HIV Research In Limbo
posted: 01/09/2008
The international Aids conference that has just closed in Mexico shone a renewed spotlight on efforts to combat the disease. It also cast a gloomy shadow: that of a series of recent setbacks to research into medical ways of preventing HIV transmission.
Just as advocates and policymakers re-emphasised the need to curb the spread of the virus alongside taking advantage of rapid advances in treatment, scientists working on prevention were attempting to put a brave face on their sombre mood.
Disappointing results from a number of clinical trials have demoralised researchers developing “biomedical interventions” that they hope can supplement condoms and other low-technology approaches, which are still failing to prevent 2.5m new HIV infections each year.
Hard data have repeatedly crushed optimistic scientific hunches, from the use of a cheap treatment for herpes – long believed to accelerate HIV’s spread – to a diaphragm to reduce women’s risk of contracting the virus. The failures have sparked a bout of reflection on the lessons to be drawn.
vaccine woes
No negative result has been more disturbing – or with potentially broader ramifications for scientific understanding and funding alike – than one experiment aimed at attaining the “holy grail” of HIV prevention, a vaccine. “We were not shocked but we were disappointed,” admits Seth Berkley, head of the International Aids Vaccine Initiative (Iavi), which funds research in the field. “My worry is that at some point, people will say: ‘Enough.’”
Last year Merck, the US pharmaceutical company, halted its Step vaccine trial early after discovering from preliminary results that not only was it proving ineffective, but in some participants it appeared to increase the risk of contracting HIV. That prompted a rethink by rival research teams, leading to the cancellation last month of another trial conducted by the Partnership for Aids Vaccine Evaluation, which was taking a similar approach.
Under test was the idea that the so-called adenovirus serotype 5 that the vaccine employed would prove effective in stimulating a strong human immune response to attack HIV. “We had to try it because it was the only approach we had, but we’re in virgin territory,” says Tony Fauci, head of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health, one of the largest funders of vaccine research.
While existing vaccines – whether for polio, smallpox or flu – boost the immune reaction to infections that the body normally defeats on its own, there is no such naturally generated and effective response to HIV. “Now, all bets are off and we have to put aside all historical lessons based on classical vaccinology,” he says.
microbicide frustrations
Just as depressing have been the outcomes of trials for microbicides, gels that are applied to the vagina designed to kill HIV during sexual intercourse. Two years ago trials of one such gel, Savvy, were stopped prematurely because of poor results, and last year so were those of Ushercell, which even increased transmission risk. This February results from trials of Carraguard, derived from seaweed, also failed to show any fall in HIV.
“It’s been a pretty demoralising time,” concedes Zeda Rosenberg, head of the International Partnership for Microbicides. But like others in the field she is determined to push ahead, stressing that each type of prevention method under investigation – let alone each individual product – is different.
“Vaccines are about science but microbicides are about engineering: it’s about getting the right drug to the right place at the right time,” she says. While the three products that failed used other chemicals, hers use high doses of antiretroviral drugs that have already been proved to kill HIV in patients.
Yet there are still risks that such microbicides may increase human susceptibility to the virus and – most importantly – that women may not use them consistently, diminishing their effectiveness outside the controlled environment of clinical trials.
learning lessons
One lesson from the failures with microbicides and vaccines alike is the need to overcome the tendency for competing researchers to push ahead with large-scale clinical trials whose risks do not justify the costs. In future there is likely to be more rigorous scientific scrutiny by government and philanthropic donors.
“The tendency has been to jump in,” says Tachi Yamada, head of global health at the Bill & Melinda Gates Foundation, a large supporter of all types of prevention research. “We have to plan more, with greater preparation going into pharmacology, toxicology and trial design.”
That trend is also recognised in the latest Aids Vaccine Blueprint issued this month by Iavi, Mr Berkley’s organisation, which calls for the adoption of more small, rapid trials to test out hypotheses at an earlier stage.
Another tactic is reflected in the recent establishment of the Global HIV Vaccine Enterprise, a co-ordinating body in the field, which Alan Bernstein, its executive director, says will act as “a neutral broker” between different researchers, identifying areas of common interest including ways to ease regulatory approval.
A second lesson is the need for new scientific approaches. Mr Bernstein argues for a rejuvenation among HIV researchers, who have aged since “the big pulse of excitement when the virus was discovered in 1983”. He calls for redoubled efforts to attract a younger generation into the field.
Meanwhile, both Iavi and the Gates Foundation have recently launched new “light touch” research awards designed to fund creative, unconventional ideas by removing the usual extensive application procedures and detailed peer reviews conducted by existing specialists.
A third lesson is the need for continued financial support for research, which remains a tiny fraction of the total now spent on HIV treatment and prevention, and which has suffered from the gradual withdrawal of pharmaceutical companies. “We don’t have the choice,” says Jean-François Delfraissy, head of the ANRS, France’s Aids research organisation, which is active in supporting work on vaccines.
Despite the problems, more money will be needed in future to support new hypotheses, fund late-stage trials and underwrite fresh approaches such as pre-exposure prophylaxis, which offers the prospect of giving healthy people at risk of HIV small oral doses of the antiretroviral drugs already prescribed to treat patients.
Mr Yamada argues that patience will be vital. “We have to prepare the public for what the pharma industry already knows: most of these trials fail, but we have to stay the course.”
source
www.ft.com/cms/s/0/fff025a4-72cb-11dd-983b-0000779fd18c.html
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