Search for success
One pregnant woman in 100 had HIV in 1990; today it is almost one in three. Every week thousands more South Africans become infected with the virus and at present about 5,4-million people in this country are living with the virus.
Despite having known about the virus for almost 30 years we have yet to find a way to curb its spread. Some prevention methods are known to work, such as safer sex, condoms and male circumcision and the prevention of mother-to-child transmission of HIV. Yet the continuing spread of HIV—despite our efforts with a suite of HIV-prevention tools—means that we must do better with proved prevention strategies and we must search for new ways to stop this virus.
Two important new technologies, microbicides and vaccines, are now being studied intensively in the hope that they may one day prove to be effective in fighting HIV.
Microbicides are compounds that kill microbes such as bacteria and viruses and are designed to be inserted into a woman’s vagina. They can be in different forms, but most commonly are gels designed to block HIV physically or chemically from infecting cells in a woman’s genital tract. Vaccines are designed to stimulate the body’s immune response either to prevent infection with HIV or to stop a person already living with HIV from developing Aids.
These new technologies can take several years to develop and they must pass stringent tests before they are available to the public. Modern research in pharmaceuticals involves computer simulations, test-tube experiments and laboratory studies with animals such as mice and monkeys. A drug will be tested in humans only if it is shown to be safe and potentially effective in these studies.
The first tests in humans—called Phase I trials—are designed to investigate safety and appropriate dose in a group of between 20 and 50 people. Phase II trials, which may involve 200 to 500 people, also assess safety and, in the case of vaccines, whether the body’s immune system is responding appropriately. If the vaccine or microbicide is shown to be safe in Phase II trials, it is tested for long-term safety and effectiveness for HIV prevention in a Phase IIb trial (1 000 to 2 000 people) or a Phase III trial (5 000 to 10 000 people). To date only three vaccines and seven microbicides have progressed to these large-scale human trials.
Instant success at first attempt is rare in science; rather, scientific discovery occurs by the painstaking process of repeated experiments in which each failure provides valuable clues to reach eventual success.
We must consider this fact in light of two recent clinical trials that caused a media furore: one involved a microbicide, cellulose sulphate, and the other an HIV vaccine, Merck Ad5.
These trials were stopped early because the data suggested that use of either product might increase the risk of acquiring HIV. These results were totally unexpected because all the safety assessments in the laboratory, in animals and in small groups of people had indicated that these products were safe and potentially effective.
The large and expensive Phase IIb and Phase III trials are designed to answer two questions: is the product safe? And does it prevent HIV infection? Both the microbicide and the vaccine trials did an outstanding job of answering these questions—even if, so far, they have not provided the answers we would like to hear. Indeed, we would not have known that the cellulose sulphate gel and the Merck Ad5 vaccine increase the risk of acquiring HIV in humans without these two important trials.
But this disappointment does not mean that we should give up on research into these technologies. The scale of the HIV epidemic is just too vast and the need for new HIV prevention technologies too pressing.
HIV is unique in that no one is known to have been cured of the disease, so we don’t know how the body would manage to counter the virus and so we also don’t know exactly what immune system responses to look for. As vaccines normally emulate the body’s natural immune defences, the lack of an effective natural immune defence against HIV has severely hampered vaccine development.
One valuable lesson from the cellulose sulphate microbicide and Merck Ad5 vaccine trials is our need to increase our understanding of the relationship between HIV and humans. But such research needs to be done in conjunction with and as part of large-scale tests in people because at the moment there is simply no other way to predict whether a product will work.
With a rampant HIV epidemic, time is not on our side. The need for new HIV prevention approaches is pressing and our joint efforts, as scientists, community and government, are urgently needed to find solutions. As scientists, it is even more important that we keep trying even when success seems to be elusive. Giving up is not an option.
Salim Abdool Karim is professor of clinical epidemiology, Mailman School of Public Health, Columbia University; the director of the Centre for the Aids Programme of Research in South Africa (Caprisa), Durban; and pro vice-chancellor (research): University of KwaZulu-Natal, Durban