Hopeful Microbicide Fails

posted: 14/12/2009

The first ever microbicide that appeared to work, announced back in February, doesn't protect women from HIV, a much more detailed study has now found. Early this year, preliminary results appeared to show the microbicide was 36% effective at reducing transmission.

A much larger study (with around twice as many people) testing the microbicide shows no difference between women given the microbicide and women given a dummy gel. This placebo-controlled trial involved 9,385 women at six research centres in four African countries and found that the risk of HIV infection in women who were supplied with PRO 2000 gel was the same as a dummy gel.

The trial, known as MDP 301, ran between September 2005 and September 2009 and was carried out by the Microbicides Development Programme (MDP), a not-for-profit partnership of 16 African and European research institutions. It was funded by the UK Department for International Development (DFID) and the UK Medical Research Council (MRC).

To date, no microbicide has been shown to be effective against HIV infection.  

Women disappointed but more empowered

A South African trial participant commented: “Even though the gel proved not to be effective, we played a role in the fight against HIV. We learnt a lot about caring for ourselves, such as using condoms. We also learnt to encourage others to test for HIV and we gained confidence in helping those who were already infected.”

Dr Maureen Chisembele, Principal Investigator of the Zambian site, said: “In Sub-Saharan Africa, nearly 60 per cent of all people living with HIV/AIDS are women. Many are highly vulnerable to HIV despite the fact that they are faithful to their partners. The women will be disappointed by this result as they really liked the gel and hoped it would work.”

Chief Investigator, Dr Sheena McCormack of the Medical Research Council said: “This result is disheartening; particularly in light of the results of a smaller trial sponsored by the US National Institutes of Health which suggested that PRO 2000 could reduce the risk of HIV infection by 30 per cent. Nevertheless we know this is an important result and it shows clearly the need to undertake trials which are large enough to provide definitive evidence for whether or not a product works.”

The full results will be presented at international conferences in 2010, and published in a scientific journal.

The figures

There were 130 HIV infections out of 3,156 women who were given the PRO 2000 gel, and 123 HIV infections out of 3,112 given the placebo gel in the main analysis. The rates of HIV infection were very similar in both groups: 4.5 per hundred women years in the PRO 2000 group, and 4.3 in the placebo group. Thus PRO 2000 gel did not reduce the risk of HIV infection, and this was confirmed in the statistical analysis.

George House Trust Comment

This is very disappointing news, particularly for women, who often find they cannot safely negotiate condom use by male partners. Women are biologically more at risk of HIV than heterosexual men and have no means to protect themselves without men's cooperation.  

It is unlikely that any microbicide will achieve the protection level of condoms, but since many women have little or no control over whether condoms are used, some protection, even if it is imperfect, is better than no protection. That is the main niche for microbicides.

The search for microbicides that work continues.

Source : Medical Research Council

Microbicide Hope for Women

posted: 13/08/2009

A new attempt at producing a HIV-blocking vaginal gel may one day become a reality, according to a study published online yesterday in the journal Advanced Functional Materials.

Unlike previous versions of microbicide, the latest gel functions more like an actual condom.

It's applied with an applicator in the hour or so before sex and later turns semi-solid in the presence of semen, physically blocking HIV (and theoretically, other viruses and semen, too) from moving through the vagina in the first place. The gel then dissolves after sex.

"It's the first microbicide of its kind," says Patrick Kiser, a bioengineer at the University of Utah and the study's lead author. "It prevents the virus from even touching the vaginal tissue."

The novel polymer gel could see its first clinical trial in three years and if all goes well, be available for widespread use a few years after that.

Women need microbicides

The need for HIV-prevention methods that women can control is undeniably urgent. Women have half of all HIV infections globally; in sub-Saharan Africa, where the disease is most prevalent, women make up 60 percent of cases.

The reason is simple: most women in the region lack the power to make men wear condoms. For a decade now, scientists have been working to develop an HIV-blocking vaginal gel, a microbicide often called a molecular condom. This form of protection could be employed without the man's knowledge or consent and has long been seen as the best hope for empowering women to protect themselves.

3 recent failures

But, like any effort to bring high-tech innovation to resource-poor settings, progress has been slow.

In 2007, one large-scale clinical trial was terminated early when the substance—cellulose sulphate—appeared to actually increase the risk of HIV infection.

Another early contender, developed in an American lab, failed to hold up in the warmer African climate (it turned from a usable gel into a messy ineffective liquid).

And Carraguard, a gel derived from seaweed extract, made it all the way to phase III clinical trials only to be abandoned late last year when results showed that it was not effective at preventing HIV: the gel was safe, but its difficult to say how well it worked because study participants only used it 40 percent of the time.

African realities

The failure underscored what has become a common complaint among some factions of global health workers: high-tech solutions that come from the west's labs often fail to account for on-the-ground realities. "There are numerous personal and cultural reasons why a microbicide may or may not be used," says Kate Morrow, a behavioural psychologist. Failure to consider these realities may have doomed some projects from the start.

In the case of Carraguard, it's not clear exactly what went wrong, but David Katz, a biomedical engineer and gynaecology professor, thinks the effort to design a molecular condom has been held back because virologists haven't asked other types of expert for their advice.

"It's a tough problem because sex is complicated, messy, and differs culturally in surprising ways," he says. "Microbicide research has been dominated by virologists, but if you really want to solve the problem, you need engineers and psychologists, as well."

It seems almost too obvious to say this, but closely involving African women from the start and throughout the process would help investigators focus on solutions that are both culturally acceptable and practical for women's daily lives in Africa.

Source

HIV Microbicide Hope

posted: 10/02/2009

For the first time a study has shown that a microbicide gel can reduce the risk of male-to-female HIV transmission. Microbicide advocates are pleased, but the results of the larger PRO2000 microbicide study, due late this year, will be crucial in determining the next steps for microbicides.
 

Some reduction in HIV transmission to women

In this study, the PRO2000 microbicide was tested in a clinical trial involving over 3000 women.
Results showed that it reduced the risk of HIV transmission by 30%. This wasn’t quite a statistically significant result. HIV was found 2.7 times per 100 person years amongst women using PRO2000 compared with 4 per 100 person years for the women in other parts of the study.
 

But when the researchers repeated their analysis and took into account the time women weren’t using the gel, their results showed that use of PRO2000 resulted in a statistically significant 36% reduction in the risk of HIV transmission.
 

Other analysis showed that the more often women used the gel, the higher the level of protection it provided.
 

Used without condoms

The researchers also tried to see how effective PRO2000 was at preventing HIV infections in women who didn’t use condoms. They found new HIV infections in 1% of women who used only the microbicide for HIV prevention. It was 4% amongst women who were given the placebo gel. They therefore concluded that, amongst women who didn’t use condoms, over 75% of HIV infections appeared to be prevented by PRO2000.
 

How would PRO2000 be used? One of the study's researchers suggested that it, "may be a niche product for women with no other choices".

It is unlikely that any microbicide will achieve the protection level of condoms, but since many women have little or no control over whether condoms are used, some protection, even if it is imperfect, is better than no protection. That is the main niche for microbicides.

Vaccines, Microbicides Update

posted: 12/12/2008

An update report on progress on developing microbicides and vaccines for HIV prevention, especially in the developing world, is now out. The problem of developing vaccines and microbicide gels, are huge. Many attempts have failed, despite the major investment of money and research time.

The Department for International Development announced a new UK £220 million fund over five years for R&D on prevention technologies for diseases primarily affecting the poor, such as HIV, TB and malaria. At the same time a group of experts met at Somerset House in London to agree the best way forward for developing new biomedical prevention tools in the fight against HIV/AIDS. More than 100 scientists, researchers, activists and industry representatives gathered.

The conference papers and report are here.

The new research is likely to include:

• New products such as gels, films or sponges that women can use to protect themselves from infection during sex. Microbicides could be designed for vaginal or rectal use and could make a big difference in highly endemic countries.
• Development of a HIV vaccine. To date, there is still no vaccine but the development of one could be the key to reversing the spread of HIV.
• New start-of-the-art drugs based on existing antiretroviral treatment, designed to protect people judged as high risk, such as those in a relationship where one partner is infected with HIV.

The new funding makes the UK a world leader on HIV research and the Minister will take the conclusions to the World Health Organisation, as the WHO forms its new taskforce on HIV.

The minister Gareth Thomas said:

"The reality is that the spread of HIV is set to spiral out of control unless we act now. Five people are infected with HIV every minute and so we must increase our efforts and increase them now. The UK Government is committed to fighting the spread of HIV and that is why we are announcing £220 million for product development research. Only through research will we find new ways to halt this epidemic, and I hope this funding will help discover new life-saving technology."

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