti-retroviral medications, taken as a single drug or as a combination, on a daily basis, with the intention of protecting people from acquiring HIV.

The successes achieved so far in the response to AIDS, and future hopes for further advances, have and will depend on such human trials.

Scientists may get promising results in laboratory experiments and from studying animals, but at the end of the day, the only way to find out whether a biomedical HIV prevention strategy is effective, whether a vaccine triggers an immune response to impede or delay the development of disease, whether an intervention has side effects, and the frequency and severity of them, the implications for drug resistance, is to try the strategy out on people.

Protecting rights

Getting scientifically valid research requires that trials be carried out where there are sufficiently high numbers of infected people, and people at high risk of HIV exposure, and where effective interventions will have the greatest effect. This often means dealing with some of the most socially vulnerable sectors of society, whether they are women and girls in sub-Saharan Africa, sex workers, men who have sex with men or injecting drug users. And often, people most at risk may not be well placed to protect their rights in the run-up to and the preparation of testing, during the trial programme itself or in its aftermath.

A lack of information and the relative powerlessness of some communities could produce situations in which there is an unequal power relationship between research sponsors and trial investigators, on the one hand, and communities and trial participants on the other. People could, for example, opt to take part out of the false belief that there will be some immediate therapeutic benefit to them, which could even lead them to behave in a more risky fashion because they feel protected. Building research literacy and community capacity to engage meaningfully in trial design, conduct, monitoring and results dissemination is essential to minimising harms and maximising the benefits for communities of participation in research.

Ethical questions

One of the most controversial incidents in the history of AIDS research occurred in the early 1990s during testing of a shorter, simpler, and presumably cheaper version of perinatal zidovudine prophylaxis. Zidovudine was already known to be an effective barrier to the transmission of HIV from a mother to her unborn or newly born infant. The trials involved randomised placebo-controlled tests and were carried out in a number of developing countries. Activists argued that a placebo controlled trial amounted to a violation of fundamental ethical principles because those being given the placebo were being denied a treatment that had already proved its worth elsewhere. Zidovudine was one of the milestones in HIV research and had been shown to cut mother-to-child transmission by over 60%, offering tremendous hope to pregnant women. Subsequent improvements have reduced such transmissions in high-income countries to just 1-2 percent.

Another well-known incident surrounded randomised placebo-controlled trials for tenofovir disoproxil fumarate used as PrEP, in Cambodia and Cameroon in 2004-5. The Cambodian trial involving sex workers was halted by the government when no agreement was reached on future access to treatment for those who became infected during the trial. The affair generated much adverse news coverage and the Cameroon government followed suit in suspending the trial underway there.

In Thailand, a trial in which the participants were injecting drug users was criticised by activists for not providing clean needles. In one protest that gained much publicity, the activist group Act-Up Paris stormed the display stand of tenofovir’s manufacturer, Gilead, during the 2004 International AIDS Society Conference.

Health community responds

Much has been learned and acted upon from these experiences. For example, in 1993 the Council for International Organisations of Medical Sciences (CIOMS) issued international ethical guidelines for biomedical research involving human subjects that stated that there was an ethical responsibility to provide treatment that conforms to the standard of care in the sponsoring country when possible.

In 2000 came the fifth revision of the Declaration of Helsinki with its stipulation that all those involved in studies be assured of the best “proven diagnostic and therapeutic method”. The same year saw publication of the UNAIDS guidance document “Ethical considerations in HIV preventive vaccine research” which has now been substantially revised in 2007 in collaboration with WHO and an expert panel to reflect changes, particularly changes in standard of prevention and access to care. “Ethical considerations in biomedical HIV prevention trials” contains 19 guidance points for ensuring that scientifically rigorous biomedical HIV prevention trials meet ethical standards.

In 2005, following the tenofovir case, UNAIDS and others organised consultations focusing on ‘partnerships’ with communities, their involvement, standards of prevention and access to care. This led to UNAIDS producing in collaboration with AVAC “Good Participatory Practice Guidelines for Biomedical HIV Prevention Trials,” It covers core principles and essential activities throughout the research life-cycle, providing a foundation for community engagement in research.

“With solid international guidance in place for community engagement and the ethical conduct of trials, there is anticipation that research, both underway in the field and planned, can offer a number of promising new avenues to prevent HIV transmission, improve treatment and mitigate against the epidemic’s impact,” said Dr Hankins.

The question of HIV trials, and in particular the involvement of women and adolescent girls in them, will be the subject of a two-day conference being hosted by UNAIDS in Geneva December 10-11. On Wednesday 5 December, part two of this special web series will take a closer look at the history and debates around the involvement of women and girls in trials. Part three, to be published on Friday 7 December will preview the Geneva meeting, featuring interviews with the four organizing partners UNAIDS, The Global Coalition on Women and Girls, Tibotec and the International Center for Research on Women (ICRW).

The HIV Vaccines and Microbicides Resource
Tracking Working Group was created to generate
and disseminate high-quality, detailed and
comparable data on annual investments in
preventive HIV vaccine and microbicide research
and development

For a comprehensive response to AIDS, developing additional HIV prevention methods and tools to prevent HIV – such as HIV vaccines and microbicides -- is a key component.

The continuing research and development of such prevention technologies relies on adequate and efficient funding and spending – and supporting this, high quality, detailed data on investment in this area of the AIDS response is critical.

In 2004, UNAIDS, the Alliance for Microbicide Development (AMD), the AIDS Vaccine Advocacy Coalition (AVAC) and the International AIDS Vaccine Initiative (IAVI) established a collaborative project to track funding for HIV vaccines and microbicide research and development.

The HIV Vaccines and Microbicides Resource Tracking Working Group was created to generate and disseminate high-quality, detailed and comparable data on annual investments in preventive HIV vaccine and microbicide research and development and policy and advocacy activities.  These data can be used to monitor current levels of effort; identify trends in investment, spending, and research focus; identify areas needing more resources and effort; assess the impact of public policies aimed at increasing investment in new prevention technologies; and provide a fact base for policy advocacy on research and development investments and allocations. 

The collaboration aims to monitor progress in the implementation of the Declaration of Commitment on HIV/AIDS, adopted at the United Nations General Assembly Special Session (UNGASS) on HIV/AIDS in 2001. This declaration contains a number of global and national indicators that are being monitored on an annual basis by UNAIDS and others. The second of the global commitment and action indicators, is the “Amount of public funds available for research and development of vaccines and microbicides.”

In August 2007, the Working Group released a summary of the resource tracking efforts – the most up to date available data on sources of global funding and its allocation. These figures are produced to support larger resource needs estimations for the global AIDS response as a whole, which will be published in the later half of 2007

Among findings within the 2007 Working Group estimates on research and development are that while the current levels of funding are significant, there is a critical need to sustain and increase research and development investments for preventive vaccines, microbicides and other new options to optimally accelerate the development of and ensure eventual access to these HIV prevention tools.

As stated in the latest estimates report from the Working Group, in 2006, total global investment in preventive HIV-vaccine research and development was an estimated US$933 million, a 23% increase over 2005 funding levels. This increase in funding can primarily be attributed to new research initiatives funded through the US National Institutes of Health (NIH), Canada, the European Commission (EC) and the Bill & Melinda Gates Foundation.

However, financing needs are likely to remain substantial in the coming years, as funding is needed to explore new approaches to vaccine and microbicide design; bring novel candidates into the pipeline; support clinical trials to test the safety, immunogenicity and efficacy of new products; and translate research results, such as those for adult male circumcision, into policies and programmes.

“The HIV Vaccines and Microbicides Resource Tracking Working Group group has systematically documented the amount of financial resources needed and the actual expenditures from public sources in research and development. This is a notable example in the resource tracking world because of the good quality of its results combined with a very dynamic group that is able to translate the financial estimates into a powerful advocacy tool”, said Jose Antonio Izazola-Licea, UNAIDS Senior Adviser, Resource and Finance Analysis.